This is the first PopPK report of sirolimus in patients with advanced cancer. These measurements were obtained from clinical trials of patients with advanced cancer who received sirolimus in a wide range of dosages (1–60 mg/week). The objective of this study was to develop a population pharmacokinetic (PopPK) model for sirolimus, while exploring possible nonlinear absorption characteristics in whole blood measurements. The detection and characterization of nonlinearities provided by population modeling allows a better understanding of how a drug should be used in clinical practice. 14, 15 These studies provided the opportunity to investigate the nonlinearity in sirolimus disposition using whole blood concentration measurements. Recently, several phase I trials of sirolimus in patients with cancer were completed, including the intermittent administration of higher doses. 13 reported the nonlinearity in the pharmacokinetics of sirolimus, but they were unable to develop an explicit model to describe this due to limited measurements. There are several publications regarding the pharmacokinetics of sirolimus in transplant patients, although none have explicitly incorporated the nonlinear pharmacokinetic characteristics into a mixed-effects population model. 7 Studies in transplant patients have demonstrated marked interindividual pharmacokinetic variability, resulting in the widespread use of therapeutic drug monitoring based on whole blood concentrations. 2, 3, 4, 5, 6 Sirolimus has low bioavailability (14% on average) and a long terminal elimination half-life of ~62 h. 1 As the prototypical inhibitor of the mammalian target of rapamycin, sirolimus (like other mammalian target of rapamycin inhibitors) has substantial antitumor activity both in animals and humans. Sirolimus (rapamycin) is commonly prescribed as an immunosuppressant and is indicated for the prevention of allograft rejection. The pharmacokinetics of sirolimus, based on whole blood concentrations, appears to be nonlinear due to saturable absorption. The visual predictive check indicated that the final pharmacokinetic model adequately predicted observed concentrations. A covariate analysis identified hematocrit as influencing the oral clearance of sirolimus. The data were well described by a two-compartment model incorporating a saturable Michaelis–Menten kinetic absorption process. Model robustness was assessed using nonparametric bootstrap and visual predictive check approaches. The influence of potential covariates was evaluated. Whole blood concentration data, obtained from four phase I clinical trials, were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach. The objective of this study was to develop a population pharmacokinetic (PopPK) model to describe the nonlinearity of sirolimus. In this study, sirolimus showed nonlinear pharmacokinetic characteristics over a wide dose range (from 1 to 60 mg/week). Sirolimus, the prototypical inhibitor of the mammalian target of rapamycin, has substantial antitumor activity.