Population Pharmacokinetic Analysis of Bintrafusp Alfa in Different Cancer Types View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-07-05

AUTHORS

Justin J. Wilkins, Yulia Vugmeyster, Isabelle Dussault, Pascal Girard, Akash Khandelwal

ABSTRACT

IntroductionBintrafusp alfa, an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, has shown promising antitumor activity and manageable safety.MethodsTo support the dosing strategy for bintrafusp alfa, we developed a population pharmacokinetics model using a full covariate modeling approach, based on pharmacokinetic and covariate data from 644 patients with various solid tumors who received bintrafusp alfa intravenously in two clinical studies.ResultsA two-compartmental linear model best described bintrafusp alfa concentrations, and no time-varying clearance was identified. Using this model, the estimated clearance was 0.0158 l/h (relative standard error, 4.1%), and the central and peripheral volume of distribution were 3.21 l (relative standard error, 3.2%) and 0.483 l (relative standard error, 9.8%), respectively. The estimated mean elimination half-life of bintrafusp alfa was 6.93 days (95% CI 4.69–9.65 days). Several intrinsic factors (bodyweight, albumin, sex, and tumor type) were found to influence bintrafusp alfa pharmacokinetics, but none of these covariate effects was considered clinically meaningful and no dosage adjustments are recommended. Notably, simulations from the model suggested less variability in exposure metrics with flat dosing versus weight-based dosing.ConclusionsPharmacokinetic analysis of bintrafusp alfa supports the use of a flat dose regimen in further clinical trials (recommended phase 2 dose: 1200 mg every 2 weeks).Trial registrationClinicalTrials.gov identifiers: NCT02517398 and NCT02699515.FundingMerck Healthcare KGaA as part of an alliance between Merck Healthcare KGaA and GlaxoSmithKline. More... »

PAGES

2414-2433

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s12325-019-01018-0

DOI

http://dx.doi.org/10.1007/s12325-019-01018-0

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https://app.dimensions.ai/details/publication/pub.1117792563

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/31278692


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