Influence of high-dose ketoconazole on the pharmacokinetics of docetaxel.
OBJECTIVE
The pharmacokinetics (PK) of docetaxel are characterized by large inter-individual variability in systemic drug exposure (AUC) and drug clearance. The PK variability is thought to be largely related to differences in the catalytic function of CYP3A, involved in docetaxel metabolism and elimination. As variability in efficacy and toxicity is associated with variability in docetaxel AUC and clearance, reducing inter-individual PK variability may help improve the risk-benefit ratio of docetaxel therapy. We investigated if high-dose ketoconazole, a potent CYP3A inhibitor, could result in a uniform reduction of docetaxel clearance and reduce the inter-individual variability in docetaxel AUC and clearance.


METHODS
Seven patients were treated in a randomized-cross over design with intravenous docetaxel (100 mg/m(2)) followed 3 weeks later by docetaxel (15 mg/m(2)) given in combination with orally administered ketoconazole (400 mg 3 times daily, up to 47 hours after docetaxel infusion) or vice versa. Docetaxel plasma concentration-time data were described by a three-compartment PK model. Ketoconazole plasma concentration-time data were described by a one-compartment PK model.


RESULTS
Docetaxel clearance was reduced by 50% (P = .018) from 32.8 +/- 13.7 L/hr to 16.5 +/- 8.15 L/hr upon ketoconazole coadministration, albeit with large inter-individual variability (fractional change in clearance, range 0.31 - 0.66). In the presence of ketoconazole, inter-individual variability in clearance and AUC, expressed as coefficient of variation, was increased from 41.6 to 49.5% and from 28.0 to 35.1%, respectively, and not, as we had hypothesized, reduced.


CONCLUSIONS
Inhibition of CYP3A by concomitant high-dose ketoconazole administration does not result in a uniform reduction of docetaxel clearance and does not reduce the inter-individual variability in docetaxel AUC or clearance. This approach is unsuitable as method to achieve a uniform docetaxel PK profile.
Engels
Frederike K
FK
Department of Medical Oncology, Daniel den Hoed Cancer Center, Erasmus MC, Rotterdam, the Netherlands. f.engels@erasmusmc.nl
Mathot
Ron A A
RA
Loos
Walter J
WJ
van Schaik
Ron H N
RH
Verweij
Jaap
J
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D020641:Polymorphism, Single Nucleotide; D043823:Taxoids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000972:Antineoplastic Agents, Phytogenic; D065692:Cytochrome P-450 CYP3A Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole