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Population Pharmacokinetics of MCLA-128, a HER2/HER3 Bispecific Monoclonal Antibody, in Patients with Solid Tumors.
- de Vries Schultink, Aurelia H M (author)
- Bol, Kees (author)
- Doornbos, Robert P (author)
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- Murat, Anastasia (author)
- Wasserman, Ernesto (author)
- Schellens, Jan H M (author)
- Beijnen, Jos H (author)
- Huitema, Alwin D R (author)
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- (creator_code:org_t)
- 2020-01-31
- 2020
- English.
- In: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 59:7, s. 875-884
- Journal article (peer-reviewed)
Abstract
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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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- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
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