J Clin Pharmacol. 2014 Oct;54(10):1108-16. doi: 10.1002/jcph.309. Epub 2014 Apr 23.

Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma.

Wang E, Kang D, Bae KS, Marshall MA, Pavlov D, Parivar K.

Abstract

Tremelimumab, a fully human monoclonal antibody specific for human cytotoxic T-lymphocyte-associated antigen 4, has been studied in clinical trials. We have reported the results of population pharmacokinetics for tremelimumab in 654 metastatic melanoma patients. Population estimates (inter-individual variability [IIV]) for pharmacokinetic parameters in a final model were clearance (CL), 0.26 L/day (31.8%) and central volume of distribution, 3.97 L (20.4%). CL was faster in males, patients with higher values of creatinine clearance and endogenous immunoglobulin, and patients with relatively poor baseline prognostic factors. No dose adjustment was needed based on the magnitude of the change of CL (<30%). The association of CL and overall survival (OS) was investigated. In a Phase 3 trial evaluating tremelimumab as first-line-treatment, median OS for the 147 patients in the fast-CL group (≥ median CL value) was 9.6 months versus 15.8 months for the 146 patients in the slow-CL group (analysis showed statistically significant association between CL and OS (P < .05). Results suggest that higher or more frequent dosing should be considered in future trials.

KEYWORDS:

drug clearance; malignancy; melanoma; overall survival; population pharmacokinetic; tremelimumab