title: Apparent low absorbers of cyclosporine microemulsion have higher requirements for tacrolimus in renal transplantation.
abstract: Bioavailability and exposure of cyclosporine microemulsion and tacrolimus in renal transplantation are governed by many complex factors. Failure to achieve therapeutic two-h post-dose (C(2)) levels despite adequate doses of cyclosporine ("low absorbers") may merit conversion to tacrolimus. We compared tacrolimus dose requirements in "low absorbers" (n = 15) with a random control group of de novo tacrolimus patients (n = 14). Low absorbers failed to reach target C(2) despite increasing dose from 10.1 to 16.2 mg/kg/d. At conversion the mean C(2) was 969 ng/mL (95% CI: 684-1255; target 1700 ng/mL). Low absorbers tended to be younger, heavier, and diabetic. Despite a similar initial tacrolimus dose (0.17-0.18 mg/kg/d), low absorbers required a much higher daily dose to achieve target; 0.25 vs. 0.16 mg/kg/d (p = 0.016). Furthermore, daily maintenance tacrolimus remained much higher in low absorbers at three wk (0.22 vs. 0.13 mg/kg/d, p = 0.012). Although not statistically significant, this group experienced an acute rejection rate of 33%, compared with 21% in the control group. Patients treated with cyclosporine as initial immunosuppression who fail to reach target C(2) levels in a timely fashion are at risk for impaired bioavailability of tacrolimus. Based on our data, a starting dose of 0.25 mg/kg/d in divided doses may be warranted for low absorbers converting to tacrolimus; however, we encourage larger studies with formal pharmacokinetic analysis in this population.
authors.affiliation: Department of Medicine, University of Western Ontario, and Multi-Organ Transplant Unit, University of Western Ontario and London Health Sciences Centre, London, ON, Canada. andrew.house@lhsc.on.ca
authors.forename: Andrew A
authors.initials: AA
authors.lastname: House
authors.forename: Mostafa
authors.initials: M
authors.lastname: Elmestiri
authors.forename: Kathy
authors.initials: K
authors.lastname: Denesyk
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Luke
authors.forename: Norman
authors.initials: N
authors.lastname: Muirhead
authors.forename: Faisal
authors.initials: F
authors.lastname: Rehman
authors.forename: Neil
authors.initials: N
authors.lastname: Boudville
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Jevnikar
mesh_terms: D000042:Absorption; D000328:Adult; D001682:Biological Availability; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004655:Emulsions; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000378:metabolism* / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000493:pharmacokinetics*
chemical_list: D004655:Emulsions; D007166:Immunosuppressive Agents; D008055:Lipids; D016572:Cyclosporine; D003404:Creatinine; D016559:Tacrolimus