Population Pharmacokinetics of MCLA-128, a HER2/HER3 Bispecific Monoclonal Antibody, in Patients with Solid Tumors.

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de Vries Schultink, Aurelia H M (author)

Population Pharmacokinetics of MCLA-128, a HER2/HER3 Bispecific Monoclonal Antibody, in Patients with Solid Tumors.

Article/chapterEnglish2020

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2020-01-31
Springer Science and Business Media LLC,2020
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LIBRIS-ID:oai:DiVA.org:uu-494227
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-494227URI
https://doi.org/10.1007/s40262-020-00858-2DOI

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Language:English
Summary in:English

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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.

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Bol, Kees (author)
Doornbos, Robert P (author)
Murat, Anastasia (author)
Wasserman, Ernesto (author)
Dorlo, Thomas P CNetherlands Cancer Institute(Swepub:uu)thodo249 (author)
Schellens, Jan H M (author)
Beijnen, Jos H (author)
Huitema, Alwin D R (author)
Netherlands Cancer Institute (creator_code:org_t)

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In:Clinical Pharmacokinetics: Springer Science and Business Media LLC59:7, s. 875-8840312-59631179-1926

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By the university: Uppsala University

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