Differences in nonclinical pharmacokinetics between species and prediction of human pharmacokinetics of TAK‐272 (SCO‐272), a novel orally active renin inhibitor

In the search for orally available drugs, the prediction of human pharmacokinetics (PK) is essential for successfully selecting compounds that will be clinically useful. This report describes the selection of TAK‐272 (SCO‐272), a novel orally active renin inhibitor, as a clinical candidate via the detailed investigation of nonclinical PK data and human PK prediction. The bioavailability (BA) of TAK‐272 after oral administration to rats and monkeys was low, especially in fasted monkeys, and the systemic exposure of TAK‐272 was highly variable in monkeys. The results of mass balance studies in animals suggested that the absorbed TAK‐272 was largely eliminated by metabolism.In vitrostudies revealed that TAK‐272 was mainly metabolized by CYP3A4/5 in humans, and it was aP‐glycoprotein substrate. PK analysis suggested that the factors responsible for the low BA were different in rats and monkeys. First‐pass hepatic extraction was high in rats, while the fraction absorbed from the gastrointestinal tract (Fa* Fg) was low in monkeys. It was predicted that humans would have a higher BA and a longer half‐life in the plasma compared with the animals by a simple calculation using intrinsic hepatic clearance in monkeys, which correlates well with human values for CYP3A4 substrates, and Fa* Fgin rats, which correlates relatively well with human values. TAK‐272 was finally selected as a clinical candidate based on the result of human PK prediction. The actual human PK after oral administration of TAK‐272 was comparable to the predicted profile and was preferable for clinical usage.