EFFECT OF SIMVASTATIN ON CYCLOSPORINE UNBOUND FRACTION AND APPARENT BLOOD CLEARANCE IN HEART-TRANSPLANT RECIPIENTS

Aims To investigate the effects of lipid lowering therapy on the fract ion unbound and dosage requirement of cyclosporine in heart transplant recipients. Methods Cyclosporine fraction unbound (fu) was measured e x vivo in plasma obtained from heart transplant recipients (n=12) befo re and after lipid lowering treatment, using equilibrium dialysis. Cyc losporine trough concentration data were also collected from cardiac t ransplant recipients (n=32) who received simvastatin for the treatment of hyperlipidaemia. Cyclosporine daily dosage and total concentration (monoclonal FPIA method) were recorded for periods up to 6 months bef ore and after simvastatin administration. The total number of dose rat e-concentration observations was 172 before and 135 after simvastatin administration respectively. Using a population pharmacokinetic approa ch (implemented in P-PHARM software) the ratio of dose rate to trough concentration at steady state (DR/C-sstrough), an estimation of appare nt clearance, was determined. The posterior Bayesian estimate of DR/C- sstrough vas calculated for each patient before and after simvastatin administration. Results The mean fu increased by 29%, from 1.40+/-0.1% (mean+/-s.d.) to 1.82+/-0.22% after simvastatin administration (P<0.0 1). Mean trough concentrations of cyclosporine in whole blood were 339 mu gl(-1) before and 242 mu gl(-1) after simvastatin administration ( P<0.0001). The mean cyclosporine daily dosage was 2.87 mg kg(-1) and 2 .33 mg kg(-1) (NS), before and after simvastatin administration respec tively. The average cyclosporine DR/C-sstrough was significantly incre ased from 24.5 l h(-1) before to 28.9 l h(-1) after simvastatin admini stration (P<0.05). Furthermore the median increase in cyclosporine DR/ C-sstrough was 18 l h(-1) to 42.1 l h(-1), interquartile range). Concl usions Cyclosporine fraction unbound and clearance are increased follo wing co-administration of lipid lowering agents, necessitating closer monitoring of cyclosporine total blood concentration when Lipid loweri ng agents are administered concomitantly with cyclosporine.