Aurelia H M de Vries Schultink1, Kees Bol2, Robert P Doornbos2, Anastasia Murat2, Ernesto Wasserman2, Thomas P C Dorlo3, Jan H M Schellens4, Jos H Beijnen3,4, Alwin D R Huitema3,5. 1. Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. ah.d.vriesschultink@nki.nl. 2. Merus N.V., Utrecht, The Netherlands. 3. Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. 4. Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. 5. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Abstract
BACKGROUND AND OBJECTIVES: MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors and is in development to overcome HER3-mediated resistance to anti-HER2 therapies. The aims of this analysis were to characterize the population pharmacokinetics of MCLA-128 in patients with various solid tumors, to evaluate patient-related factors that affect the disposition of MCLA-128, and to assess whether flat dosing is appropriate. METHODS: MCLA-128 concentration data following intravenous administration were collected in a phase I/II clinical trial. Pharmacokinetic data were analyzed using non-linear mixed-effects modeling. Different compartmental models were evaluated. Various body size parameters including body weight, body surface area, and fat-free mass were evaluated as covariates in addition to age, sex, HER2 status, and tumor burden. RESULTS: In total, 1115 serum concentration measurements were available from 116 patients. The pharmacokinetics of MCLA-128 was best described by a two-compartment model with linear and non-linear (Michaelis-Menten) clearance. Fat-free mass significantly affected the linear clearance and volume of distribution of the central compartment of MCLA-128, explaining 8.4% and 5.6% of inter-individual variability, respectively. Tumor burden significantly affected the non-linear clearance capacity. Simulations demonstrated that dosing based on body size parameters resulted in similar area under the plasma concentration-time curve for a dosing interval (AUC0-τ), maximum and trough concentrations of MCLA-128, compared to flat dosing. CONCLUSIONS: This analysis demonstrated that the pharmacokinetics of MCLA-128 exhibits similar disposition characteristics to other therapeutic monoclonal antibodies and that a flat dose of MCLA-128 in patients with various solid tumors is appropriate.
BACKGROUND AND OBJECTIVES: MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors and is in development to overcome HER3-mediated resistance to anti-HER2 therapies. The aims of this analysis were to characterize the population pharmacokinetics of MCLA-128 in patients with various solid tumors, to evaluate patient-related factors that affect the disposition of MCLA-128, and to assess whether flat dosing is appropriate. METHODS: MCLA-128 concentration data following intravenous administration were collected in a phase I/II clinical trial. Pharmacokinetic data were analyzed using non-linear mixed-effects modeling. Different compartmental models were evaluated. Various body size parameters including body weight, body surface area, and fat-free mass were evaluated as covariates in addition to age, sex, HER2 status, and tumor burden. RESULTS: In total, 1115 serum concentration measurements were available from 116 patients. The pharmacokinetics of MCLA-128 was best described by a two-compartment model with linear and non-linear (Michaelis-Menten) clearance. Fat-free mass significantly affected the linear clearance and volume of distribution of the central compartment of MCLA-128, explaining 8.4% and 5.6% of inter-individual variability, respectively. Tumor burden significantly affected the non-linear clearance capacity. Simulations demonstrated that dosing based on body size parameters resulted in similar area under the plasma concentration-time curve for a dosing interval (AUC0-τ), maximum and trough concentrations of MCLA-128, compared to flat dosing. CONCLUSIONS: This analysis demonstrated that the pharmacokinetics of MCLA-128 exhibits similar disposition characteristics to other therapeutic monoclonal antibodies and that a flat dose of MCLA-128 in patients with various solid tumors is appropriate.
Authors: Alexander Rau; Katharina Kocher; Mirjam Rommel; Lennart Kühl; Maximilian Albrecht; Hannes Gotthard; Nadine Aschmoneit; Bettina Noll; Monilola A Olayioye; Roland E Kontermann; Oliver Seifert Journal: MAbs Date: 2021 Jan-Dec Impact factor: 5.857
Authors: Shuyu Huang; Sander M J van Duijnhoven; Alice J A M Sijts; Andrea van Elsas Journal: J Cancer Res Clin Oncol Date: 2020-09-28 Impact factor: 4.553