Population pharmacokinetic modeling of pazopanib in healthy volunteers and patients with advanced renal cell carcinoma.
Baneyx G. (1), Combes F-P. (2), Huang P-H. (4) and Elmeliegy M. (3)
(1) Novartis Pharma AG, Biostatistical Sciences and Pharmacometrics, Basel, Switzerland. Novartis Pharmaceuticals Corporation, Biostatistical Sciences and Pharmacometrics (2), Oncology Clinical Pharmacology (3), Integration of Randomized Clinical Trial data (4), East Hanover, New Jersey, USA.
Objectives: Pazopanib, a tyrosine kinase inhibitor [1], has been approved as monotherapy for patients with advanced renal cell carcinoma and advanced soft tissue sarcoma. The objective of this analysis was to update the pazopanib population PK (popPK) model by considering all available historical PK data.
Methods: A pazopanib popPK model was previously developed with a subset of historical PK data and 3 aspects had to be refined: i) dose effect on oral bioavailability was only characterized for 400 and 800 mg oral doses limiting its utility; ii) oral bioavailability was predicted higher when co-administered with acid reducing agents which is in disagreement with prior knowledge; iii) one compartment disposition model was not adequate given the bi-exponential elimination observed after intravenous infusion. The structural model, parameter estimates and covariate effects were updated by analyzing all available historical PK data including 451 subjects (healthy volunteers and cancer patients) and 4011 PK observations (rich/sparse sampling) collected after a single intravenous infusion of 5 mg (7 subjects) and daily oral doses ranging from 50 to 2000 mg. Model parameters were estimated by a nonlinear mixed effect modeling approach using Monolix 4.3.2 [2].
Results: Updated structure was a two-compartment disposition model with delayed first order absorption and first-order elimination including an oral bioavailability decreasing with dose and time. After single administration of 800 mg, absolute oral bioavailability was estimated at 30% with a clearance of 0.19 L/h and a total volume of distribution of 12.9 L. Absolute oral bioavailability was 40 % higher at 400 mg than 800 mg and 30 % lower at steady state than after single administration. After single administration of 800 mg, the food intake increased oral bioavailability and absorption rate by 2.9 fold and 62%, respectively. Co-administration with acid reducing agents decreased oral bioavailability by 12% which is compatible with prior knowledge but this effect was not retained in the final model.
Conclusions: Integration of all available PK data improved the understanding and the characterization of the non-linear pazopanib exposure explained by an oral bioavailability decreasing with dose and time. Implementation of a continuous dose effect on oral bioavailability will extend the ability of the model to simulate pazopanib exposure at any dose levels.
References:
[1] Kumar et al. Mol Cancer Ther. 2007; 6: 2012-2021.
[2] Kuhn et al. Computational Statistics and Data Analysis 2005; 49:1020-1038.
