Effect of oral posaconazole on the pharmacokinetics of cyclosporine and tacrolimus

被引:113
作者
Sansone-Parsons, Angela
Krishna, Gopal
Martinho, Monika
Kantesaria, Bhavna
Gelone, Steven
Mant, Tim G.
机构
[1] Schering Plough Res Inst, Kenilworth, NJ USA
[2] Temple Univ, Sch Pharm, Philadelphia, PA 19122 USA
[3] Guys Hosp, Quintiles Guys Drug Res Unit, London SE1 9RT, England
来源
PHARMACOTHERAPY | 2007年 / 27卷 / 06期
关键词
posaconazole; tacrolimus; cyclosporine; drug interaction;
D O I
10.1592/phco.27.6.825
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Study Objective. To analyze the pharmacokinetic properties of the immunosuppressants cyclosporine and tacrolimus when either is coadministered with oral posaconazole. Design. Two single-center, open-label pharmacokinetic studies of cyclosporine in a multiple-dose design and of tacrolimus in a one-sequence, crossover, single- and multiple-dose design. Setting. One clinical investigative center in the United States and one in the United Kingdom. Subjects. Four adult heart transplant recipients in the cyclosporine study and 36 healthy adult volunteers in the tacrolimus study. Interventions. In the cyclosporine study, patients who took an established cyclosporine dose 3 times/day for 6 weeks or longer were given posaconazole. 200 mg/day for 10 days. In the tacrolimus study, subjects received tacrolimus 0.05 mg/kg/day on days 1 and 14 and posaconazole 400 mg twice/day on days 7-14. Measurements and Main Results. In the cyclosporine study, blood samples were collected on day 1 to determine cyclosporine pharmacokinetics and on day 10 to measure the pharmacokinetics of cyclosporine and posaconazole. Coadministration of posaconazole increased cyclosporine exposure and necessitated dosage reductions of 14-29% for cyclosporine in three subjects. In the tacrolimus study, blood samples were collected on days 12-14 to assess posaconazole pharmacokinetics and on days 1 and 14 for as long 72 hours after dosing to evaluate tacrolimus pharmacokinetics. Posaconazole increased the maximum blood concentration and the area under the concentration-time curve for tacrolimus by 121% and 358%, respectively, on day 14 compared with day 1 (both p=0.001). In both studies, posaconazole pharmacokinetics were unaffected. Conclusion. These findings suggest that the dosage of cyclosporine or tacrolimus should be reduced when posaconazole therapy is started and that plasma levels of the immunosuppressant should be monitored during and at the discontinuation of posaconazole therapy so that dosages are adjusted accordingly. This recommendation is consistent with current standard of care for patients receiving cyclosporine or tacrolimus with concomitant azole antifungal therapy.
引用
收藏
页码:825 / 834
页数:10
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