The Pharmacokinetics of a Microemulsion Formulation of Cyclosporine in Primary Renal Allograft Recipients1

Abstract

This study was a randomized, double-blind, 12-week comparison of the pharmacokinetics, safety, and tolerability of two cyclosporine (CsA) formulations, cyclosporine emulsion capsules and oral solution for microemulsion and cyclosporine, in the postoperative management of renal transplant patients. Of the 101 patients, aged 18 to 65, who entered the study, 89 were evaluable for pharmacokinetics. Initial dosage was 10 mg/kg per day, administered twice daily in two equal doses. Dosages were adjusted to achieve target CsA concentrations. The pharmacokinetic (PK) parameters (dose-normalized) of greatest interest were maximum blood concentration (C(max)/dose), time to reach maximum concentration (t(max), area under the blood concentration-vs.-time curve (AUC/dose), and trough blood concentrations (Co h/dose). The relative CsA bioavailabilty was found to be significantly enhanced with cyclosporine emulsion compared with cyclosporine with a 16% to 31% increase in AUC and a 32% to 42% increase in C(max). Intrapatient variability of PK parameters was significantly lower with cyclosporine emulsion than with cyclosporine for AUC, C(oh), t(max), and C(max) in many instances. This indicates a more consistent, rapid, and more complete total absorption of CsA. Despite higher CsA C(max) levels and AUCs with cyclosporine emulsion, safety and tolerability (detailed in a parallel report) were comparable to those of cyclosporine. The PK advantages of cyclosporine emulsion over cyclosporine are either independent of food conditions or possibly reflective of more consistent absorption of CsA with cyclosporine emulsion. The findings suggest that de novo use of cyclosporine emulsion may simplify and improve management of organ transplant recipients and that the PK advantages of cyclosporine emulsion may translate into clinical benefits.

Preparation, characterization and relative bioavailability of oral elemene o/w microemulsion

“…In other studies docetaxel o/w microemulsion is reported to have a relative bioavailability of 519.2% over taxotere, 6 while the relative bioavailabity of cyclosporine microemulsion was enhanced with a 16% to 31% increase in AUC and a 32% to 42% increase in C max. 13 Our findings with elemene microemulsion in this work were in agreement with the literature reports. Although the enhanced extent of bioavailability of the elemene microemulsion is a little less than desired, the surfactant content used is a little lower.…”

“…Although the enhanced extent of bioavailability of the elemene microemulsion is a little less than desired, the surfactant content used is a little lower. 6,13,14 These results encourage further development of elemene microemulsions as an oral drug delivery system.…”

Is Absorption Profile of Cyclosporine Really Important for Effective Immunosuppression?

“…However, C 0 monitoring was not very effective in preventing acute rejection and toxicity in clinical practice because the conventional CsA (Sandimmune; SIM) exhibited considerable inter-individual variability in pharmacokinetics due to an unstable absorption profiling. [6][7][8] Recently, introduction of the microemulsion formulation of CsA (Neoral; NEO), which has consistent absorption patterns and improved bioavailability, and has thus reduced inter-and intra-individual variability in pharmacokinetics, has enhanced the significance of TDM. [6][7][8] CsA exposure in the first 4 h postdose (AUC 0-4 ) or a single blood concentration measurement at 2 h postdose (C 2 ) was recommended as an effective monitoring strategy.…”

Apports récents de la pharmacologie des traitements immunosuppresseurs utilisés en transplantation d’organe

“…Même si les concentrations résiduelles (C0) n'ont qu'une mauvaise valeur prédictive individuelle [3], elles sont devenues le standard du suivi en raison de la facilité de leur réalisation pratique en clinique humaine puisque les patients viennent dans ce cas réaliser leurs examens sanguins à jeun et avant toute prise médicamenteuse. Lors de l'introduction d'une nouvelle forme galénique de CsA (microémulsion ou Néoral ® ), des profils pharmacocinétiques complets ont été réalisés [4,5]. Ces études ont démontré que l'exposition à la CsA pendant les 4 premières heures suivant l'administration (aire sous la courbe de 0 à 4 heures ou AUC 0-4 ) était corrélée à l'AUC durant l'intervalle complet entre deux prises (AUC 0-12 ) puisque la période entre 0 et 4 heures est celle au cours de laquelle existe la plus grande variabilité de la concentration sanguine de CsA (Figure 1 [4] en transplantation rénale [7], hépatique [8], cardiaque [9] et pulmonaire [10].…”