Doxycycline Hyclate
Doxycycline Hyclate
Doxycycline Hyclate
ABSTRACT: Literature data relevant to the decision to allow a waiver of in vivo bioequivalence
(BE) testing for the approval of immediate release (IR) solid oral dosage forms containing
doxycycline hyclate are reviewed. According to the Biopharmaceutics Classification System
(BCS), doxycycline hyclate can be assigned to BCS Class I. No problems with BE of IR
doxycycline formulations containing different excipients and produced by different manufacturing
methods have been reported and hence the risk of bioinequivalence caused by these factors appears
to be low. Doxycycline has a wide therapeutic index. Further, BCS-based dissolution methods have
been shown to be capable of identifying formulations which may dissolve too slowly to generate
therapeutic levels. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms
containing doxycycline hyclate as the single Active Pharmaceutical Ingredient (API) provided that
(a) the test product contains only excipients present in doxycycline hyclate IR solid oral drug
products approved in the International Conference on Harmonization (ICH) or associated
countries; and (b) the comparator and the test products comply with the BCS criteria for ‘‘very
rapidly dissolving’’ or,
A project of the International Pharmaceutical Federation (FIP), Correspondence to: D.M. Barends (Telephone:
BCS and Biowaiver, www.fip.org/bcs. 30-
This article reflects the scientific opinion of the authors and not 2744209; Fax: 31-30-2744462; E-mail: dirk.barends@rivm.nl)
the policies of regulating agencies, the International Journal of Pharmaceutical Sciences, Vol. 99, 1639–1653 (2010)
Pharmaceutical Federation (FIP) and the World Health 2009 Wiley-Liss, Inc. and the American Pharmacists Association
Organization (WHO).
alternatively, when similarity of the dissolution profiles can be demonstrated and the two products are ‘‘rapidly
dissolving.’’ 2009 Wiley-Liss, Inc. and the American Pharmacists
Association J Pharm Sci 99:1639–1653, 2010
Keywords: absorption; biopharmaceutics classification system (BCS); doxycycline hyclate; permeability; regulatory
science; solubility
INTRODUCTION propranolol hydrochloride,1 pyrazinamide,18
quinidine sulfate,19 ranitidine hydrochloride,20
A biowaiver monograph for doxycycline rifampicin,21 and verapamil hydrochloride.1
hyclate based on literature data, together with They are also available online at
some additional experimental data, is presented. http://www.fip.org/bcs. 22
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BIOWAIVER MONOGRAPH FOR DOXYCYCLINE HYCLATE 1641
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1642 JANTRATID ET AL.
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BIOWAIVER MONOGRAPH FOR DOXYCYCLINE HYCLATE 1643
have been demonstrated in the dose range 100– 600 (regardless of the meal type) were found to be in the
mg.40 A peak plasma doxycycline concentration of therapeutic range (4.4 mg/mL vs.
about 2.6 mg/mL is reached within approximately 2– 4.0 mg/mL), indicating little or no clinical
3.5 h after a dose of 200 mg.26,40,42 Different salt significance of the food effect. 67 Although milk and
forms demonstrated no significant influences on dairy products reduce the exposure of several
doxycycline absorption.37,40,65 tetracycline antibiotics significantly, this is not the
Unlike tetracycline, food only slightly reduces the case for doxycycline.26 Dairy products have at most a
area under the plasma concentration–time curve
(AUC) and the mean plasma concentrations of
doxycycline.54,67,68 The mean serum concentrations of
doxycycline obtained during a multipledosage
regimen of 200 mg/day in the fasted and fed states
a
Experiments performed at the Institute of Pharmaceutical product separately from drugs containing di and/or
Technology, Goethe University, Frankfurt am Main, Germany.
trivalent cations, for example, antacids
minor influence on doxycycline absorption.26
Nevertheless, it is recommended to take doxycycline
Table 1. Excipients Present in Doxycycline Hyclate IR Solid Oral Drug Products with a Marketing Authorization (MA) in
Germany (DE), Denmark (DK), Finland (FI), France (FR), the Netherlands (NL), Spain (ES), the United
Kingdom (UK) and the United States (US), and the Minimal and Maximal Amount of that Excipient Present Per
Dosage Unit in Solid Oral Drug Products with an MA in the US,y
Colorants, flavors, and ingredients present in the printing ink are not included. Coating substances are excluded if in the SmPC
the constituents of core and coating are stated separately.
Excluded are: soft gelatin capsules filled with a solution and oral suspensions.
An apparent permeability coefficient (P app) of Doxycycline is slowly eliminated via the kidneys
doxycycline of 17.5 106 cm/sec using the Caco- to an extent of approximately 30–40% in patients
2 monolayer system was reported.70 In the same with normal renal function.26,40 A renal clearance of
study a high permeability internal standard 1.8–2.1 L/h was reported.40 The rest of the dose is
suggested by the US FDA,3 antipyrine, eliminated through the digestive tract and excreted in
demonstrated a Papp of 45.3 106 cm/sec.70 By the feces, probably due to partial biliary elimination
comparing the drug permeability between in addition to diffusion through the intestinal wall
Caco-2 and PAMPA assay, it was demonstrated and subsequent chelation with the metal ions, for
that transcellular but not paracellular example, Ca2þ, Mg2þ present in the small intestine. 26,40
permeation is the main transport pathway of The nonchelated doxycycline is reabsorbed and
doxycycline.70 undergoes enterohepatic cycling.26,40 The elimination
half-life (t1/2b) of doxycycline varies from about 12 to
25 h 26,40,42,74,75 after single dosing and between 17
Distribution and 24 h after multiple dosing.76 These values do not
change in the elderly patients although the serum and
The volume of distribution of doxycycline at
tissue concentrations are higher than those observed
steady-state (Vdss) varies between approximately
in young adults.40 In renal failure patients, the t 1/2b and
53 and 134 L and the volume of the central
AUC remain unchanged and no accumulation is
compartment (Vc) is 22 L.40 These values can
observed even after repeated doses in anuric
vary slightly according to the doxycycline salt.65
patients.40 At first glance, these results appear to be
In the elderly, the volume of distribution is
inconsistent with renal elimination as the major route
higher than in young patients.71 Doxycycline
of doxycycline elimination. However, a decrease in
distributes effectively into the body tissues
the fraction of doxycycline bound to plasma proteins
especially liver, kidneys, and digestive tract. 26,40
in renal failure patients appears to result in an
Doxycycline as well as other tetracycline
increase in nonrenal clearance, which then
antibiotics can be retained at the sites of new
compensates for the decrease in renal clearance.77
bone formation and impair calcification in
developing teeth, and in some injured soft
tissues.26 The plasma protein binding of
doxycycline is the highest among tetracycline DOSAGE FORM PERFORMANCE
antibiotics, between 80% and 95% at usual
therapeutic concentrations.26,40,42 Bioavailability and Bioequivalence
Several reports in the literature have demon-
strated BE of doxycycline products.37,65,67,74,75,78–87
Metabolism and Excretion The study details, BE criteria, and results of the
pharmacokinetic studies conducted from 1975 to
No problems with instability of doxycycline in the 2007 are summarized in Table 2. All studies reported
GI tract have been reported. the pharmacokinetic parameters between
Although it has been demonstrated that no doxycycline hyclate products, various doxycycline
metabolites of doxycycline are found in blood, urine, salt forms and different dosage forms of doxycycline
or feces,40 some reference sources indicate that some to be ‘‘bioequivalent’’ or ‘‘not significantly
metabolism does occur.42,71,72 Additionally, a decrease different.’’ It should be noted that doxycycline can
in the area under the plasma concentration–time be regarded as a borderline ‘‘highly variable drug’’
curve (AUC) of doxycycline was observed during based on the data from Kitzes-Cohen et al.86 Indeed,
concomitant treatment with drugs that induce hepatic the Central Laboratory of German Pharmacists
enzymes, for instance, alcohol (chronic use), proposed using a 95% confidence interval (CI) and
rifampicin, carbamazepine, phenobarbital, phenytoin, an acceptance range of 70–130% to assess BE. 88
and primidone, owing to the increased metabolism of Nevertheless, most studies showed that the 90% CI
doxycycline.26,73 of the AUC and Cmax of the multisource products lay
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1646 JANTRATID ET AL.
within the 80–125% range of those of the has been reported in the literature. However,
comparator. studies on the effects of antacids and drugs that
can modify the GI environment on doxycycline
absorption have been reported.91 These results
Excipients can indirectly be applied to the excipients
having similar characteristics, since the same
Table 1 shows the excipients present in IR influence on doxycycline absorption can be
doxycycline hyclate products with an MA in a anticipated.
large number of countries. In view of their A randomized, crossover study conducted by
MAs, it may be supposed that most of these Deppermann et al.91 investigated the influence of
drug products successfully had passed an in antacids on the BA of doxycycline. The antacid
vivo BE study. In this respect, the regulatory studied contained 900 mg of aluminum
authorities of DE classified doxycycline an API hydroxide (Al(OH)3) and 600 mg of magnesium
for which in vivo BE testing is required, 89 but in hydroxide (Mg(OH)2) per dose. The results of
NL doxycycline was, and still is, exempted this study indicated that antacids, such as a
from in vivo BE studies for national MAs. 90 For mixture of Al(OH)3 and Mg(OH)2, lead to
other countries no such information was subtherapeutic serum levels of doxycycline.
available and hence it is not possible to judge Administration of doxycycline after antacid
which products had actually passed an in vivo treatment resulted in approximately 85%
BE study. However, due to their MAs, and reduction in absorption, leading to a relative BA
hence use in clinical practice, it is concluded of only 15%. The ability of doxycyline to form
that the risk of excipients listed in Table 1 chelates with metal ions such as Fe2þ, Al3þ, Ca2þ,
exerting a significant effect on the extent and Zn2þ, and Mn2þ was used to explain the results.
rate of absorption of doxycycline is probably
The second part of the same study was a
small.
randomized, double-blind study
No study directly investigating the influence
of excipients on the absorption of doxycycline
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BIOWAIVER MONOGRAPH FOR DOXYCYCLINE HYCLATE 1647
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1648 JANTRATID ET AL.
%CIBioequivalentNo
%BioequivalentNo %BioequivalentNo
Disintegration BioequivalentNo
within15min
disintegrated
Tests
both
InVitro
—
tests
130 125
StatisticsResults 90
cantly
testNotsigni
different
fi
Bioequivalence
70
Criteria, %
ANOVA,90% 80
125
%CI, %CI,
– –
95 tStudent –CI,80 90
s
’
StudiedCompositionSubjectsPrandialStudyDesign
Pharmacokinetic
,MRT
Parameters
2/ 2/
max
, max , max 1 , max , max 1
max t max max t max
C
AUC, C
AUC, C
AUC, , C
AUC, C
AUC, ,
T T T T
crossover/washout crossover/washout crossover/washout crossover/washout crossover/washout
singledose, Randomized,
Randomized, singledose, Randomized,
singledose, Randomized,
singledose, Randomized,
singledose,
two-way, two-way, two-way, weeks two-way, weeks two-way, days
week week
1 1 2 2 16
)
volunteers ) ) ) )
yo yo yo yo yo
26 26 32 43 43
hydrochloridetablets
doxycyclinehyclate doxycyclinehyclate
Formulations mgdoxycycline
monohydrateand
hyclatecapsules
brands,100mg hyclatecapsules
brands,100mg brands,100mg brands,100mg
yo,yearsold.
Gschwendetal.
Table2. etal.(1998)
Kitzes-Cohen Alsarraetal.
( Baloghetal.
Saketetal.
86
84 85 87 74
(1991) (1993) (2004) (2007)
Refs.
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