Pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone and sirolimus in adrenalectomized rats

Prednisolone (Pred) and sirolimus (SIR) are immunosuppressive compounds acting through different mechanisms with moderate synergism found in vitro. Both drugs are metabolized partly by CYP3A enzymes. After i.v. administration of placebo, Pred (5 mg/kg), SIR (1 mg/kg), or Pred with SIR (5 and 1 mg/kg doses) to adrenalectomized male rats, Pred plasma and SIR whole blood concentrations were followed for 48 hr along with circulating T-helper and T-cytotoxic cell counts. Ex vivo whole blood lymphocyte proliferation marked host responsiveness. An extended indirect PK/PD model was used to describe responses to these drugs, alone or combined. An interactive two-stage population analysis showed no modification in drug PK. Mean Pred plasma clearance was 0.655 L/hr (interrat++ variability: 11%) and significantly increased with weight. Mean SIR whole blood volume of distribution and clearance were 5.6 L (62%) and 0.28 L/hr (32%), and animal scaling showed weight-power proportionality. In vitro metabolism studies showed no significant inhibition of Pred or prednisone CYP3A metabolism by SIR (50 microM), but this pathway accounted for less than 5% of Pred metabolism. Pred decreased numbers of T-helper lymphocytes with a mean IC50 of 37.8 nM (21%) alone or 12.3 nM (130%) with SIR. Results for T-cytotoxic lymphocytes were similar. SIR increased lymphocyte numbers with a mean IC50 of 52.2 nM (24%) for T-helper and 28.8 nM (51%) for T-cytotoxic cells. Taking into account drug effects on lymphocyte trafficking, Pred directly inhibited ex vivo lymphocyte proliferation with a mean IC50 of 1.08 nM (38%). SIR, after a transduction step, inhibited proliferation with a mean IC50 of 1.00 nM (26%). Responses measured after drug coadministration were reasonably quantitated by addition of single drug effects. Since, at pharmacologic concentrations in rats, Pred and SIR did not interact in their PK but synergistically or additively interact in their dynamics, their joint therapeutic use is promising. The adrenalectomized rat may be a suitable animal model to characterize drug effects on lymphocyte trafficking and reactivity.