Potential differences in pharmacokinetics (PK) between healthy subjects and patients with
cancer were investigated using a physiologically based pharmacokinetic approach integrating demographic and physiological data from patients with
cancer. Demographic data such as age, sex and
body weight, and clinical laboratory measurements such as
albumin, alpha-1
acid glycoprotein (AAG) and hematocrit were collected in ~2500 patients with
cancer. A custom oncology population profile was built using the observed relationships among demographic variables and laboratory measurements in Simcyp® software, a population based ADME simulator. Patients with
cancer were older compared with the age distribution in a built-in healthy volunteer profile in Simcyp. Hematocrit and
albumin levels were lower and AAG levels were higher in patients with
cancer. The custom population profile was used to investigate the disease effect on the pharmacokinetics of two probe substrates,
saquinavir and
midazolam. Higher
saquinavir exposure was predicted in patients relative to healthy subjects, which was explained by the altered
drug binding due to elevated AAG levels in patients with
cancer. Consistent with historical clinical data, similar
midazolam exposure was predicted in patients and healthy subjects, supporting the hypothesis that the
CYP3A activity is not altered in patients with
cancer. These results suggest that the custom oncology population profile is a promising tool for the prediction of PK in patients with
cancer. Further evaluation and extension of this population profile with more compounds and more data will be needed.