Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients
Background and Objective: As pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib affect systemic pazopanib concentrations. Methods: The decreased function alleles CYP3A4 15389 C > T (*22), ABCB1 3435 C >T, ABCG2 421 C >A, and ABCG2 34G >A were analyzed within a recently developed population-pharmacokinetic model. Results: Incorporation of CYP3A4*22 in the model resulted in a 35% lower clearance for variant carriers (0.18 vs. 0.27 L/h; difference in objective function value: − 9.7; p < 0.005). Simulated median trough concentrations of cancer patients with CYP3A4*22 with 600 mg once daily or 800 mg once daily were 31 and 35 mg/L, respectively. The simulated trough concentrations for the population excluding the CYP3A4*22 carriers after 600 mg once daily or 800 mg once daily were 18 and 20 mg/L, respectively. Conclusion: This analysis shows that CYP3A4*22 heterozygotes have a substantial lower pazopanib clearance and that dose adjustments based on CYP3A4*22 status could be considered.
|Organisation||Department of Medical Oncology|
Bins, S, Huitema, A.D.R, Laven, P. (Pim), Bouazzaoui, S. (Samira el), Yu, H, Erp, N.P, … Koolen, S.L.W. (2018). Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients. Clinical Pharmacokinetics. doi:10.1007/s40262-018-0719-5