Evidence for Earlier Stabilization of Cyclosporine Pharmacokinetics in De Novo Renal Transplant Patients Receiving a Microemulsion Formulation

Abstract

Sequential cyclosporine pharmacokinetic assessments were performed at four centres within the context of a double-blind, multicenter clinical trial comparing the safety and tolerability of the conventional formulation with cyclosporine for microemulsion in de novo renal transplant patients. The initial average daily oral dose was 9.3 mg/kg given in two divided doses every 12 hr with subsequent dose reductions individually titrated to maintain trough concentrations within the target therapeutic range. Pharmacokinetic profiles were assessed at week 2, once between weeks 4-6, and at week 12 in 12 patients on the conventional formulation and 9 patients on the microemulsion. Over the study duration, cyclosporine daily doses were comparable in both study arms and were reduced in parallel from 9.2 to 6.9 to 4.7 mg/kg/day at the three successive pharmacokinetic visits. Dose-normalized peak and area-under-the-curve (AUC) increased between the week 2 and week 4-6 assessments for both formulations. Thereafter, these parameters continued to increase for the conventional formulation but exhibited a high degree of within-in patient stability for the microemulsion between week 4-6 and week 12. Between-formulation comparisons indicated that the rate and extent of cyclosporine absorption from the microemulsion were significantly higher over the study duration. Specifically, at week 2, 4-6 and 12, dose-normalized AUC was 49%, 63%, and 32% higher for the microemulsion. Intrasubject coefficients of variability for pharmacokinetic parameters of the conventional formulation ranged from 26.3% to 68.2%. Corresponding values for the microemulsion were reduced by approximately half, ranging from 13.1% to 38.7%. The correlation between predose trough concentration and AUC was stronger for the microemulsion (r(2)0.819 vs. 0.635) over the full range of systemic exposures attained throughout the study. These results provide initial evidence that, as doses are reduced with time posttransplant, the cyclosporine dose-exposure relationship from the microemulsion may stabilize earlier than that from the conventional formulation, allowing increased pharmacokinetic control over cyclosporine use in this critical posttransplant period.

Time-dependent changes in cyclosporine exposure: implications for achieving target concentrations

“…No differences were observed when we compared CO, Cmax, C12, AUC, or Cavg obtained at day 4 or month 2, although doses were 88% higher at day 4. From month 2 to month 6, no differences were observed on dose-adjusted pharmacokinetic parameters, which suggests that pharmacokinetic stability had been achieved by month 2, as previously demonstrated by Kovarik et al [26].…”

“…It is unlikely that the magnitude of differences observed in dose-adjusted cyclosporine pharmacokinetic parameters is exclusively due to lack of doseeconcentration linearity at cyclosporine doses used early after transplantation. Moreover, the changes in pharmacokinetics did not correlate with the increase in hemoglobin over time [26].…”

“…During this period, physiological and biochemical changes are greater and complicated by anesthesia and postoperative ileus, all significantly affecting the absorption of orally delivered drugs [12] and increasing the risk of acute rejection due to insufficient drug exposure [ 121. Although therapeutic cyclosporine concentrations can be achieved more rapidly and with lower doses of cyclosporine microemulsion than with the oil-based formulation [l], the higher initial cyclosporine doses necessary during this period complicate cyclosporine dose adjustment, because these doses lie outside the linear doseconcentration range [26,381. Alternatively, pre-transplant cyclosporine test doses, which could minimize this difficulty, have failed to predict consistently and accurately initial doses in the majority of patients and are very difficult to determine, especially in recipients of cadaveric allografts [7].…”

Decreased cyclosporine exposure during the remission of nephrotic syndrome

“…Patient 6 was in remission during both pharmacokinetic profiles, and is the only one in whom the AUC was higher at 24 weeks. A higher CsA bioavailability over time has been reported in transplant recipients [37,38] and has been attributed to increased cyclosporine binding to blood components (rise in hematocrit), rather than changes in metabolism or elimination. In our study, the difference in hematocrit between 1 and 24 weeks was not statistically significant.…”

Immunosuppressive agents in transplantation: Mechanisms of action and current anti-rejection strategies

“…CsA microemulsion has been accepted as a superior vehicle for oral administration and produces more linear, rapid, constant and complete absorption of CsA than previous formulations. 7,8 Microemulsion decreases both interpatient and intrapatient variability of CsA levels, 9,10 resulting in more predictable pharmacokinetics. 11 Tacrolimus (FK506).…”