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Clinical Pharmacokinetics

, Volume 53, Issue 3, pp 261–269 | Cite as

Predictive Value of CYP3A and ABCB1 Phenotyping Probes for the Pharmacokinetics of Sunitinib: the ClearSun Study

  • Jacqueline S. L. Kloth
  • Heinz-Josef Klümpen
  • Huixin Yu
  • Karel Eechoute
  • Caroline F. Samer
  • Boen L. R. Kam
  • Alwin D. R. Huitema
  • Youssef Daali
  • Aeilko H. Zwinderman
  • Bavanthi Balakrishnar
  • Roelof J. Bennink
  • Mark Wong
  • Jan H. M. Schellens
  • Ron H. J. Mathijssen
  • Howard GurneyEmail author
Original Research Article

Abstract

Background and Objective

The wide inter-patient variability in drug exposure partly explains the toxicity and efficacy profile of sunitinib treatment. In this prospective study cytochrome P450 (CYP) 3A and adenosine triphosphate binding cassette (ABC) B1 phenotypes were correlated to the pharmacokinetics of sunitinib and its active metabolite N-desethylsunitinib.

Methods

A correlation analysis was performed between sunitinib pharmacokinetics and 1′OH-midazolam/midazolam ratio and parameters derived from technetium-99m-2-methoxy isobutyl isonitrile (99mTc-MIBI) scans, respectively. A population pharmacokinetic model using non-linear mixed-effects modeling software NONMEM was built, which included the phenotype tests as covariate.

Results

In 52 patients, the mean trough concentration of sunitinib plus metabolite increased from 21.4 ng/mL at day 1 of a cycle to 88.1 ng/mL in the fourth week of treatment. A trend for a correlation was observed between 99mTc-MIBI elimination constant and trough concentrations of N-desethylsunitinib; however, this was not significant. Correlations were found between 1′OH-midazolam/midazolam ratio and sunitinib clearance (P = 0.008) and day 1 N-desethylsunitinib trough concentrations (P = 0.005), respectively. Moreover, patients suffering from grade 3 toxicities had significant lower clearance of sunitinib than patients without grade 3 toxicities (34.4 vs. 41.4 L/h; P = 0.025).

Conclusions

Phenotype tests for ABCB1 and CYP3A4 did not explain inter-individual variability of sunitinib exposure sufficiently. However, the correlation between sunitinib clearance and the occurrence of severe toxicity suggests a direct exposure–toxicity relationship.

Keywords

Sunitinib Trough Concentration Electronic Supplementary Material Figure CYP3A Activity Metabolic Ratio 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We would like to thank Bo Gao, Peter de Bruijn, Chris Liddle, and Anneke Westermann for their specific contributions to this study.

This work was sponsored by Pfizer Australia, and was presented in part at the 37th ESMO Annual Meeting (Vienna, Austria, 28 September– 2 October 2012), abstract no. 1678.

Conflict of interest

The authors declared no conflicts of interest.

Supplementary material

40262_2013_111_MOESM1_ESM.doc (87 kb)
Supplementary material 1 (DOC 87 kb)

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Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Jacqueline S. L. Kloth
    • 1
  • Heinz-Josef Klümpen
    • 2
  • Huixin Yu
    • 3
  • Karel Eechoute
    • 1
  • Caroline F. Samer
    • 4
    • 5
  • Boen L. R. Kam
    • 6
  • Alwin D. R. Huitema
    • 3
  • Youssef Daali
    • 4
  • Aeilko H. Zwinderman
    • 7
  • Bavanthi Balakrishnar
    • 8
  • Roelof J. Bennink
    • 9
  • Mark Wong
    • 8
  • Jan H. M. Schellens
    • 10
    • 11
  • Ron H. J. Mathijssen
    • 1
  • Howard Gurney
    • 8
    Email author
  1. 1.Department of Medical OncologyErasmus MC Cancer InstituteRotterdamThe Netherlands
  2. 2.Department of Medical OncologyAcademic Medical Center AmsterdamAmsterdamThe Netherlands
  3. 3.Department of Pharmacy and PharmacologySlotervaart HospitalAmsterdamThe Netherlands
  4. 4.Department of Clinical Pharmacology and ToxicologyGeneva University HospitalsGenevaSwitzerland
  5. 5.Swiss Center of Applied Human ToxicologyBaselSwitzerland
  6. 6.Department of Nuclear MedicineErasmus University Medical CenterRotterdamThe Netherlands
  7. 7.Clinical Epidemiology, Biostatistics and BioinformaticsAcademic Medical Center AmsterdamAmsterdamThe Netherlands
  8. 8.Department of Medical OncologyUniversity of Sydney, Westmead HospitalWestmeadAustralia
  9. 9.Department of Nuclear MedicineAcademic Medical Center AmsterdamAmsterdamThe Netherlands
  10. 10.Department of Clinical PharmacologyNetherlands Cancer InstituteAmsterdamThe Netherlands
  11. 11.Division of Drug Toxicology, Department of Pharmaceutical Sciences, Science FacultyUtrecht UniversityUtrechtThe Netherlands

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