Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations

This study correlated the dynamic effects of sirolimus (rapamycin; RAPA) an d cyclosporine (CsA) alone versus in combination to produce renal dysfuncti on, myelosuppression, or hyperlipidemia, with their corresponding blood and tissue concentrations. After salt-depleted rats were treated with RAPA (0. 4 to 6.4 mg/kg per d) and/or CsA (2.5 to 20.0 mg/kg per d) for 14 d, the GF R, lipid levels, bone marrow cellularity, and CsA/RAPA concentrations in wh ole blood versus liver or renal tissues were measured, and the median effec t model was used to discern the type of drug interactions. Compared with ve hicle controls (1.98 +/- 0.34 ml/min), GFR values were reduced only by larg e doses of drug monotherapy, namely RAPA (3.2 mg/kg per d = 1.2 +/- 0.02 ml /min or 6.4 mg/kg per d = 1.3 +/- 0.2 ml/min; both P < 0.01) or CsA (10.0 m g/kg per d = 1.2 +/- 0.1 ml/min or 20.0 mg/kg per d = 0.8 +/- 0.4 ml/min; b oth P < 0.01). In contrast, hosts that were treated with smaller doses of C sA/RAPA combinations showed more pronounced effects in reduction of GFR val ues: 2.5/0.4 mg/kg per d, modestly (1.5 +/- 0.5 ml/min; P < 0.01); 5.0/0.8 mg/kg per d, moderately (0.23 +/- 0.01 ml/min; P < 0.001); and higher-dose groups, markedly. The exacerbation of renal dysfunction seemed to be due to a pharmacokinetic interaction of RAPA to greatly increase CsA concentratio ns in whole blood and, particularly, in kidney tissue. In contrast, the pha rmacodynamic effects of CsA to potentiate two RAPA-mediated toxicities-myel osuppression and increased serum cholesterol/low-density lipoprotein choles terol-occurred independently of pharmacokinetic interactions. RAPA aggravat es CsA-induced renal dysfunction owing to a pharmacokinetic interaction, wh ereas CsA produces a pharmacodynamic effect that augments RAPA-induced myel osuppression and hyperlipidemia.