Polymorphisms of multidrug resistance gene (MDR1) and cyclosporine absorption in de novo renal transplant patients.

BACKGROUND: Several single nucleotide polymorphisms (SNPs) in the multidrug resistance (MDR1) gene may play a role in the interindividual variation of cyclosporine A (CsA) absorption in renal transplant patients. METHODS: An analysis of CsA absorption measured by the dose- and weight-adjusted 4 hr area under the time-concentration curve, AUC(0-4)/mg doseCsA/kg, was conducted on day 3 after transplantation, in 69 de novo renal transplant patients who were genotyped for MDR1 SNPs. Follow-up pharmacogenomic analysis at 1 month posttransplant was performed utilizing dose- and weight-adjusted 2-hour postdose CsA concentration (C2). RESULTS: AUC(0-4)/mg doseCsA/kg was significantly higher (P=0.024) in (C/C)3435 individuals than in a grouped population of (C/T)3435 and (T/T)3435 patients on postoperative day 3. G2677T variants were not significantly correlated with CsA absorption (P=0.084). The number of C3435-G2677 haplotypes was the best predictor of CsA exposure. At 1 month posttransplant, no correlation was seen between MDR1 SNPs and CsA exposure. The frequency of wild-type variants for C3435T and G2677T were 61% and 77.6%, respectively. SNPs at G2677T and C3435T loci were found to be in linkage disequilibrium. CONCLUSIONS: MDR1 polymorphisms are associated with differences in CsA exposure only in the first posttransplant week.

Early recurrence of primary focal segmental glomerulosclerosis in an older cadaveric renal allograft recipient resistant to plasmapheresis.

We report an unusual case of recurrent primary focal segmental glomerulosclerosis in an apparent low-risk cadaveric renal allograft recipient only 2 days after transplantation, who did not respond to repeated courses of plasmapheresis.

An economic model of 2-hour post-dose ciclosporin monitoring in renal transplantation.

BACKGROUND: Monitoring of microemulsion ciclosporin (cyclosporine; Neoral) by 2-hour post-dose drug concentrations (C2) is an accurate measure of ciclosporin absorption efficiency and exposure, and appears superior to trough (C0) monitoring for prediction of rejection risk. A predictive decision model was used to determine if this approach also reduces total treatment costs in the first 12 months after renal transplantation. METHODS: Parameter estimates for key clinical events were derived from the literature and from prospective pharmacokinetic studies comprising 234 adult HLA-non-identical renal graft recipients at seven Canadian centres. Patients were treated with microemulsion ciclosporin (Neoral), corticosteroids and azathioprine or mycophenolate mofetil. Using the perspective of the Canadian healthcare provider, total treatment costs for the C2 versus the C0 strategy were modelled over 12 months, and then remodelled using conservative estimates to extend the timeframe to 5 years. Health resources were valued in 1999 Canadian dollars. RESULTS: The incidence of acute rejection was estimated to be 25% at 1 year in patients monitored by C0 and 18% in those monitored by C2. Patient survival was considered to be independent of monitoring strategy, and graft loss was predicted to be 1.4% lower in the C2 group. The studies suggested no important differences in comorbidity and the costs of C0 and C2 monitoring and ambulatory-based adverse events were held equivalent. Using these inputs, the average cost per patient for the first year post-transplant was Can dollars 46,857 for C0 monitoring and Can dollars 45,306 for C2 monitoring, rising to Can dollars 146,879 and Can dollars 142,569 after 5 years. The predicted cost for initial hospitalisation was Can dollars 11,280 for C0 and Can dollars 10,806 for C2 monitoring. The cost of maintenance immunosuppressive drug use, graft loss and dialysis was Can dollars 19,098 in the C0 group and Can dollars 18,612 in the C2 group, while acute rejection treatment costs were Can dollars 2169 and Can dollars 1577, respectively. An additional Can dollars 14,310 was consumed by other events, including repeat hospitalisation, for each group. Sensitivity analysis indicated that the most influential parameters affecting savings due to C2 monitoring were a reduction in the duration of initial and follow-up hospitalisations and reduced risks of acute rejection and subsequent graft loss. CONCLUSIONS: Compared with traditional trough concentration monitoring, ciclosporin monitoring at 2 hours post-dose produced a predicted saving of Can dollars 1551 during the first year after renal transplant. Although modelling assumptions become more restrictive over time, this projection allows a preliminary assessment of the long-term economic impact of the routine use of C2 monitoring.

Early adequate mycophenolic acid exposure is associated with less rejection in kidney transplantation.

This study examines the importance of early mycophenolic acid (MPA) exposure in the cyclosporine- and mycophenolate mofetil (MMF)-treated kidney transplant population. We prospectively evaluated 94 first solitary kidney transplant patients treated with cyclosporine (Neoral), MMF, and prednisone. Basiliximab was also given to 72 recipients. MPA exposure was measured by HPLC using a limited sampling estimate of 12 h area under the curve (AUC [0-12]) within the first week. Efficacy was determined by the occurrence of acute rejection and toxicity by the need to reduce MMF doses within the first 3 months post-transplantation. Acute rejection was observed in 14 (15%) and MMF toxicity in 27 (29%). Receiver operator curve analysis shows that MPA AUC [0-12] on day 3 was predictive of efficacy (c = 0.72, p = 0.007) but not toxicity (c = 0.57, p = 0.285). A separate analysis of only patients on basiliximab shows that the MPA AUC [0-12] on day 3 was also predictive of efficacy (c = 0.80, p = 0.01). Therefore early adequate exposure to MPA by day 3 is associated with low acute rejection but cannot predict toxicity. Adequate MPA exposure is also important with basiliximab induction therapy.

Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients.

Cyclosporine (CsA) is a critical-dose drug for which a minor change in absorption can have important clinical implications. Generic formulations of CsA are becoming more widely available, but standard criteria for bioequivalence require only that a single study in healthy volunteers demonstrate that mean pharmacokinetic parameters fall within 80-125% of the mean values for Neoral, the reference formulation of CsA. However, CsA absorption is known to differ between healthy volunteers and transplant patients and between different types of transplant patients, such that standard bioequivalence testing may be inadequate to ensure interchangeability of CsA formulations in all patients. The limited available clinical evidence has shown that stable renal transplant patients receiving Neoral have a significant reduction in mean CsA trough level after transfer to the Cicloral formulation. Mean pharmacokinetic values have been reported as equivalent following transfer to Gengraft in one study, but mean CsA trough fell and mean serum creatinine rose significantly in a separate trial. The only clinical outcomes data available are from a retrospective study of de novo renal transplant patients, which reported a significantly higher incidence of biopsy-proven acute rejection in patents receiving Gengraf versus Neoral (39% versus 25%, P<0.05). Until robust clinical data demonstrate that different formulations of CsA are interchangeable, it is advisable to prescribe CsA by brand, and any transfer to a different CsA formulation should be undertaken with close supervision and only at the direction of the transplant physician.

A pharmacokinetic and clinical review of the potential clinical impact of using different formulations of cyclosporin A. Berlin, Germany, November 19, 2001.

A meeting of 14 transplant and pharmacokinetic specialists from Europe and North America was convened in November 2001 to evaluate scientific and clinical data regarding the use of different formulations of cyclosporin A (CsA). The following consensus was achieved. (1) CsA is a critical-dose drug with a narrow therapeutic window. Clinical outcomes after transplantation are affected by the pharmacokinetic properties of CsA, particularly by its bioavailability, and by intrapatient variability in CsA exposure. (2) Standard bioequivalence criteria do not address differences in CsA pharmacokinetics between transplant recipients and healthy volunteers, or between subpopulations of transplant recipients. (3) In some circumstances, currently available formulations of CsA that meet standard bioequivalence criteria are likely to be nonequivalent with respect to pharmacokinetic characteristics. (4) The choice of CsA formulation can affect the short- and long-term clinical outcome. Currently, there is a lack of clinical comparisons between generic CsA formulations and the Neoral formulation (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey). Initial retrospective data from the Collaborative Transplant Study suggest that use of generic CsA formulations may result in reduced graft survival at 1 year. (5) Management of transplant recipients by monitoring Neoral concentrations 2 hours after dosing (C(2)) reduces the incidence and severity of acute rejection compared with monitoring of trough concentrations with no increase in toxicity. C(2) monitoring has been developed based on the pharmacokinetics of Neoral only and has not been evaluated or validated for generic formulations of CsA. (6) The major costs of care after transplantation relate to the management of poor clinical outcomes and toxicity. CsA formulations with different pharmacokinetic properties may be associated with varying clinical outcomes, which would be expected to affect total health care costs. (7) The transplant physician is responsible for selecting immunosuppressive agents and formulations for his or her patients. Any switch between CsA formulations in a particular patient should take place only in a controlled setting with adequate pharmacokinetic monitoring.

Approaching the therapeutic window for cyclosporine in kidney transplantation: a prospective study.

Neoral dosing is traditionally based on cyclosporine (CyA) trough levels (C(0)). Four-h area under the curve (AUC(0-4)) for Neoral in the early posttransplantation period was shown previously to have a better correlation to acute rejection (AR) and CyA nephrotoxicity (CyANT), compared with C(0). An AUC(0-4) range of 4400 to 5500 microg/h per L during the first week was associated with the lowest AR and CyANT. This article describes a prospective study to assess the feasibility, safety, and efficacy of dosing Neoral solely by AUC(0-4) monitoring, regardless of C(0), in the first 3 mo after kidney transplantation. Fifty-nine kidney transplant recipients received Neoral-based triple immunosuppression. AUC(0-4) was measured on days 3, 5, 7, 10, and 14 and weeks 3, 4, 6, and 8, then monthly. Target AUC(0-4) was 4400 to 5500 microg/h per L. Dose was adjusted by percentage difference from target AUC(0-4). Ninety-four percent of AUC were performed on the scheduled day or close to it. No patients had CyANT while AUC(0-4) was in target range. Four patients had reversible CyANT with AUC(0-4) > 5500. Only 1 of 33 patients (3%) who achieved and maintained AUC(0-4) > 4400 by day 3 posttransplantation had AR, whereas 10 of 22 (45%) of those with day 3 to 5 AUC(0-4) < 4400 had AR (P: = 0.0002). In logistic regression analysis, higher early AUC(0-4) was the only significant variable associated with lower serum creatinine at 3 mo. Neoral dose monitoring by AUC(0-4) is a potentially valuable tool for optimizing Neoral immunosuppression. Attainment of a target range of 4400 to 5500 microg/h per L for AUC(0-4) early after transplantation has been demonstrated to reduce significantly the risk of AR and CyANT.