Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients

Author(s):
Bins, S.; Huitema, A.D.R.; Laven, P.; Bouazzaoui, S. el; Yu, H.X.; Erp, N. van; Herpen, C. van; Hamberg, P.; Gelderblom, H.; Steeghs, N.; Sleijfer, S.; Schaik, R.H.N. van; Mathijssen, R.H.J.; Koolen, S.L.W.
Published
2019
Publication type
Article / Letter to editor

Abstract

Background and ObjectiveAs 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.MethodsThe 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.ResultsIncorporation 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 600mg once daily or 800mg once daily were 31 and 35mg/L, respectively. The simulated trough concentrations for the population excluding the CYP3A4*22 carriers after 600mg once daily or 800mg once daily were 18 and 20mg/L, respectively.ConclusionThis analysis shows that CYP3A4*22 heterozygotes have a substantial lower pazopanib clearance and that dose adjustments based on CYP3A4*22 status could be considered.

Date issued
2019-05-01
Language
English
Publisher
ADIS INT LTD
Is part of
Clinical Pharmacokinetics (2019), Vol. 58, no. 5, p. 651-658
hdl
1887/122788
doi
10.1007/s40262-018-0719-5