PHASE-I SAFETY AND PHARMACOKINETIC STUDIES OF BREQUINAR SODIUM AFTER SINGLE ASCENDING ORAL DOSES IN STABLE RENAL, HEPATIC, AND CARDIAC ALLOGRAFT RECIPIENTS

Brequinar sodium (BQR), a substituted 4-quinoline carboxylic acid, was in clinical development in combination with cyclosporine (CsA) as a p otentially effective therapy for the treatment and prophylaxis of reje ction in organ transplant patients. This phase I study was performed i n stable renal, hepatic, and cardiac transplant patients receiving CsA and prednisone maintenance therapy for immunosuppression. The pharmac okinetic objectives of this study were to characterize the pharmacokin etics of (a) single oral 0.5- to 4-mg/kg doses of BQR when given in co mbination with CsA and prednisone to stable renal, hepatic, and cardia c transplant patients and (b) steady-state oral doses of CsA, with and without single oral doses of BQR. In all three patient populations, t he pharmacokinetics of BQR were characterized by a lower oral clearanc e (12-19 mL/min) than that seen in previous studies in patients with c ancer (similar to 30 mL/min at similar doses) and a long terminal half life (13-18 hrs). This slower oral clearance for BQR could be due eit her to a drug interaction between BQR and CsA or to altered clearance or metabolic processes in patients with transplants. Steady-state CsA trough levels and the oral clearance of CsA were not affected by BQR c oadministration. Among the three transplant populations, the cardiac t ransplant patients had lower oral clearance values of BQR and of CsA. The cause of this lower clearance is not known. Safety results indicat e that BQR was well tolerated by this patient population.