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Poster display session

3418 - Impact of CYP3A4*22 on pazopanib pharmacokinetics in cancer patients

Date

10 Sep 2017

Session

Poster display session

Presenters

Stijn Koolen

Citation

Annals of Oncology (2017) 28 (suppl_5): v295-v329. 10.1093/annonc/mdx371

Authors

S.L.W. Koolen1, A. Huitema2, P. Laven1, S. El Bouazzaoui3, H. Yu2, N.P. Erp4, C.M.L. Herpen5, P. Hamberg6, H. Gelderblom7, N. Steeghs8, S. Sleijfer1, R.H.N. van Schaik3, R.H.J. Mathijssen1, S. Bins1

Author affiliations

  • 1 Medical Oncology, Erasmus MC Cancer Institute, 3008EA - Rotterdam/NL
  • 2 Dept. Of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam/NL
  • 3 Clinical Chemistry, Erasmus University Medical Center, 3015 CE - Rotterdam/NL
  • 4 Clinical Pharmacy, Radboud University Medical Center, Nijmegen/NL
  • 5 Medical Oncology, Radboud University Medical Center, Nijmegen/NL
  • 6 Internal Medicine, Franciscus Gasthuis, Rotterdam/NL
  • 7 Medical Oncology, Leiden University Medical Center (LUMC), 2300 RC - Leiden/NL
  • 8 Medical Oncology, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, 1066 CX - Amsterdam/NL
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Resources

Abstract 3418

Background

Pazopanib is characterized by a large interpatient variability in systemic drug exposure. As pazopanib trough levels (>20.5 mg/L) are correlated with clinical outcome (Suttle et al, BJC 2014) in metastatic renal cell carcinoma (mRCC) patients, it is vital to identify factors that influence pazopanib pharmacokinetics (PK). The objective of the current analysis was to evaluate if single nucleotide polymorphisms (SNPs) in the metabolic pathway of pazopanib (i.e. CYP3A4, ABCB1 and ABCG2) affect systemic pazopanib concentrations.

Methods

We analyzed 97 patients who participated in 3 pazopanib PK studies. Starting point of the current analysis was a population PK model for pazopanib (Yu et al, Clin Pharmacokinet 2017). Four SNPs located on 3 genes, that were associated with decrease of function were analyzed using real time PCR: CYP3A4 15389 C>T (*22), ABCB1 3435 C>T, and the ABCG2 SNPs 421 C>A, and 34G>A. The influence of these SNPs on pazopanib bioavailability and clearance (CL) was explored with NONMEM. Statistical significance was determined with the likelihood ratio test using the objective function value (OFV). Trough concentrations (Ctrough) at 6 weeks after start with doses of 400 to 800 mg once daily (OD), were simulated. A threshold Ctrough of 20.5 mg/L was used as reference.

Results

From 3 patients, insufficient DNA was isolated to run a PCR analysis. All SNPs were in Hardy-Weinberg equilibrium. Eleven patients (12%) had a variant allele at CYP3A4*22, all of whom were heterozygous. Incorporation of CYP3A4*22 in the NONMEM model resulted in a 35% lower CL for the variant carriers (0.18 L/h vs 0.27 L/h; ΔOFV = -7.8; P 

Conclusions

Our analysis shows that CYP3A4*22 carriers have a clinically relevant lower pazopanib CL. Prospective analysis should point out whether CYP3A4*22 carriers are at risk for more toxicity and require a lower pazopanib starting dose.

Clinical trial identification

Legal entity responsible for the study

Erasmus MC, Rotterdam, The Netherlands

Funding

None

Disclosure

All authors have declared no conflicts of interest.

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