A RANDOMIZED, PROSPECTIVE MULTICENTER PHARMACOEPIDEMIOLOGIC STUDY OF CYCLOSPORINE MICROEMULSION IN STABLE RENAL GRAFT RECIPIENTS

Background. The safety, tolerability, and pharmaco; kinetics of conven tional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) we re compared under conditions of normal clinical practice in a prospect ive, randomized, concentration-controlled, pharmacoepidemiologic study . Methods. Between September 1994 and March 1995, 1097 stable renal tr ansplant recipients in 14 Canadian centers were randomized 2:1 to trea tment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose w as adjusted to maintain predose whole blood cyclosporine concentration s within the therapeutic range established for each center, Prednisone and azathioprine were continued unless dose adjustment was required f or clinical reasons. Results. The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up, The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment g roups, but there was a transient increase in neurological and gastroin testinal complications in the group receiving MeCsA within the first m onth after conversion (P<0.05). Serum creatinine and creatinine cleara nce did not change in either treatment group throughout the study, Bio psy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histolo gically proven acute rejection in an additional three patients (0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA (P=NS). Seru m creatinine rose transiently in 35 patients (9.8%) receiving ConCsA a nd 138 patients (18.7%) receiving MeCsA (P<0.05) and resolved either s pontaneously or after a reduction in the cyclosporine dose, One graft was lost in the MeCsA group due to irreversible rejection, and seven p atients died, three in the group receiving ConCsA and four of those re ceiving MeCsA (P=NS). Absorption of cyclosporine was more rapid and co mplete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug (P<0.0 01). There was close correlation between area under the time-concentra tion curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, makin g AUC over the first 4 hr a good predictor of total cyclosporine expos ure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 an d 6, whereas there was no change in those who continued on ConCsA. A l imited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, p articularly for patients receiving MeCsA (r(2)=0.94 MeCsA vs. r(2)=0.8 9 ConCsA). Conclusions. MeCsA appears to be a safe and effective thera py in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Trans ient toxicity after conversion to MeCsA occurs in some patients, and m ay reflect the increased exposure to cyclosporine. Use of a limited sa mpling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.