Towards better dose individualisation: metabolic phenotyping to predict cabazitaxel pharmacokinetics in men with prostate cancer.

Abstract:

BACKGROUND:Cabazitaxel is approved for treatment of castration-resistant metastatic prostate cancer. The current dosing strategy of cabazitaxel is based on body surface area (BSA). Body surface area is known as a poor predictor for total systemic exposure to drugs, since it does not take into account variability in activity of metabolising enzymes, necessary for clearance of drugs. As exposure to cabazitaxel is related to treatment response, it is essential to develop a better individualised dosing strategy. METHODS:Ten patients with metastatic castration-resistant prostate cancer, who received cabazitaxel dosed on BSA as a part of routine palliative care, were enrolled in this study. Midazolam was administered as phenotyping probe for cytochrome P450 isoenzyme 3A (CYP3A). The relationship between midazolam and cabazitaxel clearance was investigated using non-linear mixed effects modelling. RESULTS:The clearance of Midazolam highly correlated with cabazitaxel clearance (R=0.74). Midazolam clearance significantly (P<0.004) explained the majority (∼60%) of the inter-individual variability in cabazitaxel clearance in the studied population. CONCLUSIONS:Metabolic phenotyping of CYP3A using midazolam is a promising strategy to individualise cabazitaxel dosing. Before clinical application, a randomised study is warranted.

journal_name

Br J Cancer

authors

Janssen A,Verkleij CPM,van der Vlist A,Mathijssen RHJ,Bloemendal HJ,Ter Heine R

doi

10.1038/bjc.2017.91

subject

Has Abstract

pub_date

2017-05-09 00:00:00

pages

1312-1317

issue

10

eissn

0007-0920

issn

1532-1827

pii

bjc201791

journal_volume

116

pub_type

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