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.
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Authors | Aurelia H M de Vries Schultink, Kees Bol, Robert P Doornbos, Anastasia Murat, Ernesto Wasserman, Thomas P C Dorlo, Jan H M Schellens, Jos H Beijnen, Alwin D R Huitema |
Journal | Clinical pharmacokinetics
(Clin Pharmacokinet)
Vol. 59
Issue 7
Pg. 875-884
(07 2020)
ISSN: 1179-1926 [Electronic] Switzerland |
PMID | 32006223
(Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Bispecific
- Antibodies, Monoclonal
- Immunoglobulin G
- zenocutuzumab
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Topics |
- Antibodies, Bispecific
(pharmacokinetics)
- Antibodies, Monoclonal
(pharmacokinetics)
- Humans
- Immunoglobulin G
- Models, Biological
- Neoplasms
(therapy)
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