Jm. Kovarik et al., EVIDENCE FOR EARLIER STABILIZATION OF CYCLOSPORINE PHARMACOKINETICS IN DE-NOVO RENAL-TRANSPLANT PATIENTS RECEIVING A MICROEMULSION FORMULATION, Transplantation, 62(6), 1996, pp. 759-763
Sequential cyclosporine pharmacokinetic assessments were performed at
four centres within the context of a double-blind, multicenter clinica
l trial comparing the safety and tolerability of the conventional form
ulation with cyclosporine for microemulsion in de novo renal transplan
t patients, The initial average daily oral dose was 9.3 mg/kg given in
two divided doses every 12 hr with subsequent dose reductions individ
ually titrated to maintain trough concentrations within the target the
rapeutic 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 durati
on, cyclosporine daily doses were comparable in both study arms and we
re reduced in parallel from 9.2 to 6.9 to 4.7 mg/kg/day at the three s
uccessive pharmacokinetic visits, Dose-normalized peak and area-under-
the-curve (AUG) increased between the week 2 and week 4-6 assessments
for both formulations, Thereafter, these parameters continued to incre
ase for the conventional formulation but exhibited a high degree of wi
thin-patient stability for the microemulsion between week 4-6 and week
12, Between-formulation comparisons indicated that the rate and exten
t 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 paramet
ers of the conventional formulation ranged from 26.3% to 68.2%, Corres
ponding values for the microemulsion were reduced by approximately hal
f,ranging from 13.1% to 38.7%. The correlation between predose trough
concentration and AUC was stronger for the microemulsion (r(2) 0.819 v
s. 0.635) over the full range of systemic exposures attained throughou
t the study, These results provide initial evidence that, as doses are
reduced with time posttransplant, the cyclosporine dose-exposure rela
tionship from the microemulsion may stabilize earlier than that from t
he conventional formulation, allowing increased pharmacokinetic contro
l over cyclosporine use in this critical posttransplant period.