Effect of oral posaconazole on the pharmacokinetics of cyclosporine and tacrolimus.
OBJECTIVE
To analyze the pharmacokinetic properties of the immunosuppressants cyclosporine and tacrolimus when either is coadministered with oral posaconazole.


METHODS
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.


METHODS
One clinical investigative center in the United States and one in the United Kingdom.


METHODS
Four adult heart transplant recipients in the cyclosporine study and 36 healthy adult volunteers in the tacrolimus study.


METHODS
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.


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.


CONCLUSIONS
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.
Sansone-Parsons
Angela
A
Schering-Plough Research Institute, Kenilworth, New Jersey, USA. angela.sansone@spcorp.com
Krishna
Gopal
G
Martinho
Monika
M
Kantesaria
Bhavna
B
Gelone
Steven
S
Mant
Tim G
TG
D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D014230:Triazoles; C101425:posaconazole; D016572:Cyclosporine; D016559:Tacrolimus