Neil Leaver

ATP-binding cassette subfamily B member 1 polymorphisms do not determine cyclosporin exposure, acute rejection or nephrotoxicity after heart transplantation.

Background. We hypothesized that genetic variation of ATP-binding cassette subfamily B member 1 (ABCB1) that encodes P-glycoprotein (involved in the uptake of cyclosporin A [CsA]) contributes to trough drug concentrations and thereby to CsAs immunosuppressive and toxic effects. Methods. Three hundred thirty-seven adult heart transplant recipients were studied retrospectively. White recipients receiving CsA at month 3 and years 1 to 5 after transplantation (n=192, 168, 156, 130, 95, and 74, respectively) were then studied with respect to ABCB1 genotype or haplotype and CsA disposition. Genotyping was performed using a gel-based polymerase chain reaction method. Dose- and weight-adjusted CsA trough concentrations ([&mgr;g/L]/[mg/kg]), time to first endomyocardial biopsy-proven acute rejection episode (grade≥3A), weaning from steroids at 1 year, and renal function at 1 year posttransplant were measured. Results. An association between dose- and weight-adjusted CsA trough concentrations and ABCB1 haplotypes was found, with 12/1236, 21/2677, 26/3435 CC/GG/CC individuals having significantly higher concentrations than TT/TT/TT individuals at years 1 and 5 (68.9±26.9 vs. 54.9±19.5 and 70.6±35 vs. 50.0±12.2 [&mgr;g/L]/[mg/kg] P<0.05, respectively) There was no difference in the incidence of acute rejection, steroid weaning, or renal impairment between the genotype or haplotype groups. Conclusions. The association of ABCB1 12/1236, 21/2677, and 26/3435 CC/GG/CC haplotype with increased CsA dose- and weight-adjusted CsA trough concentrations in this group of adult white heart transplant recipients was not consistent over time and had no effect on the incidence of acute rejection or on the development of renal impairment.

Transfer from ciclosporin to mycophenolate-sirolimus immunosuppression for chronic renal disease after heart transplantation: safety and efficacy of two regimens

BACKGROUND Chronic kidney disease is common after heart transplantation, and is related to ciclosporin (CsA) therapy. We compared the safety and efficacy of two ciclosporin withdrawal regimens. METHODS CsA was stopped and sirolimus (SRL) commenced immediately and the transfer was covered with prednisolone. Those on azathioprine (AZA) were transferred to MMF. In protocol A, the SRL target concentration was 16 (12-20) ng/ml; in protocol B, the target concentration was 7(5-10) ng/ml, but mycophenolate (MMF) and steroids were commenced prior to the transfer. RESULTS Baseline characteristics were similar in both groups except that group B were switched later after transplantation. Renal function improved significantly in both groups; this was maintained up to 1 year. Two patients in group A experienced acute rejection (ISHLT grade 3A or 2R); none was seen in group B. Six patients (46%) remained on protocol A and 22 (85%) remained on protocol B at 1 year. CONCLUSIONS MMF-SRL substitution resulted in a rapid but partial improvement in renal function; the lower dose SRL regimen was better tolerated.

A pharmacokinetic comparison of cyclosporin oral solution and cyclosporin capsules in heart and lung transplant recipients

Abstract  Pharmacokinetic profiles were obtained for 16 heart or lung recipients following the administration of identical doses of cyclosporin as oral solution and capsules on consecutive days. A comparison of pharmacokinetic parameters (AUC, Cmax, Cmin and tmax) showed that there were no significant differences between the two formulations except for the tmax, which was significantly longer for the capsules. The mean variation in day‐to‐day trough levels produced by the two different forms was 25.6%. A retrospective study was carried out of consecutive cyclosporin levels in patients at steady state on oral solution. The mean variation in day‐to‐day trough levels was 32.3%. This was not significantly different from the variation in consecutive trough levels seen in the oral solution/capsule comparison. This study shows that cyclosporin capsules can be substituted for oral solution without causing acute changes in cyclosporin blood levels, and that the pharmacokinetics of the two formulations are similar.