Effect of CYP2D6 genetic polymorphism on the population pharmacokinetics of tipifarnib.
OBJECTIVE
Evaluate the effect of CYP2D6 genotype on the pharmacokinetics of tipifarnib.


METHODS
A total of 268 subjects included in six clinical trials were treated orally with tablet formulation of tipifarnib, as a single dose or as multiple b.i.d. doses (range 50-600 mg), and/or intravenously following 1, 2, and 24 h infusions. A total of 2,575 tipifarnib concentrations were fitted to an open three-compartment linear disposition model with sequential zero-order input into the depot compartment, followed by a first-order absorption process, and lag time, using NONMEM V. The effect of CYP2D6 genotype was explored as a covariate for tipifarnib systemic clearance and absolute bioavailability. Likelihood ratio test was used to compare these parameters in homozygous extensive metabolizers (EM) (N=152), heterozygous EM (N=97), or poor metabolizers (PM) (N=19). Computer simulations were undertaken to explore the CYP2D6 genotype effect on the tipifarnib pharmacokinetics.


RESULTS
The ratio of tipifarnib systemic clearance for the heterozygous EM and the PM subjects, relative to the homozygous EM group, were 0.95 (95%CI 0.87-1.03) and 0.96 (95%CI 0.82-1.11), respectively (chi2=2.376, df=2, P=0.305). The ratio of tipifarnib absolute bioavailability for the heterozygous EM and the PM, relative to the homozygous EM, were 1.06 (95%CI 0.83-1.30) and 0.95 (95%CI 0.55-1.34), respectively (chi2=1.398, df=2, P=0.497).


CONCLUSIONS
These results indicate that CYP2D6 genetic polymorphism does not appreciably influence the pharmacokinetics of tipifarnib. Hence, concomitant administration of potent CYP2D6 inhibitors is anticipated to have little or no significant impact on the systemic exposure to tipifarnib.
Clinical Pharmacology and Experimental Medicine Division, Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica NV. Turnhoutseweg 30, 2340, Beerse, Belgium. jperezru@prdbe.jnj.com
Juan Jose
JJ
Perez-Ruixo
Peter
P
Zannikos
Vural
V
Ozdemir
Monique A
MA
Franc
Stephan
S
Francke
Vladimir
V
Piotrovsky
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001682:Biological Availability; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005260:Female; D005838:Genotype; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D015363:Quinolones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D004791:Enzyme Inhibitors; D015363:Quinolones; D019389:Cytochrome P-450 CYP2D6; D051231:Farnesyltranstransferase; C402769:tipifarnib