Differentiation of innovator versus generic cyclosporine via a drug interaction on sirolimus.
OBJECTIVE
Both sirolimus and cyclosporine are immunosuppressants used in a combined regimen after organ transplantation. When coadministered with the innovator formulation of cyclosporine, sirolimus blood levels increase 3.3-fold due to a pharmacokinetic interaction. We assessed this drug interaction for potential differences when the innovator formulation is replaced by a generic cyclosporine.


METHODS
In this randomized single-dose crossover study, 28 healthy subjects received 5 mg sirolimus oral solution with 250 mg cyclosporine soft gelatin capsules given as the innovator formulation (reference treatment) versus a generic formulation (test treatment). Sirolimus peak blood concentration (Cmax) and area under the concentration-time curve (AUC) were compared between test and reference treatments by standard bioequivalence testing.


RESULTS
Sirolimus Cmax was significantly lower by 17% in the presence of generic versus innovator cyclosporine (p=0.0003) and failed bioequivalence criteria with a test/reference ratio of 0.83 (90% confidence interval, 0.77-0.90). Nearly half of the subjects (46%) had sirolimus Cmax changes which fell outside the bioequivalence window with individual Cmax decreases up to 52% and increases up to 39%. Sirolimus AUC was significantly lower by 11% in the presence of generic versus innovator cyclosporine (p=0.041) but satisfied average bioequivalence criteria with a test/reference ratio of 0.89 (0.83-0.95). Nonetheless, over a third of the subjects (43%) had sirolimus AUC changes outside the standard bioequivalence window with individual AUC decreases up to 39% and increases up to 42%.


CONCLUSIONS
Switching between innovator and generic cyclosporine may have a clinically-relevant impact on coadministered sirolimus pharmacokinetics. If such a switch is initiated by the prescriber, follow-up therapeutic monitoring of both cyclosporine and sirolimus blood levels should be performed to guide dose adjustments as necessary. If the switch is made without consulting the prescriber, potentially significant changes in sirolimus exposure could go unnoticed by the clinician and patient.
Novartis Pharmaceuticals, Building WSJ 103.426, 4002 Basel, Switzerland. john.kovarik@novartis.com
John M
JM
Kovarik
Adele
A
Noe
Yibin
Y
Wang
Irene
I
Mueller
Gilberto
G
DeNucci
Robert L
RL
Schmouder
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D004347:Drug Interactions; D011307:Drug Prescriptions; D004359:Drug Therapy, Combination; D016568:Drugs, Generic; D005215:Fasting; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency; D013997:Time Factors
D016568:Drugs, Generic; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus