Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139-4242, USA.
Br J Clin Pharmacol. 2013 Feb;75(2):431-9. doi: 10.1111/j.1365-2125.2012.04345.x.
To evaluate the effects of ketoconazole, rifampicin and efavirenz on the pharmacokinetics of telaprevir in healthy volunteers.
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.
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).
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.
评估酮康唑、利福平、依非韦伦对健康志愿者体内特拉匹韦药代动力学的影响。
描述了三项临床研究的结果。（1）志愿者单次接受 750mg 特拉匹韦，同时单次给予 400mg 酮康唑。（2）志愿者（a）单次接受 1250mg 特拉匹韦，然后每 8 小时给予 3 次 750mg 剂量；（b）每 8 小时给予 4 次 1250mg 特拉匹韦，同时第 4 次给予 400mg 酮康唑。（3）志愿者单次接受 750mg 特拉匹韦，同时或不接受每日 600mg 利福平，或每 8 小时接受 750mg 特拉匹韦，同时或不接受每日 600mg 依非韦伦。
单次给予 400mg 酮康唑使单次给予特拉匹韦的暴露量增加：C(max) 的几何均数最小二乘比（GLSMR，90%置信区间）为 1.24（1.10，1.41），AUC(0,∞)为 1.62（1.45，1.81）。然而，在多次给予特拉匹韦后，酮康唑对特拉匹韦暴露量没有明显影响。稳态时联合利福平可显著降低单次给予特拉匹韦的暴露量，C(max) 的 GLSMR 为 0.14（0.11，0.18），AUC(0,∞)为 0.08（0.07，0.11），而当两种药物同时稳态给予时，依非韦伦对特拉匹韦的暴露量影响较小，C(max)、C(min)、AUC(0,8 h)的 GLSMR 分别为 0.91（0.81，1.02）、0.53（0.44，0.65）、0.74（0.65，0.84）。
根据其效力，CYP3A 诱导剂利福平、依非韦伦可不同程度地降低特拉匹韦的暴露量。酮康唑作为特拉匹韦代谢抑制剂的作用在单次给予特拉匹韦后比重复给予时更为明显。
