Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients
Bins, Sander; Huitema, Alwin D R; Laven, Pim; Bouazzaoui, Samira El; Yu, Huixin; van Erp, Nielka; van Herpen, Carla; Hamberg, Paul; Gelderblom, Hans; Steeghs, Neeltje; Sleijfer, Stefan; van Schaik, Ron H N; Mathijssen, Ron H J; Koolen, Stijn L W
(2019) Clinical Pharmacokinetics, volume 58, issue 5, pp. 651 - 658
(Article)
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
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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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Keywords: Journal Article
ISSN: 0312-5963
Publisher: Adis International Ltd
Note: Funding Information: Conflict of interest 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. Funding Information: The authors thank Djoeke de Wit for her assistance in collecting clinical data, and Daan Hurkmans for designing Fig.?1. The authors also thank Roxanne C. Jewell (GSK/Novartis) and Gaaled Haj Mohammad (GSK/Novartis) for providing raw pazopanib data from two clinical trials (VEG109601 [1 ] and VEG110725 [2 ]). Publisher Copyright: © 2018, The Author(s).
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