May Garrett

Axitinib in Metastatic Renal Cell Carcinoma: Results of a Pharmacokinetic and Pharmacodynamic Analysis

Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second‐line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients with other solid tumors in 17 trials, the disposition of axitinib was best described by a 2‐compartment model with first‐order absorption and a lag time, with estimated mean systemic clearance (CL) of 14.6 L/h and central volume of distribution (Vc) of 47.3 L. Of 12 covariates tested, age over 60 years and Japanese ethnicity were associated with decreased CL, whereas Vc increased with body weight. However, the magnitude of predicted changes in exposure based on these covariates does not warrant dose adjustments. Multivariate Cox proportional hazard regression and logistic regression analyses showed that higher exposure and diastolic blood pressure were independently associated with longer progression‐free and overall survivals and higher probability of partial response in metastatic RCC patients. These findings support axitinib dose titration to increase plasma exposure in patients who tolerate axitinib, and also demonstrate diastolic blood pressure as a potential marker of efficacy.

Pharmacokinetic interaction between amprenavir and delavirdine: Evidence of induced clearance by amprenavir

Our objective was to determine the pharmacokinetic interaction between amprenavir and delavirdine.

Population pharmacokinetic analysis of axitinib in healthy volunteers

AIMS Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy volunteers. METHODS Plasma concentration-time data from 337 healthy volunteers in 10 phase I studies were analyzed, using non-linear mixed effects modelling (nonmem) to estimate population pharmacokinetic parameters and evaluate relationships between parameters and food, formulation, demographic factors, measures of renal and hepatic function and metabolic genotypes (UGT1A1*28 and CYP2C19). RESULTS A two compartment structural model with first order absorption and lag time best described axitinib pharmacokinetics. Population estimates for systemic clearance (CL), central volume of distribution (Vc ), absorption rate constant (ka ) and absolute bioavailability (F) were 17.0 l h(-1) , 45.3 l, 0.523 h(-1) and 46.5%, respectively. With axitinib Form IV, ka and F increased in the fasted state by 207% and 33.8%, respectively. For Form XLI (marketed formulation), F was 15% lower compared with Form IV. CL was not significantly influenced by any of the covariates studied. Body weight significantly affected Vc , but the effect was within the estimated interindividual variability for Vc . CONCLUSIONS The analysis established a model that adequately characterizes axitinib pharmacokinetics in healthy volunteers. Vc was found to increase with body weight. However, no change in plasma exposures is expected with change in body weight; hence no dose adjustment is warranted.

Significant Interactions between CYP Probes in A 6-Drug Cocktail

Clinical Pharmacology & Therapeutics (2003) 73, P80–P80; doi:

Abstract B213: Pharmacokinetics (PK) and efficacy of axitinib in patients (pts) with sorafenib‐refractory metastatic renal cell carcinoma (mRCC)

Background: Axitinib (AG‐013736) is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, 3. The objectives of this analysis were to assess the impact of food, gender, race, weight, age, and disease status on axitinib PK and to explore the relationship between PK, diastolic blood pressure (dBP), and clinical efficacy in sorafenib‐refractory mRCC pts. A relationship has been previously reported in refractory mRCC pts. Methods: Pooled PK data were analyzed using nonlinear mixed‐effects modeling to estimate population PK parameters (mean and inter‐individual variability; Rixe et al. ASCO Annual Meeting 2009; abstract 5045). Efficacy data from sorafenib‐refractory mRCC pts (n=59) were included in the PK/pharmacodynamic analysis. Mean steady‐state area under the plasma concentration‐time curve (AUC) at the end of cycle 1 and dBP during axitinib therapy were utilized as predictors of clinical efficacy in the mRCC pts using logistic regression and Kaplan‐Meier survival analyses. Results: Median overall survival (OS) for sorafenib‐refractory mRCC pts with an AUC below the median (662 ng·hr/mL; n=29) was 42 weeks vs 84 weeks (P Conclusions: Increased exposure to axitinib and dBP ≥90 mmHg during axitinib therapy are associated with greater probability of a PR and longer median OS in sorafenib‐refractory mRCC pts. These data support an ongoing, pivotal, phase III trial in previously‐treated mRCC that incorporates a dosetitration scheme based on patient tolerance and BP. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B213.