The effect of CYP3A inhibitors and inducers on the pharmacokinetics of telaprevir in healthy volunteers.
OBJECTIVE
To evaluate the effects of ketoconazole, rifampicin and efavirenz on the pharmacokinetics of telaprevir in healthy volunteers.


METHODS
Results from three clinical studies are described. (1) Volunteers received a single 750 mg dose telaprevir with and without a single 400 mg dose ketoconazole. (2) Volunteers received (a) 1250 mg telaprevir followed by three 750 mg doses given every 8 h and (b) four 1250 mg telaprevir doses given every 8 h, with a single 400 mg dose ketoconazole given with the fourth dose of telaprevir. (3) Volunteers received either a single 750 mg dose telaprevir with or without 600 mg once daily rifampicin, or 750 mg every 8 h telaprevir with and without 600 mg once daily efavirenz.


RESULTS
A single 400 mg dose of ketoconazole increased single dose telaprevir exposure: the geometric least-squares mean ratio (GLSMR, with 90% confidence limits) was 1.24 (1.10, 1.41) for C(max) and 1.62 (1.45, 1.81) for AUC(0,∞). However, after multiple doses of telaprevir, there was no discernible effect of ketoconazole on telaprevir exposure. Co-administration of rifampicin at steady-state markedly reduced single dose telaprevir exposure with GLSMRs of 0.14 (0.11, 0.18) for C(max) and 0.08 (0.07, 0.11) for AUC(0,∞), whereas efavirenz had a smaller effect on telaprevir exposure when both drugs were co-administered at steady-state, with GLSMRs of 0.91 (0.81, 1.02) for C(max) , 0.53 (0.44, 0.65) for C(min), and 0.74 (0.65, 0.84) for AUC(0,8 h).


CONCLUSIONS
CYP3A inducers, rifampicin and efavirenz, can reduce telaprevir exposure to varying degrees based on their potency. The effect of ketoconazole as an inhibitor of telaprevir metabolism is more pronounced after a single dose of telaprevir than after repeated administration.
Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139-4242, USA. varun_garg@vrtx.com
Varun
V
Garg
Gurudatt
G
Chandorkar
Yijun
Y
Yang
Nathalie
N
Adda
Lindsay
L
McNair
Katia
K
Alves
Frances
F
Smith
Rolf P G
RP
van Heeswijk
D000328:Adult; D000480:Alkynes; D019540:Area Under Curve; D048588:Benzoxazines / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D003521:Cyclopropanes; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004338:Drug Combinations; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C486464:telaprevir; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz; D007654:Ketoconazole; D012293:Rifampin