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A concentration-guided study was designed to maintain adequate immunosuppression and avoid excessive drug exposure while determining steady-state relative bioavailability of two cyclosporine G (CyG) oral formulations in stable renal transplant patients. In period I (week 1), 26 patients taking cyclosporine A (CyA)-based immunosuppressive regimens entered the study. Doses were titrated to maintain trough concentrations within a predefined range, as measured by fluorescence polarization immunoassay (FPIA). Patients were given an oral solution of CyG in period II (weeks 2-3), and a microemulsion capsule formulation of CyG in period III (weeks 4-5), with dose titration as necessary to achieve trough concentrations in a predefined range, as measured by FPIA. Full pharmacokinetic profiles were obtained on the last day of each study period. Treatment with CyA was reinitiated in period IV (week 6) at the same doses as at study entry. All blood samples were analyzed at the conclusion of the study using CyG- and CyA-specific high-performance liquid chromatography (HPLC). When changing from oral solution to capsule for CyG, an average 19% dose reduction was necessary to compensate for the elevated trough concentrations resulting from the increased bioavailability of the capsule formulation. The concentration-guided strategy was successful in avoiding over-exposure, and resulted in comparable values for area under the concentration-time curve (AUC) for both formulations of CyG. Dose normalization of the pharmacokinetic parameters subsequently allowed calculation of the relative bioavailability. Specifically, a faster rate and greater extent of CyG absorption from the capsule than the oral solution were manifested as a slightly earlier time to peak concentration (tmax), an average 44% increase in the maximum concentration (Cmax), and an average 29% increase in AUC. This experience demonstrated that a concentration-guided trial design allowed a drug development question for a compound with a narrow therapeutic index to be addressed safely and directly in the target patient population.

A microemulsion formulation of CsA, which was anticipated to be independent of bile for oral absorption, was compared with the currently marketed formulation in liver transplant patients with external biliary drainage. Eleven patients aged 47.6 +/- 13.1 years and weighing 75.8 +/- 5.7 kg received single 400-mg oral doses of each formulation in a randomized, crossover protocol on days 4 and 6 after transplant. Serial venous blood samples were collected over a 12-hr period after each administration and whole blood CsA concentrations were determined by a validated RIA specific for the parent compound. Systemic exposure to CsA was consistently higher from the microemulsion formulation in all patients, as judged by the peak concentration and the area under the curve. Specifically, the area under the concentration-time curve was 943 +/- 400 vs. 2378 +/- 911 ng.hr/ml, indicating an average 156% higher bioavailability from the microemulsion compared with the currently marketed formulation in liver transplant patients in the absence of bile.

Cyclosporine pharmacokinetics were reported to be influenced in patients with Crohn's disease. To explore the relationship between Crohn's disease and cyclosporine pharmacokinetics, this investigation was performed in 20 patients with varying Crohn's Disease Activity Index (CDAI). A single oral dose of 300 mg of cyclosporine was given and serial blood samples were obtained over 52 hours. Cyclosporine whole blood concentrations were determined by a specific monoclonal radioimmunoassay. Pharmacokinetic parameters were comparable with those of healthy volunteers. No statistically significant difference between the pharmacokinetic parameters of the patients with CDAI values less than 150 and those with CDAI values 150 or greater could be shown. Although several factors associated with the pathology of Crohn's disease theoretically could influence the pharmacokinetics of orally administered cyclosporine, this investigation did not identify statistically significant differences in cyclosporine pharmacokinetics in Crohn's disease patients with different disease activities or different localization of inflammation as compared with healthy volunteers. However, if large parts of the small bowel were removed, a decrease of absorption of cyclosporine could be observed. In any case, it is important to be aware of the clinical variability of Crohn's disease and its potential implications in cyclosporine absorption.

Potential differences in the acute effect of cyclosporin on renal function when dosed orally as the current market formulation or following a milligram-to-milligram conversion to a new microemulsion formulation were investigated in 14 stable kidney transplant patients. The study consisted of three sequential periods of 2 weeks duration each. Patients entered (period I) and completed (period III) the investigation with the market formulation and received the microemulsion formulation in period II; individualized cyclosporin doses remained unchanged throughout the study. Over one steady-state dosing interval at the end of each study period, whole blood cyclosporin pharmacokinetic profiles were assessed in parallel with endogenous creatinine clearances over sequential 1- to 2-h intervals. The rate and extent of cyclosporin absorption were significantly greater (P < 0.01) from the microemulsion formulation with average increases of 73% in peak concentration and 44% in area under the curve compared to the market formulation. Sequential creatinine clearances exhibited a transient decrease with the nadir occurring on average between 4 and 6 h post dose followed by a rapid return to baseline. Specifically in period I on the market formulation, clearances decreased from a baseline of 71.7 +/- 20.6 to a minimum of 51.1 +/- 17.9 ml/min per 1.73 m2 (similar values in period III) and from 76.8 +/- 24.8 to 53.5 +/- 17.5 ml/min 1.73 m2 in period II on the microemulsion. Neither the baseline nor minimum clearances were significantly different among the study periods.(ABSTRACT TRUNCATED AT 250 WORDS)