A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation.
Adult
Antibodies, Monoclonal, Humanized
/ administration & dosage
Antineoplastic Agents, Immunological
/ administration & dosage
Computer Simulation
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Humans
Infusions, Intravenous
/ methods
Male
Middle Aged
Models, Biological
Neoplasms
/ blood
Randomized Controlled Trials as Topic
Time Factors
Treatment Outcome
Anti-PD-1
Dosing
Immunotherapy
Modelling
Pembrolizumab
Pharmacokinetics
Journal
European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
16
01
2020
accepted:
10
02
2020
pubmed:
19
4
2020
medline:
28
10
2020
entrez:
19
4
2020
Statut:
ppublish
Résumé
Pembrolizumab is approved for multiple cancer types at 200 mg and 2 mg/kg dose every 3 weeks (Q3W). We used a model-based approach to compare the exposure of pembrolizumab 400 mg dose every 6 weeks (Q6W) with the Q3W regimens. The Q6W dose was selected by matching exposure with the 200 mg and 2 mg/kg Q3W doses. Concentration-time profiles were simulated using the established population pharmacokinetic model of pembrolizumab based on 2993 subjects from five clinical trials across tumour types. Efficacy was bridged by evaluating projections of average concentration over the dosing interval (C The 400 mg Q6W dose had similar predicted exposure (C Exposures expected for pembrolizumab 400 mg Q6W were similar to the 200 mg and 2 mg/kg Q3W and below the 10 mg/kg Q2W regimens. Established exposure-response relationships for pembrolizumab over a 5-fold dose range (2 mg/kg Q3W to 10 mg Q2W) support that clinical efficacy and safety of 400 mg Q6W would be similar to the 200 mg and 2 mg/kg Q3W doses across tumour types. NCT01295827, NCT01704287, NCT01866319, NCT01905657, NCT02142738.
Sections du résumé
BACKGROUND
Pembrolizumab is approved for multiple cancer types at 200 mg and 2 mg/kg dose every 3 weeks (Q3W). We used a model-based approach to compare the exposure of pembrolizumab 400 mg dose every 6 weeks (Q6W) with the Q3W regimens.
METHODS
The Q6W dose was selected by matching exposure with the 200 mg and 2 mg/kg Q3W doses. Concentration-time profiles were simulated using the established population pharmacokinetic model of pembrolizumab based on 2993 subjects from five clinical trials across tumour types. Efficacy was bridged by evaluating projections of average concentration over the dosing interval (C
RESULTS
The 400 mg Q6W dose had similar predicted exposure (C
CONCLUSIONS
Exposures expected for pembrolizumab 400 mg Q6W were similar to the 200 mg and 2 mg/kg Q3W and below the 10 mg/kg Q2W regimens. Established exposure-response relationships for pembrolizumab over a 5-fold dose range (2 mg/kg Q3W to 10 mg Q2W) support that clinical efficacy and safety of 400 mg Q6W would be similar to the 200 mg and 2 mg/kg Q3W doses across tumour types.
CLINICAL TRIAL REGISTRATION NUMBERS
NCT01295827, NCT01704287, NCT01866319, NCT01905657, NCT02142738.
Identifiants
pubmed: 32305010
pii: S0959-8049(20)30070-8
doi: 10.1016/j.ejca.2020.02.016
pii:
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Antineoplastic Agents, Immunological
0
pembrolizumab
DPT0O3T46P
Banques de données
ClinicalTrials.gov
['NCT01866319', 'NCT01905657', 'NCT01704287', 'NCT02142738', 'NCT01295827']
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
68-75Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest statement M.L., T.R.L., D.P.d.A., V.S., K.M., E.C., H.A. and L.J. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock or stock options in the Company. M.L., E.C. and L.J. have a patent pending for pembrolizumab 400 mg Q6W dose regimen. N.Y. has received research grants from Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical Co., Ltd, Takeda, Janssen Pharma, MSD, Merck and GSK; honoraria from Ono Pharmaceutical Co., Ltd, Chugai, AstraZeneca, Pfizer, Lilly, BMS and Sysmex; consultation fees from Eisai, Otsuka, Takeda, Boehringer Ingelheim and Cimic, LLS has received consultancy fees from Merck, Pfizer, Celgene, Astra/Zeneca/Medimmune, Morphosys, Roche/Genentech, GeneSeeq, Loxo, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi and Treadwell Therapeutics and has received institutional support for clinical trials from Novartis, Bristol-Myers Squibb, Pfizer, Boerhingher-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks Labs Inc. and Avid Therapeutics.