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 fraction unbound and dosage requirement of cyclosporine in heart transplant recipients.Methods Cyclosporine fraction unbound (fu) was measured ex vivo in plasma obtained from heart transplant recipients (n=12) before and after lipid lowering treatment, using equilibrium dialysis. Cyclosporine trough concentration data were also collected from cardiac transplant 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 before and after simvastatin administration. The total number of dose rate-concentration observations was 172 before and 135 after simvastatin administration respectively. Using a population pharmacokinetic approach (implemented in P-PHARM software) the ratio of dose rate to trough concentration at steady state (DR/C_sstrough ), an estimation of apparent clearance, was determined. The posterior Bayesian estimate of DR/C_sstrough was 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<0.01). Mean trough concentrations of cyclosporine in whole blood were 349 μg l⁻¹ before and 242 μg l⁻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 respectively. The average cyclosporine DR/C_sstrough was significantly increased from 24.5 l h⁻¹ before to 28.9 l h⁻¹ after simvastatin administration (P<0.05). Furthermore the median increase in cyclosporine DR/C_sstrough was 18 l h⁻¹ (−3.1 to 42.1 l h⁻¹, interquartile range).Conclusions Cyclosporine fraction unbound and clearance are increased following co-administration of lipid lowering agents, necessitating closer monitoring of cyclosporine total blood concentration when lipid lowering agents are administered concomitantly with cyclosporine.