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Clinical Trial
. 2019 May;58(5):651-658.
doi: 10.1007/s40262-018-0719-5.

Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients

Sander Bins  1 , Alwin D R Huitema  2   3 , Pim Laven  1 , Samira El Bouazzaoui  4 , Huixin Yu  2 , Nielka van Erp  5 , Carla van Herpen  6 , Paul Hamberg  7 , Hans Gelderblom  8 , Neeltje Steeghs  9 , Stefan Sleijfer  1 , Ron H N van Schaik  4 , Ron H J Mathijssen  1 , Stijn L W Koolen  10   11
Affiliations
Clinical Trial

Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients

Sander Bins et al. Clin Pharmacokinet. 2019 May.

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.

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Conflict of interest statement

Huixin Yu is currently employed by Novartis. All her contributions to this article were made before that employment. Nielka van Erp received grants from Astellas, Janssen-Cilag BV, Novartis, GSK, Boehringer-Ingelheim, Ipsen, Roche, Pfizer, Gilead, and Sanofi and payment for lectures by Novartis, Bayer, and Sanofi. Ron H.J. Mathijssen received grants and payment for lectures by Novartis. Stijn L.W. Koolen received payment for lectures by Novartis. Sander Bins, Alwin D.R. Huitema, Pim Laven, Samira el Bouazzaoui, Carla van Herpen, Paul Hamberg, Hans Gelderblom, Neeltje Steeghs, Stefan Sleijfer, and Ron H.N. van Schaik have no conflicts of interest that are directly relevant to the contents of this article.

Figures

Fig. 1
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
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
See this image and copyright information in PMC

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