A Limited Sampling Strategy for Estimating Sirolimus Area-Under-the-Concentration Curve

Sirolimus (SRL), a promising new immunosuppressive macrolide (1)(2)(3), displays unpredictable pharmacokinetic properties in humans. Measurement of a single trough concentration may reflect total drug exposure for drugs with consistent bioavailability and elimination properties, but not for drugs such as SRL that have variable bioavailability and unpredictable elimination characteristics. For such agents, area-under-the-concentration–time-curve (AUC) measurements have been used to estimate total drug exposure because they often correlate with pharmacodynamic effects (4)(5)(6). Although the relation between SRL AUC, the therapeutic effects of SRL, and toxicity has not been investigated, such a study might help elucidate the optimal therapeutic regimen for the drug. Sampling regimens for full pharmacokinetic profiles are frequently not clinically feasible because of both time and cost restraints. Therefore, limited sampling strategies have been devised to obtain reasonable estimates of drug exposure. Limited sampling AUC strategies have been used to monitor the exposure of patients to oil-based (Sandimmune®; Sandoz, Basel, Switzerland) (7)(8) or microemulsion (Neoral®, Sandoz) (9) formulations of cyclosporine (CsA) and to chemotherapeutic agents such as cyclophosphamide (10). The present report describes a clinically reliable sampling strategy to predict the AUC values for SRL to more efficiently evaluate the clinical significance of total exposure.