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

Abstract

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 vitro studies revealed that TAK-272 was mainly metabolized by CYP3A4/5 in humans, and it was a P-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 (F * F ) 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 F * F in 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.

Efficacy and Safety of Imarikiren in Patients with Type 2 Diabetes and Microalbuminuria

“…Imarikiren hydrochloride (TAK-272; SCO-272) is a novel orally bioavailable direct renin inhibitor (12). The bioavailability of this agent in humans was calculated to be 77% (13). In animal studies, urinary or biliary excretion of imarikiren as unchanged drug was #3% (13).…”

“…The bioavailability of this agent in humans was calculated to be 77% (13). In animal studies, urinary or biliary excretion of imarikiren as unchanged drug was #3% (13). In phase 1 clinical studies, treatment with imarikiren resulted in doseproportional pharmacokinetics, strong and sustained suppression of plasma renin activity, and a favorable safety and tolerability profile (14,15).…”

Pharmacokinetics and Safety After a Single Dose of Imarikiren in Subjects with Renal or Hepatic Impairment

“…In non-clinical studies, imarikiren showed potent renin inhibitory activity equivalent to aliskiren, but with increased bioavailability in animals [4]. In an in vitro analysis of metabolism using hepatic microsomes, the major metabolite of imarikiren in humans was M-I and it was shown that cytochrome P450 (CYP) 3A4/5 was mainly involved in human metabolism of imarikiren [6]. In in vitro tests, imarikiren and M-I demonstrated strong inhibition of plasma renin activity in humans, with half-maximal inhibitor concentrations of 2.1 and 0.43 nM, respectively.…”

“…In in vitro tests, imarikiren and M-I demonstrated strong inhibition of plasma renin activity in humans, with half-maximal inhibitor concentrations of 2.1 and 0.43 nM, respectively. In vitro plasma protein binding of imarikiren in mice, rats, monkeys, and humans decreased in proportion to plasma imarikiren concentration in all species [6]. An analysis of imarikiren using a variety of protein solutions indicated that imarikiren may mainly bind to α 1 -acid glycoprotein (AGP) in human plasma [7].…”

“…An analysis of imarikiren using a variety of protein solutions indicated that imarikiren may mainly bind to α 1 -acid glycoprotein (AGP) in human plasma [7]. In an in vivo study, while imarikiren and M-I were detected in the urine and feces of rats and monkeys and in the bile of rats, the excretion of imarikiren as unchanged drug in urine and bile was low [6]. Thus, absorbed imarikiren was thought to be eliminated from the body by metabolism.…”