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Clin Pharmacokinet. 2017 Mar;56(3):293-303. doi: 10.1007/s40262-016-0443-y.

Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients.

Author information

1
Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek and MC Slotervaart, Louwesweg 6, PO Box 90440, 1006 BK, Amsterdam, The Netherlands. h.yu@nki.nl.
2
Department of Clinical Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
3
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
4
Department of Medical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
5
Department of Clinical Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
6
Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
7
Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek and MC Slotervaart, Louwesweg 6, PO Box 90440, 1006 BK, Amsterdam, The Netherlands.

Abstract

BACKGROUND AND OBJECTIVE:

Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients.

METHODS:

Pharmacokinetic data were available from 96 patients from three clinical studies. A multi-compartment model including (i) a complex absorption profile, (ii) the potential non-linear dose-concentration relationship and (iii) the potential long-term decrease in exposure was developed.

RESULTS:

A two-compartment model best described pazopanib pharmacokinetics. The absorption phase was modelled by two first-order processes: 36 % (relative standard error [RSE] 34 %) of the administered dose was absorbed with a relatively fast rate (0.4 h-1 [RSE 31 %]); after a lag time of 1.0 h (RSE 6 %), the remaining dose was absorbed at a slower rate (0.1 h-1 [RSE 28 %]). The relative bioavailability (rF) at a dose of 200 mg was fixed to 1. With an increasing dose, the rF was strongly reduced, which was modelled with an E max (maximum effect) model (E max was fixed to 1, the dose at half of maximum effect was estimated as 480 mg [RSE 23 %]). Interestingly, the plasma exposure to pazopanib also decreased over time, modelled on rF with a maximum magnitude of 50 % (RSE 27 %) and a first-order decay constant of 0.15 day-1 (RSE 43 %). The inter-patient and intra-patient variability on rF were estimated as 36 % (RSE 16 %) and 75 % (RSE 22 %), respectively.

CONCLUSION:

A popPK model for pazopanib was developed that illustrated the complex absorption process, the non-linear dose-concentration relationship, the high inter-patient and intra-patient variability, and the first-order decay of pazopanib concentration over time. The developed popPK model can be used in clinical practice to screen covariates and guide therapeutic drug monitoring.

PMID:
27534647
DOI:
10.1007/s40262-016-0443-y
[Indexed for MEDLINE]

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