Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients

Abstract

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.

Fig. 1

Schematic overview of the pazopanib (pazo) pharmacokinetic model [16]. ALAG lag time, CL clearance, fr fraction of pazopanib, KaF fast absorption rate constant, KaS slow absorption rate constant, Vc central volume of distribution, Vp peripheral volume of distribution

Fig. 2

Median simulated pazopanib trough concentration after a single dose at steady state. The red line and the red dashed line represent the simulated concentration–time curves for CYP3A4*22 patients, treated with 800 mg and 600 mg of pazopanib daily, respectively. The black line and the black dashed line represent the simulated concentration–time curve for wild-type (WT) patients for CYP3A4, treated with 800 mg and 600 mg of pazopanib daily, respectively. 1dd once daily