DRUG INFORMATION QUERY 3

1. INTRODUCTION:
Praseltinib is a RET tyrosine kinase inhibitor indicated for the treatment of metastatic RET-driven
non- small cell lung cancer.1 RET (rearranged during transfection) is a receptor tyrosine kinase
involved in the development of neural crest derived cell lineages, kidney, and male germ cells.
Different human cancers, including papillary and medullary thyroid carcinomas, lung
adenocarcinomas, and myeloproliferative disorders display gain-of-function mutations in RET.
Accordingly, RET protein has become a promising molecular target for cancer treatment.2
Praseltinib is a kinase inhibitor with enhanced specificity for RET tyrosine kinase receptors (RTKs)
over other RTK classes.3 Although a phase 1/2 trial of pralsetinib termed ARROW (NCT03037385) is
still ongoing, pralsetinib was granted accelerated FDA approval on September 4, 2020, for the
treatment of metastatic RET-fusion positive non-small cell lung cancer.

2. INDICATIONS:
 Treatment of metastatic non-small cell lung cancer (NSCLC) in adult patients who are
confirmed to possess a rearranged during transfection (RET) gene fusion, as determined by
an FDA approved test- FISH (Fluorescence In-sithu Hybridization).
 Adult and paediatric patients 12 years of age and older for the treatment of advanced or
metastatic RET-mutant medullary thyroid cancer.
 Treatment of advanced or metastatic RET fusion-positive thyroid cancer who require
systemic therapy and for whom radioactive iodine is not appropriate.1

3. Availability/Cost:
Brand Gavreto
Cost 11, 186 USD (60 capsules)

4. ADMINISTRATION/DOSE:

4.1 Patient Selection:

The patients should be selected based on the presence of a RET gene fusion. 4

4.2 Recommended Dosage:

o The recommended dosage of Praseltinib is 400 mg orally once daily on an
empty stomach.
o No food intake for at least 2 hours before and at least 1 hour after taking
Praseltinib.
o If a dose is missed, it can be taken as soon as possible on the same day,
resume the regular dose schedule from next day.
o Do not take additional dose if vomiting occurs, but continue with the next
dose as scheduled.4

4.3 Dose modifications for Adverse Reactions:

The recommended dose reduction for occurrence of adverse reactions is –
Dose Reduction Recommended Dosage
First 300mg
Second 200mg
Third 100mg
This drug should be completely discontinued if the patient cannot tolerate a dose more than
100mg taken orally once a day.4
 4.4 Dose modification for use with Combined P- glycoprotein (P-gp) and Strong
CYP3A inhibitors:
Avoid co-administration of this drug with combined P-gp and strong CYP3A inhibitors.
If co-administration cannot be avoided, make dose adjustments as follows-

Current Dose Recommended Dose

400 mg 200 mg
300 mg 200 mg
200 mg 100 mg4

4.5 Dose modifications for use with strong CYP3A inducers:

If co-administration cannot be avoided, increase the starting dose of Praseltinib to
double the current dose starting on Day 7 of co-administration. After the inducer has been
discontinued for at least 14 days, resume the normal dose taken prior to initiating the strong
CYP3A inducer.4

5.0 PHARMACOKINETICS
At 400mg dose and at fasting condition, maximum plasma concentration was observed to be
0.00283mg/ml and Area Under the Curve (AUC) was found to be 0.0439h.mg/ml. C max and AUC
increased inconsistently over the dose range of 60 mg to 600 mg once daily (0.15 to 1.5 times the
recommended dose). Pralsetinib plasma concentrations reached steady state by 3 to 5 days. 4

5.1 Absorption:
The median time to peak concentration (T max) ranged from 2 to 4 hours following
single doses of pralsetinib 60 mg to 600 mg.
Following administration of a single dose of 400mg with a high fat meal, the mean
Cmax was found to be increased by 104% and mean AUC was increased by 122%. The T max was found
to be decreased from 4 to 8.5 hours, compared to fasting state.4

5.2 Distribution:
The mean apparent volume of distribution is 228L. Protein binding of pralsetinib is
97.1% and is independent of concentration. The blood-to-plasma ratio is 0.6 to 0.7. 4

5.3 Elimination:
The mean plasma half-life is 14.7 hours following single doses and 22.2 hours
following multiple doses. The mean apparent oral clearance is 9.1 L/h at steady state.4

5.4 Metabolism:
Pralsetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 and
CYP1A2. A study to estimate metabolism was done by taking a single dose of 310mg radiolabelled
pralsetinib to healthy subjects, pralsetinib metabolites from oxidation and glucuronidation were
detected as 5% or less.4

5.5 Excretion:
It is majorly excreated by feces (73% of unchanged drug) and around 6% is excreated
4
by urine.

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6.0 THERAPY EVALUATION

6.1 Therapeutic
6.1.1 Laboratory Parameters
Select patients for treatment based on the presence of a RET gene fusion
(non-small cell lung cancer [NSCLC] or thyroid cancer) or RET gene mutation
(medullary thyroid cancer [MTC]).5

6.1.2 Physical Findings

Tumour response may be indicative of efficacy.5
6.2 Toxic

6.2.1 Laboratory Parameters

 Closely monitor patients at risk for tumor lysis syndrome, especially
in those with rapidly growing tumors, a high tumor burden, renal
dysfunction, or dehydration.
 Monitor ALT and AST prior to initiating therapy, every 2 weeks
during the first 3 months, then monthly thereafter, and as clinically
indicated.5

6.2.2 Physical Findings

 Closely monitor patients at risk for tumor lysis syndrome, especially
in those with rapidly growing tumors, a high tumor burden, renal
dysfunction, or dehydration.
 Monitor blood pressure after 1 week of therapy, at least monthly
thereafter, and as clinically indicated.
 Monitor for pulmonary symptoms indicative of interstitial lung
disease or pneumonitis.
 Verify pregnancy status of women of reproductive potential with
pregnancy testing prior to initiating therapy.5

7.0 DRUG INTERACTIONS:

Drug-Drug
Severity Mechanism Inference
Interactions
Concurrent use of PRALSETINIB and
Induction of CYP3A- STRONG CYP3A INDUCERS may
Strong CYP3A
Major mediated pralsetinib result in decreased pralsetinib
Inducers
metabolism exposure, which may decrease
efficacy.
Concurrent use of PRALSETINIB and
Inhibition of CYP3A-
Strong CYP3A STRONG CYP3A INHIBITORS may
Major mediated pralsetinib
Inhibitors result in increased pralsetinib
metabolism
exposure.
Inhibition of P-gp efflux Concurrent use of PRALSETINIB and
P-gp and strong
transport and CYP3A- P-GP AND STRONG CYP3A
CYP3A Major
mediated metabolism of INHIBITORS may result in increased
inhibitors
pralsetinib pralsetinib exposure.6

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8.0 DOSAGE REGIMEN RECOMMENDATIONS:
Capsules: 100 mg, light blue, opaque, hard hydroxypropyl methylcellulose (HPMC) capsule
printed with “BLU-667” on the capsule shell body and “100 mg” on the capsule shell cap. 4

9.0 ADVERSE DRUG REACTIONS:

Adverse drug reactions in patients who received Gavreto (Pralsetinib) are-
Pralsetinib
Adverse Reaction (N=220)
Grades 1-4 (%) Grades 3-4 (%)
GENERAL
Fatigue 35 2.3
Pyrexia 20 0
Edema 20 0
GASTROINTESTINAL
Constipation 35 1
Diarrhea 24 3.2
Dry Mouth 16 0
MUSCULOSKELETAL DISORDERS
Musculoskeletal Pain 32 0
VASCULAR
Hypertension 28 14
RESPIRATORY, THORACIC AND MEDIASTINAL
Cough 23 0.5
INFECTIONS
Pneumonia 17 8

10.0 USE IN PREGNANCY

Based on findings from animal studies and its mechanism of action, Pralsetinib can cause
fetal harm when administered to a pregnant woman. There are no available data on Pralsetinib use
in pregnant women to inform drug-associated risk. Oral administration of pralsetinib to pregnant
rats during the period of organogenesis resulted in malformations and embryo lethality at maternal
exposures below the human exposure at the clinical dose of 400 mg once daily. Advise pregnant
women of the potential risk to a fetus.4

11.0 USE IN LACTATION

There are no data on the presence of pralsetinib or its metabolites in human milk or their
effects on either the breastfed child or on milk production. Because of the potential for serious
adverse reactions in breastfed children, advise women not to breastfeed during treatment with
Pralsetinib and for 1 week after the final dose.4

12.0 USE IN PEDIATRICS

The safety and efficacy for the use of pralsetinib in pediatrics is not well established.

4
REFERENCES:

1. Pralsetinib [Internet]. Uses, Interactions, Mechanism of Action | DrugBank Online. [cited

2023Mar12]. Available from: https://go.drugbank.com/drugs/DB15822.
2. Santoro M, Carlomagno F. Central role of Ret in Thyroid Cancer. Cold Spring Harbor
Perspectives in Biology. 2013;5(12).
3. Subbiah V, Yang D, Velcheti V, Drilon A, Meric-Bernstam F. State-of-the-art strategies for
targeting ret-dependent cancers. Journal of Clinical Oncology. 2020;38(11):1209–21.
4. HIGHLIGHTS OF PRESCRIBING INFORMATION [Internet]. access.fda.gov. [cited 2023Mar12].
Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213721s000lbl.pdf
5. Product Information: GAVRETO(TM) oral capsules, pralsetinib oral capsules. Blueprint
Medicines Corporation (per FDA), Cambridge, MA, 2020.
6. Micromedex [Internet]. Drug Reference- Pralsetinib. [cited 2023Mar12]. Available from:
https://www.micromedexsolutions.com/micromedex2/librarian/PFDefaultActionId/evidenc
expert.DoIntegratedSearch?navitem=topHome&isToolPage=true#