Intrapatient Variability in Trough Drug Concentrations in Renal Transplant Patients Receiving Branded (Prograf®) and Generic (Adoport®) Tacrolimus: A Retrospective Cohort Analysis.

Abstract

Introduction Tacrolimus has a narrow therapeutic index; subtherapeutic blood concentrations are associated with inadequate immunosuppression, while acutely high calcineurin inhibitor concentrations may cause nephrotoxicity. High intrapatient variability in trough tacrolimus blood concentrations in the period 6-12 months post-renal transplant is associated with a higher risk of graft failure(Borra,et al. Nephrol Dial Trans 2010;25:2757). The initiator brand of twice-daily tacrolimus (Prograf®) came off-patent in April 2008. Many centres have since moved to a generic formulation (such as Adoport®), leading to considerable interest in comparing pharmacokinetic and clinical profiles of generics with Prograf®. Currently there are no published data on intrapatient variability for patients receiving generic tacrolimus preparations. Methods Our centre switched from Prograf® (initiator) to Adoport® (generic) for de novo renal transplant patients on 1 July 2012. We performed a retrospective cohort study to examine the degree of intrapatient variability in tacrolimus concentration at 6-12 months post-transplant, in patients started on Prograf® and an equivalent cohort started on Adoport® at induction. Trough tacrolimus concentrations measured by immunoassay in outpatient clinics in the 6-12 month period were retrospectively reviewed and adjusted for dose. Intrapatient variability was calculated as coefficient of variation. Results In our preliminary findings from 52 patients (27 on Prograf® and 25 on Adoport®), there was no significant difference in intrapatient variability according to tacrolimus formulation (coefficients of variation 29.9%±14.6 vs 31.4%±16.1, p=0.71). This sample size would detect a net difference in coefficient of variation of 12% with 80% power. This is less than the difference in mean coefficient of variation between the high- and low-variability groups in Borra et al (14.6%), suggesting that we would be likely to detect any clinically significant difference. There was no statistically significant difference between the number of dose changes with Prograf® and Adoport® (0.57±0.78 vs 1.0±0.95 per 100 days of follow-up, p=0.057) but this requires more investigation with a larger sample size. Conclusion Preliminary analysis has found no difference in intrapatient variability of trough tacrolimus concentrations between renal transplant patients taking Prograf® and Adoport®. DISCLOSURES:Popoola, J.: Grant/Research Support, Astellas (manufacturer of Prograf), Financial support of research and conferences, Sandoz (manufacturer of Adoport), Financial support of research and conferences. MacPhee, I.: Grant/Research Support, Astellas (manufacturer of Prograf), Speaker's Bureau, Astellas (manufacturer of Prograf), Speaker honaria;, conference expenses.