AU759386B2 - Use of Ritonavir (ABT-538) for improving the pharmacokinetics of drugs metabolized by cytochrome P450 in a method of treating AIDS - Google Patents

Description

W (I S&F Ref: 394129D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Abbott Laboratories CHAD 0377/AP6D-2 100 Abbott Park Road Abbott Park Illinois 60064-3500 United States of America Daniel W Norbeck, Dale J Kempf, John M Leonard, Richard J Bertz Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Use of Ritonavir (ABT-53 8) for Improving the Pharmacokinetics of Drugs Metabolized by Cytochrome P450 in a Method of Treating AIDS The following statement is a full description of this invention, including the best method of performing it known to me/us:- P Australa |fc- Documents received on SEP 2t000 5845c USE OF RITONAVIR (ABT-538) FOR IMPROVING THE PHARMACOKINETICS OF DRUGS METABOLIZED BY CYTOCHROME P450 IN A METHOD OF TREATING AIDS Technical Field lhe present invention relates to a novel composition and a method for improving the phaImacokinctics of drugs, which are metabolized by cytochrome lP450 monooxygenase. In addition, the present invention relates to a novel composition and a method for inhibiting retroviral proteases and in particular flor inhibiting human immunodeficienc virus (-IIV) protease and a composition and a method for inhibiting a retroviral infection, in particular I1 an H \I inection.

Background of the Invention Infection by the retrovirus known as human immunodeficiency virus (I-IlV\) continues to be a serious human health problem. Methods lfor treating I-HIV infections include adiinistering agents which inhibit the activity of1 viral enzymes which are essential to the is life cycle of the virus.

The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products.

See Wellink, Arch. Virol. 98 1 (1988). Retroviral proteases most commonly process the gag precursor into core proteins, and also process the pol precursor into reverse transcriptase and 2o retroviral protease. Retroviral proteases are known to be sequence specific. See Pearl, Nature 328 482 (1987).

The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of infectious virions. It has been shown that in vi/ro mutagenesis that produces protease-defective virus leads to the production of immature core forms which 2i lack infectivity. See Crawford, J. Virol. 53 899 (1985); Katoh, et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya, Nature 325 775 (1987).

It has recently been disclosed that the HIV protease inhibitor ritonavir (also known as A131-538) is effective in humans for inhibiting an H-IIV infection.

Sn It has also been discovered that ritonavir is an inhibitor of the metabolic enzyme cytochrome P450 monooxygenase.

Some drugs and, in particular, some HIV protease inhibitors are metabolized by cytochrome P450 monooxygenase, leading to unfavourable pharmacokinetics and the need 1or more frequent and higher doses than are most desirable. Administration of such drugs with an agent that inhibits metabolism by cytochromrne P450 monooxygenase will improve the pharmacokinetics increase half-life, increase the time to peak plasma concentration, increase blood levels) of the drug.

I R:\L 31TjlO8887speci.doc:njc 2 It has been discovered that coadministration of ritonavir with a drug which is metabolized by cytochrome P450 monooxygenase, especially the P450 3A4 isozyme, causes an improvement in the pharmacokinetics of such a drug.

In particular, it has been discovered that coadministration of ritonavir with an HIV protease inhibitor which is metabolized by cytochrome P450 monooxygenase causes an unexpected improvement in the pharmacokinetics of such an HIV protease inhibitor.

Disclosure of the Invention According to a first embodiment of the invention there is provided a method for inhibiting cytochrome P450 monooxygenase comprising administering to a human in need thereof an amount effective to inhibit cytochrome P450 monooxygenase of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof.

According to a second embodiment of the invention there is provided a method for inhibiting cytochrome P450 monooxygenase comprising contacting the cytochrome P450 monooxygenase with an amount effective to inhibit cytochrome P450 monooxygenase of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof.

According to a third embodiment of the invention there is provided a method for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase comprising administering to a human in need of such treatment an amount effective to inhibit cytochrome P450 monooxygenase of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof.

According to a fourth embodiment of the invention there is provided a method for 9 increasing human blood levels of a drug which is metabolized by cytochrome P450 monooxygenase comprising administering to a human in need of such treatment an amount effective to inhibit cytochrome P450 monooxygenase of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof.

According to a fifth embodiment of the invention there is provided use of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 2a monooxygenase or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting cytochrome P450 monooxygenase in a human in need thereof.

According to a sixth embodiment of the invention there is provided a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof when used in an effective amount for inhibiting cytochrome P450 monooxygenase in a human in need thereof.

According to a seventh embodiment of the invention there is provided use of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting cytochrome P450 monooxygenase.

According to an eighth embodiment of the invention there is provided a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof when used in an effective amount for inhibiting cytochrome P450 monooxygenase.

•According to a ninth embodiment of the invention there is provided use of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof for the preparation of a medicament for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase.

According to an tenth embodiment of the invention there is provided a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 i monooxygenase or a pharmaceutically acceptable salt thereof when used in an effective amount for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase.

o 0 According to an eleventh embodiment of the invention there is provided use of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof for the preparation of a medicament for increasing human blood levels of a drug which is metabolized by cytochrome P450 monooxygenase.

According to a twelfth embodiment of the invention there is provided a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof when used in an effective 2b amount for increasing human blood levels of a drug which is metabolized by cytocbrome P450 monooxygenase.

In accordance with the present invention, there is disclosed a method of improving the pharmacokinetics of a drug (or a pharmaceutically acceptable sat thereof) which is metabolized by cytochromne P450 monooxygenase to, too.C #*0 [1:\DayLib\LIB3FF]08887aspeci.doc:JFM comprising coadministering ritonavir or a Pharmaceutically acceptable salt thereof. When administered in combination, the two therapeutic agents can be formulated as separate compositions which are administered at the same time or different times, or the two therapeutic agents can be administered as a single composition.

Drugs which are metabolized by cytochrome P450 monooxygenase and which benefit from coadministration with ritonavir include the immunosuppressants cyclosporine, FK-506 and rapamycin, the chemotherapeutic agents taxol and taxotere, the antibiotic clarithromycin and the HIV protease inhibitors A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629 (N,N-dimethylglycyl-N-( 2 hyrdoxy-3-(((4-methoxyphenyl)sulphonyl)( 2 -methylpropyl)amino)-1- (phenylmethyl)propyl)-3-methyl-L-valinamide), KNI-272, CGP 53437, CGP 57813 and U-103017.

:In a preferred embodiment of the present invention, there is disclosed a method for improving the pharmacokinetics of an HIV protease inhibitor (or a "Pharmaceutically acceptable salt thereof) which is metabolized by cytochrome P450 monooxygenase comprising coadministering ritonavir or a Pharmaceutically acceptable salt thereof. Such a combination of ritonavir or a pharmaceutically acceptable salt thereof and an HIV protease inhibitor or a Pharmaceutically acceptable salt thereof which is metabolized by cytochrome P450 monooxygenase is useful for inhibiting HIV protease in humans and is also useful for inhibition, treatment or prophylaxis of an HIV infection or AIDS (acquired immune deficiency syndrome) in humans. When administered in combination, the two therapeutic agents can be formulated as separate compositions which are administered at the same time or different times, or the two therapeutic agents can be administered as a single composition.

Preferred HIV protease inhibitors which are metabolized by cytochrome P450 monooxygenase include A-77003, A-80987, MK-639, saquinavir, VX-478 and AG 1343.

Ritonavir is 2

S,

3 S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4.

thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane or a Pharmaceutically acceptable salt thereof. Ritonavir can be synthesized by the procedures disclosed in PCT Patent Application No. W094/1443 6 published July 7, 1994, and the U.S. patent application Serial No. 08/469,965, filed June 6, 1995, both of which are incorporated herein by reference.

VX-478 is H OH NH 2 o 0 Oph- 00 Ph or a pharmaceutically acceptable salt thereof. VX-478 can by synthesized by the procedures disclosed in PCT Patent Application No. W094/05639, published March 17, 1994, which is incorporated herein by reference.

A-77003 is 2

S,

3 R,4S,5S)-2,5-Di-(N-((N-methyl).N.(( 2 pyridinyl)methyl)amino)carbonylvalinylamino).3,4-dihydroxy-1,6-diphenyl hexane or a pharmaceutically acceptable salt thereof and is disclosed in U.S.

S

Patent No. 5,142,056, issued August 25, 1992, which is incorporated herein by reference.

A-80987 is 2 S,3S,5S)-2-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-5-(N-(3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3hydroxyhexane or a pharmaceutically acceptable salt thereof and is disclosed in U.S. Patent No. 5,354,866, issued October 11, 1994, which is incorporated herein by reference.

MK-639 is N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4(S).

hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido).piperazinyl))pentaneamide or a Pharmaceutically acceptable salt thereof and is disclosed in European Patent Application No. EP541168, published May 12, 1993 and U.S.

Patent No. 5,413,999, issued May 9, 1995, both of which are incorporated herein by reference.

Saquinavir is N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N- (2-quinolylcarbonyl)-L-asparaginylJamino]butylJ]( 4 aS,8aS).isoquinoline-3(S) carboxamide or a pharmaceutically acceptable salt thereof and is disclosed in U.S. Patent No. 5,196,438, issued March 23, 1993, which is incorporated herein by reference.

AG1343 is

HH

H

N

OI

N

'H

HO0 PhS

H

PhS or a Pharmaceutically acceptable salt thereof and is disclosed in PCT Patent Application No. W095/09843 Spublished April 13, 1995 and U.S. Patent No. 5,484,926, issued January 16, 1996, both of which are incorporated herein by reference.

DMP-323 is H 0 N N

OH

HO

OH

or a pharmaceutically acceptable salt thereof and is disclosed in PCT Patent Application No. W093/07128 published April 15, 1993, which is incorporated herein by reference.

XM-450 is or a pharmaceutically acceptable salt thereof and is disclosed in PCT Patent Application No. W093/07128 published April 15, 1993, which is incorporated herein by reference.

BILA 2011 BS is

S

*.5b

S

N

H

or a pharmaceutically acceptable salt thereof and is disclosed in European Patent Application No. EP560268, published September 15, 1993, which is incorporated herein by reference.

BILA 1096 BS is

N

.Val-NH

N

H

or a pharmaceutically acceptable salt thereof and is disclosed in European Patent Application No. EP560268, published September 15, 1993, which is incorporated herein by reference.

BILA 2185 BS is 'N fOH 'S N' Val-NH

N

0 Nk O O N

S

H

or a pharmaceutically acceptable salt thereof and is disclosed in European Patent Application No. EP560268, published September 15, 1993, which is incorporated herein by reference.

BMS 186,318 is OH

OH

H

BocNH, N..N NHBoc Ph

O

0 or a pharmaceutically acceptable salt thereof and is disclosed in European Patent Application No. EP580402, published January 26, 1994, which is incorporated herein by reference.

LB71262 is CH3 H3C---

H

3 C SO2CH 3

NO

H

3 C CH 3 and is disclosed in European Patent Application No. EP687675, published December 20, 1995, which is incorporated herein by reference.

SC-52151 is -dimethylethyl)amino]carbonyl](2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-2- [(2-quinolinylcarbonyl)amino]-butanediamide or a pharmaceutically acceptable salt thereof and is disclosed in PCT Patent Application No. W092/08 7 0 1 published May 29, 1992 and PCT Patent Application No. W093/2336 8 published November 25, 1993, both of which are incorporated herein by reference.

SC-629 (N,N-dimethylglycyl-N-(2-hyrdoxy-3-((( 4 methoxyphenyl)sulphonyl)(2-methylpropyl)amino)-1-(phenylmethyl)propyl)-3 methyl-L-valinamide) is CH3 CH3 :I t-Bu OH CH3 HOCH3

O

KNI-272 is N 0 SCH OH HS O N N N

H

or a pharmaceutically acceptable salt thereof and is disclosed in European Patent Application No. EP574135, published December 15, 1993, which is incorporated herein by reference.

CGP 53437 is OH ^Ph BocNH Val-Phe- N O Ph< O and is disclosed in European Patent Application No. EP532466, published March 17, 1993, which is incorporated herein by reference.

CGP 57813 is

OCH

3

OH

and is disclosed in European Patent Application No. EP618222, published October 5, 1994, which is incorporated herein by reference.

U-103017 is

OH

O O H C N H N

NS

0 0 and is disclosed in PCT Patent Application No. W094/418188, published August 18, 1994, which is incorporated herein by reference.

The terms and configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl.

Chem. (1976) 45, 13- The term "Val" as used herein refers to valine. Unless otherwise noted when "Val" is used herein it refers to the L-isomer. In general, the amino acid abbreviations used herein follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature for amino acids and peptides (Eur. J. Biochem.

1984, 158, 9-31).

The ability of a compound to inhibit HIV protease can be demonstrated i: according to the methods disclosed in PCT Patent Application No.

W094/14436.

The ability of an HIV protease inhibitor to inhibit an HIV infection can be demonstrated according to the methods disclosed in PCT Patent Application No. W094/14436.

Inhibition of Cytochrome P450 The ability of ritonavir to inhibit cytochrome P450 monooxygenase activity was tested with terfenadine as the probe substrate (Yun, et al., Drug Metabolism Disposition, Vol. 21 403-407 (1993)). Ritonavir inhibited the terfenadine hydroxylase activity representing the most abundant form of cytochrome P450 (CYP3A4) present in human liver with an IC50 of 0.25 uM.

Pharmacokinetic Improvement The ability of ritonavir to improve the pharmacokinetics of a compound which is metabolized by cytochrome P450 monooxygenase can be demonstrated by the test method described below, wherein VX-478 is used as an example.

Rats (male, Sprague-Dawley derived, 0.3-0.45 kg) were fasted overnight prior to dosing, but were permitted water ad libitum. For combination dosing, a single solution containing both ritonavir and VX-478 (5 mg/ml each) was prepared in a vehicle of 20% ethanol 30% propylene glycol and D5W with an appropriate number of molar equivalents of methane sulfonic acid to assist in -11solubilization. Separate solutions of VX-478 and ritonavir were also prepared and these solutions were used to evaluate the pharmacokinetics of VX-478 and ritonavir when administered as a single agent in rats. The solutions, administered orally by gavage to a group of rats at a dose volume of 2 ml/kg, provided a 10 mg/kg dose of each compound. Blood samples were obtained from a tail vein of each rat 0.25, 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hours after dosing.

The plasma was separated from the red cells by centrifugation and frozen (-300C) until analysis. Concentrations of both ritonavir and VX-478 were determined simultaneously by reverse phase HPLC with low wavelength

UV

detection following liquid-liquid extraction of the plasma samples. The peak S: plasma concentration (Cmax) and time to peak plasma concentration (Tmax) for each rat were obtained directly from the plasma concentration data. The area under the curve was calculated by the trapezoidal method over the time course of the study. The plasma elimination half life was obtained from NONLIN84 or from a log-linear regression of the terminal plasma concentrations as a function of time after dosing. Each combination was evaluated in a group containing at least three rats; the values reported are averages for each group of animals. The data obtained from the combination was compared to data obtained from a separate group of.rats which received a single, separate dose of the compound under evaluation.

Below in Table 1 are shown the results from the pharmacokinetic experiments with VX-478 and other HIV protease inhibitors in rats. The maximum plasma levels (Cmax), time to maximum plasma level (Tmax) and area under the plasma concentration curve (AUC) for an 8-hour sampling interval following dosing of the HIV protease inhibitor alone vs. dosing in combination with ritonavir are provided.

Compound VX-478t VX-478 (+ritonavir) A-77003t A-77003 (+ritonavir) A-80987t A-80987 (+ritonavir) Saquinavirt

S

Saquinavir (+ritonavir) MK-639t MK-639 (+ritonavir) AG 1343t AG1343 (+ritonavir) Table 1 Cmax mca/m I) 1.61 2.88 0.07 0.96 2.42 4.47 0.08 1.48 1.03 1.40 0.40 1.81 Tmax h (hr) 0.42 1.5 0.25 0.67 0.25 1.7 0.18 3.0 0.5 3.0 0.75 4.0 AUC(O-8h) (mcgohr/mI) 1.69 13.50 0.025 1.39 1.45 25.74 0.029 8.52 0.81 6.51 1.14 11.92 t compound administered as a single agent The ability of ritonavir to improve the pharmacokinetics of clarithromycin in humans was demonstrated according to the method described below.

Clarithromycin (500 mg/BIAXIN® tablet every 12 hours) and a combination of ritonavir (200 mg of liquid formulation every 8 hours) and clarithromycin (500 mg every 12 hours) were administered to groups of 4 healthy human volunteers. Blood samples were collected on day four of dosing for HPLC determination of plasma concentrations of clarithromycin.

Below in Table 2 are shown the results from the pharmacokinetic experiments with clarithromycin in humans. The mean maximum plasma levels (Cmax) and area under the plasma concentration curve (AUC) calculated using noncompartmental methods for the 0-24 hour time interval on day four of dosing of clarithromycin alone vs. dosing in combination with ritonavir are provided.

-13- Table 2 Cmax AUC(0-24h) Compound (mc/ml) (mcg.hr/ml) clarithromycint 3.93 49.04 clarithromycin (+ritonavir) 5.13 86.88 t compound administered as a single agent .The therapeutic agents of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, "benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2 -naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,

S

3 -phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen- .:containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oilsoluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.

-14- The administration of ritonavir and a compound which is metabolized by cytochrome P450 monooxygenase is useful for improving in humans the pharmacokinetics of the compound which is metabolized by cytochrome P450 monooxygenase.

In particular, the administration of ritonavir and an HIV protease inhibitor which is metabolized by cytochrome P450 monooxygenase is useful for improving in humans the pharmacokinetics of the HIV protease inhibitor which is metabolized by cytochrome P450 monooxygenase.

The combination of ritonavir and an HIV protease inhibitor which is metabolized by cytochrome P450 monooxygenase is also useful for inhibiting a retroviral protease, in particular HIV protease, vitro or in vivo (especially in mammals and in particular in humans). This combination of therapeutic agents is also useful for the inhibition of retroviruses in vivo, especially human immunodeficiency virus (HIV). This combination of therapeutic agents is also useful for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, in a human or other mammal.

*The total daily dose of ritonavir to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 50 mg/kg and even more usually 0.1 to 25 mg/kg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.

The total daily dose of the drug which is metabolized by cytochrome P450 monooxygenase to be administered to a human or other mammal is well known and can be readily determined by one of ordinary skill in the art.

Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form of each drug, individually or in combination, will vary depending upon the host treated and the particular mode of administration.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.

The combination of therapeutic agents of the present invention (as individual compositions or as a single composition) may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administratiorn may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous or :i oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.

In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

-16- Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

The combination of therapeutic agents of the present invention (as individual compositions or as a single composition) can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used. The present compositions in liposome form can contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natureal and synthetic.

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

Preferred dosage forms for ritonavir include a liquid dosage form for Gt ,oral administration as disclosed in U.S. Serial No. 08/283, 239, filed July 29, 1994 (now U.S. Patent No. 5,484,801, issued January 16, 1996), which is incorporated herein by reference, an encapsulated solid or semi-solid dosage form as disclosed in PCT Patent Application No. W095/07696, published March 23, 1995 and U.S.

Serial No. 08/402,690, filed March 13, 1995, both of which are incorporated herein by reference and an encapsulated solid dosage form as disclosed in PCT Patent Application No. W095/09614, published April 13, 1995, which is incorporated herein by reference.

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which -17are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims (85)

1. A method for inhibiting cytochrome P450 monooxygenase comprising administering to a human in need thereof an amount effective to inhibit cytochrome P450 monooxygenase of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof.

2. The method of Claim 1 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is ritonavir or AG1343.

3. The method of Claim 1 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG 1343.

4. The method of Claim 1 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK-639. S 5. The method of Claim 1 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX-478.

6. The method of any one of Claims 1 to 5 wherein the cytochrome P450 15 monooxygenase is P450 3A4.

7. A method for inhibiting cytochrome P450 monooxygenase comprising contacting the cytochrome P450 monooxygenase with an amount effective to inhibit cytochrome P450 monooxygenase of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically S 20 acceptable salt thereof.

8. The method of Claim 7 wherein the compound which is both an HIV protease Sinhibitor and an inhibitor of cytochrome P450 monooxygenase is ritonavir or AG1343.

9. The method of Claim 7 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG1343.

10. The method of Claim 7 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK-639.

11. The method of Claim 7 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX-478.

12. The method of any one of Claims 7 to 11 wherein the cytochrome P450 monooxygenase is P450 3A4.

13. A method for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase comprising administering to a human in need of such treatment an amount effective to inhibit cytochrome P450 monooxygenase of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 4 5 monooxygenase or a pharmaceutically acceptable salt thereof. [I:\DayLib\LBFF]09001 aspeci.doc:JFM 19

14. The method of Claim 13 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is ritonavir or AG1343. The method of Claim 14 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 1o 16. The method of Claim 14 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- S80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 15 17. The method of Claim 14 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, MK-639, saquinavir, VX-478 and AG1343.

18. The method of Claim 14 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir.

19. The method of Claim 14 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639.

20. The method of Claim 14 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478.

21. The method of Claim 14 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG 1343.

22. The method of Claim 13 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG1343.

23. The method of Claim 22 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017.

24. The method of Claim 22 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- [I:\DayLib\LIBFF]09001 aspeci.doc:JFM BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. The method of Claim 22 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- S 80987, MK-639, saquinavir and VX-478.

26. The method of Claim 22 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir.

27. The method of Claim 22 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639.

28. The method of Claim 22 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478.

29. The method of Claim 13 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK-639.

30. The method of Claim 29 wherein the drug which is metabolized by 15s cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, AG1343, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629. KNI-272, CGP 53437, CGP 57813 and U-103017. 20 31. The method of Claim 29 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, AG1343, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017.

32. The method of Claim 29 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, AG1343, saquinavir and VX-478.

33. The method of Claim 29 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 3o 34. The method of Claim 29 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. The method of Claim 29 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478,

36. The method of Claim 13 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX-478. I IR:\LI IFI]0900 I speci.docmjc 21 36. The method of Claim 13 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX-478.

37. The method of Claim 36 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017.

38. The method of Claim 36 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, MK-639, saquinavir, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, o CGP 57813 and U-103017.

39. The method of Claim 36 wherein the drug which is metabolized by 15 cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, MK-639, saquinavir and AG1343. The method of Claim 36 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir.

41. The method of Claim 36 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639.

42. The method of Claim 36 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343.

43. The method of any one of Claims 13 to 42 wherein the cytochrome P450 monooxygenase is P450 3A4.

44. A method for increasing human blood levels of a drug which is metabolized by cytochrome P450 monooxygenase comprising administering to a human in need of such treatment an amount effective to inhibit cytochrome P450 monooxygenase of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof.

45. The method of Claim 44 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is ritonavir or AG1343.

46. The method of Claim 45 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, 4_ 35 FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, [[:\D~ayLib\LIBFF]09001 aspeci.doc:JFM I (a 22

47. The method of Claim 45 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017.

48. The method of Claim 45 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, MK-639, saquinavir, VX-478 and AG1343. S

49. The method of claim 45 wherein the drug which is to cytochrome P450 monooxygenase is saquinavir. The method of Claim 45 wherein the drug which is cytochrome P450 monooxygenase is MK-639.

51. The method of Claim 45 wherein the drug which is cytochrome P450 monooxygenase is VX-478.

52. The method of Claim 45 wherein the drug which is cytochrome P450 monooxygenase is AG1343.

53. The method of Claim 44 wherein the compound which metabolized by metabolized by metabolized by metabolized by is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG1343.

54. The method of claim 53 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin. taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017.

55. The method of Claim 53 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, MK-639, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017.

56. The method of Claim 53 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, MK-639, saquinavir and VX-478.

57. The method of Claim 53 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. [R:\L-IBFF]09001 speci.doc:injc (4 23

58. The method of Claim 53 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639.

59. The method of Claim 53 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478.

60. The method of Claim 44 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK-639.

61. The method of Claim 60 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, AG1343, Io saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 13S, BMS 186318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. a

62. The method of Claim 60 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- I 80987, AG1343, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 *B S, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CG 57813 and U-103017.

63. The method of Claim 60 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, AG1343, saquinavir and VX-478.

64. The method of Claim 60 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. The method of Claim 60 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343.

66. The method of Claim 60 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478.

67. The method of Claim 44 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX-478.

68. The method of Claim 67 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine. FK-506. rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, AG1343, saquinavir, MK-639, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 arid U-103017. IR:\LI 13FF]0900 I speci.doc:njc 24 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 arid U-103017.

69. The method of Claim 67 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, AG1343, saquinavir, MK-639, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. The method of Claim 67 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A- 80987, AG1343, saquinavir and MK-639.

71. The method of Claim 67 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir.

72. The method of Claim 67 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. 15 73. The method of Claim 67 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639.

74. The method of any one of Claims 44 to 73 wherein the cytochrome P450 monooxygenase is P450 3A4. Cytochrome P450 monooxygenase whenever inhibited by the method of any 20 one of the preceding Claims.

76. Use of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting cytochrome P450 monooxygenase in a human in need thereof.

77. Use of Claim 76 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is ritonavir or AG 1343.

78. Use of Claim 76 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG 1343.

79. Use of Claim 76 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK-639. Use of Claim 76 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX-478.

81. Use of any one of Claims 76 to 80 wherein the cytochrome P450 monooxygenase is P450 3A4. [I:\DayLib\LIBFF]09001aspeci.doc:JFM

82. A compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof when used in an effective amount for inhibiting cytochrome P450 monooxygenase in a human in need thereof.

83. A compound when used according to Claim 82 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is ritonavir or AG 1343.

84. A compound when used according to Claim 82 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG 1343. A compound when used according to Claim 82 wherein the compound which Sis both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK-639.

86. A compound when used according to Claim 82 wherein the compound which 15 is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX-478.

87. A compound when used according to any one of Claims 82 to 86 wherein the cytochrome P450 monooxygenase is P450 3A4.

88. Use of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting cytochrome P450 monooxygenase.

89. Use of Claim 88 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is ritonavir or AG1343.

90. Use of Claim 88 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG1343.

91. Use of Claim 88 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK-639.

92. Use of Claim 88 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX-475.

93. Use of any one of Claims 88 to 92 wherein the cytochrome P450 monooxygenase is P450 3A4.

94. A compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof when g R, used in an effective amount for inhibiting cytochrome P450 monooxygenase. [I:\DayLib\LIBFF]09001aspeci.doc:JFM 'VT O~[I:\DayLib\LIB FF]09001 aspeci.doc:JFM 26 A compound when used of Claim 94 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is ritonavir or AG1343.

96. A compound when used of Claim 94 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG1343.

97. A compound when used of Claim 94 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK-639.

98. A compound when used of Claim 94 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX-475.

99. A compound when used of any one of Claims 94 to 98 wherein the cytochrome P450 monooxygenase is P450 3A4. S* 100. Use of a compound which is both an HIV protease inhibitor and an inhibitor .of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof for the preparation of a medicament for improving the pharmacokinetics of a drug which is 15 metabolized by cytochrome P450 monooxygenase.

101. Use of Claim 100 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is ritonavir or AG1343.

102. Use of Claim 101 wherein the drug which is metabolized by cytochrome P450 S.monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX- "478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-

103017. 103. Use of Claim 101 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 104. Use of Claim 101 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, VX-478 and AG1343. 105. Use of Claim 101 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 106. Use of Claim 101 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639. [I:\DayLib\LIBFF]09001 aspeci.doc:JFM 27 107. Use of Claim 101 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478. 108. Use of Claim 101 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG 1343. 109. Use of Claim 100 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG1343. 110. Use of Claim 109 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX- 0o 478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 111. Use of Claim 109 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 DS, BILA 1096 BS, BILA 2185 15 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 112. Use of Claim 109 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir and VX-478. 20 113. Use of Claim 109 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 114. Use of Claim 109 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639. 115. Use of Claim 109 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478. 116. Use of Claim 100 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK-639. 117. Use of Claim 116 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, AG1343, saquinavir, VX- 478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629. KNI-272, CGP 53437, CGP 57813 and U-103017. 118. Use of Claim 116 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, Ssaquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 [I:\DayLib\LIBFF]09001 aspeci.doc:JFM 28 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 119. Use of Claim 116 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, saquinavir and VX-478. 120. Use of Claim 116 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 121. Use of Claim 116 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. 122. Use of Claim 116 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478, 123. Use of Claim 100 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX-478. 124. Use of Claim 123 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U- 103017. 125. Use of Claim 123 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 126. Use of Claim 123 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir and AG1343. 127. Use of Claim 123 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 128. Use of Claim 123 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639. 129. Use of Claim 123 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. 130. Use of any one of Claims 100 to 129 wherein the cytochrome P450 monooxygenase is P450 3A4. [I:\DayLib\LIBFF]09001 aspeci.doc:JFM 29 131. A compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof when used in an effective amount for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase. 132. A compound when used of Claim 131 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is ritonavir or AG1343. 133. A compound when used of Claim 132 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, *CGP 57813 and U-103017. 134. A compound when used of Claim 132 wherein the drug which is metabolized 15 by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, VX-478 and AG1343. 135. A compound when used of Claim 132 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 136. A compound when used of Claim 132 wherein the drug which is metabolized 20 by cytochrome P450 monooxygenase is MK-639. 137. A compound when used of Claim 132 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478. 138. A compound when used of Claim 132 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG 1343. 139. A compound when used of Claim 131 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG1343. 140. A compound when used of Claim 139 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. S 141. A compound when used of Claim 139 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, [I:\DayLib\LIBFF]09001aspeci.doc:JFM A-80987, MK-639, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 DS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 142. A compound when used of Claim 139 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir and VX-478. 143. A compound when used of Claim 139 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 144. A compound when used of Claim 139 wherein the drug which is metabolized to by cytochrome P450 monooxygenase is MK-639. 145. A compound when used of Claim 139 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478. 146. A compound when used of Claim 131 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK- 15 639. 147. A compound when used of Claim 146 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, AG1343, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, 20 BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629. KNI-272, CGP 53437, CGP 57813 and U-103017. 148. A compound when used of Claim 146 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 149. A compound when used of Claim 146 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, saquinavir and VX-478. 150. A compound when used of Claim 146 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 151. A compound when used of Claim 146 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. 152. A compound when used of Claim 146 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478, [1:\DayLib\LIBFF]09001 aspeci.doc:JFM 31 153. A compound when used of Claim 131 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX- 478. 154. A compound when used of Claim 153 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 155. A compound when used of Claim 153 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. S• 15 156. A compound when used of Claim 153 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir and AG1343. 157. A compound when used of Claim 153 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 158. A compound when used of Claim 153 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639. S 159. A compound when used of Claim 153 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. 160. A compound when used of any one of Claims 131 to 159 wherein the cytochrome P450 monooxygenase is P450 3A4. 161. Use of a compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof for the preparation of a medicament for increasing human blood levels of a drug which is metabolized by cytochrome P450 monooxygenase. 162. Use of Claim 161 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is ritonavir. 163. Use of Claim 162 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX- j 478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, [1:\DayLib\LIBFF]09001 aspeci.doc:JFM 32 BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U- 103017. 164. Use of Claim 162 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 165. Use of Claim 162 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, VX-478 and AG1343. 166. Use of Claim 162 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. .:167. Use of Claim 162 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639. 15 168. Use of Claim 162 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478. 169. Use of Claim 162 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. 170. Use of Claim 161 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG1343. 171. Use of Claim 170 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin. taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX- 478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 172. Use of Claim 170 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 173. Use of Claim 170 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir and VX-478. 174. Use of Claim 170 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. [1:\DayLib\LIBFF]09001aspeci.doc:JFM 33 175. Use of Claim 170 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639. 176. Use of Claim 170 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478. 177. Use of Claim 161 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK-639. 178. Use of Claim 177 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, AG1343, saquinavir, VX- o0 478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 179. Use of Claim 177 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 15 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 180. Use of Claim 177 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, saquinavir and VX-478. 20 181. Use of Claim 177 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 182. Use of Claim 177 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. 183. Use of Claim 177 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478. 184. Use of Claim 161 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX-478. 185. Use of Claim 184 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine. FK-506. rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, AG1343, saquinavir, MK- 639, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 arid U-103017. 186. Use of Claim 184 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, saquinavir, MK-639, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 [I:\DayLib\LIFF]09001 aspeci.doc:JFM 34 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 187. Use of Claim 184 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, saquinavir and MK-639. 188. Use of Claim 184 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 189. Use of Claim 184 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. 190. Use of Claim 184 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639. 191. Use of any one of Claims 161 to 190 wherein the cytochrome P450 monooxygenase is P450 3A4. 192. A compound which is both an HIV protease inhibitor and an inhibitor of 15 cytochrome P450 monooxygenase or a pharmaceutically acceptable salt thereof when used in an effective amount for increasing human blood levels of a drug which is metabolized by cytochrome P450 monooxygenase. 193. A compound when used of Claim 192 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is 20 ritonavir. 194. A compound when used of Claim 193 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 195. A compound when used of Claim 193 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 196. A compound when used of Claim 193 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, VX-478 and AG1343. [I:\DayLib\LIBFF]0900laspeci.doc:JFM 197. A compound when used of Claim 193 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 198. A compound when used of Claim 193 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639. 199. A compound when used of Claim 193 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478. 200. A compound when used of Claim 193 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. 201. A compound when used of Claim 192 wherein the compound which is both o0 an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is AG1343. 202. A compound when used of Claim 201 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin. taxol, taxotere, clarithromycin, A-77003, A-80987, 15 MK-639, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 203. A compound when used of Claim 201 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, 20 A-80987, MK-639, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, o* -CGP 57813 and U-103017. 204. A compound when used of Claim 201 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir and VX-478. 205. A compound when used of Claim 201 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 206. A compound when used of Claim 201 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639. 207. A compound when used of Claim 201 wherein the drug which is metabolized by cytochrome P450 monooxygenase is VX-478. 208. A compound when used of Claim 192 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is MK- 639. [I:\DayLib\LIBFF]09001 aspeci.doc:JFM 36 209. A compound when used of Claim 208 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, AG1343, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 210. A compound when used of Claim 208 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, saquinavir, VX-478, DMP-323, XM-450, BILA 2011 BS, BILA 1096 to BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 211. A compound when used of Claim 208 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, saquinavir and VX-478. 15 212. A compound when used of Claim 208 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 213. A compound when used of Claim 208 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. 214. A compound when used of Claim 208 wherein the drug which is metabolized 0 20 by cytochrome P450 monooxygenase is VX-478. .i 215. A compound when used of Claim 192 wherein the compound which is both an HIV protease inhibitor and an inhibitor of cytochrome P450 monooxygenase is VX- 478. 216. A compound when used of Claim 215 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of cyclosporine. FK-506. rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, AG1343, saquinavir, MK-639, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 arid U-103017. 217. A compound when used of Claim 215 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, saquinavir, MK-639, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. [I:\DayLib\LLBFF]09001aspeci.doc:JFM 37 218. A compound when used of Claim 215 wherein the drug which is metabolized by cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, AG1343, saquinavir and MK-639. 219. A compound when used of Claim 215 wherein the drug which is metabolized by cytochrome P450 monooxygenase is saquinavir. 220. A compound when used of Claim 215 wherein the drug which is metabolized by cytochrome P450 monooxygenase is AG1343. 221. A compound when used of Claim 215 wherein the drug which is metabolized by cytochrome P450 monooxygenase is MK-639. 222. A compound when used of any one of Claims 192 to 221 wherein the cytochrome P450 monooxygenase is P450 3A4. S 223. A compound when used of Claim 132 wherein the drug which is metabolized Sby cytochrome P450 monooxygenase is selected from the group consisting of A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, i. BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629, KNI-272, CGP 53437, CGP 57813 and U-103017. 224. A compound when used of Claim 223 wherein the cytochrome P450 monooxygenase is P450 3A4. 20 Dated 3 January, 2003 Abbott Laboratories *.0 S Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [I:\DayLib\LBFF]09001aspeci.doc:JFM