Time-Varying Clearance and Impact of Disease State on the Pharmacokinetics of Avelumab in Merkel Cell Carcinoma and Urothelial Carcinoma.

Autor: Wilkins JJ; Occams, Amstelveen, The Netherlands., Brockhaus B; Merck Healthcare KGaA, Darmstadt, Germany., Dai H; EMD Serono, Billerica, Massachusetts, USA., Vugmeyster Y; EMD Serono, Billerica, Massachusetts, USA., White JT; EMD Serono, Billerica, Massachusetts, USA., Brar S; Pfizer Inc., San Diego, California, USA., Bello CL; Pfizer Inc., San Diego, California, USA., Neuteboom B; EMD Serono, Billerica, Massachusetts, USA., Wade JR; Occams, Amstelveen, The Netherlands., Girard P; Merck Institute of Pharmacometrics, Merck Serono S.A., Lausanne, Switzerland., Khandelwal A; Merck Healthcare KGaA, Darmstadt, Germany.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2019 Jun; Vol. 8 (6), pp. 415-427. Date of Electronic Publication: 2019 Apr 25.
DOI: 10.1002/psp4.12406
Abstrakt: Avelumab, a human anti-programmed death ligand 1 immunoglobulin G1 antibody, has shown efficacy and manageable safety in multiple tumors. A two-compartment population pharmacokinetic model for avelumab incorporating intrinsic and extrinsic covariates and time-varying clearance (CL) was identified based on data from 1,827 patients across three clinical studies. Of 14 tumor types, a decrease in CL over time was more notable in metastatic Merkel cell carcinoma and squamous cell carcinoma of the head and neck, which had maximum decreases of 32.1% and 24.7%, respectively. The magnitude of reduction in CL was higher in responders than in nonresponders. Significant covariate effects of baseline weight, baseline albumin, and sex were identified on both CL and central distribution volume. Significant covariate effects of black/African American race, C-reactive protein, and immunogenicity were found on CL. None of the covariate or time-dependent effects were clinically important or warranted dose adjustment.
(© 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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