Dataset Information

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.

SUBMITTER: Bins S

PROVIDER: S-EPMC6451710 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients.

Bins Sander S Huitema Alwin D R ADR Laven Pim P Bouazzaoui Samira El SE Yu Huixin H van Erp Nielka N van Herpen Carla C Hamberg Paul P Gelderblom Hans H Steeghs Neeltje N Sleijfer Stefan S van Schaik Ron H N RHN Mathijssen Ron H J RHJ Koolen Stijn L W SLW

Clinical pharmacokinetics 20190501 5

<h4>Background and objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>Incorporation of CYP3A4*22 in the model ...[more]

PMID: 30367352

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Dataset Information

Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients.

Background and objective

Methods

Results

Conclusion

Publications

Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients.

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