imarikiren (TAK-272) / Takeda - LARVOL DELTA

A Phase 1, Drug-Drug Interaction Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics of TAK-272 and the Effect of TAK-272 on the Pharmacokinetics of Digoxin and Midazolam (clinicaltrials.gov) - P1; N=34; Completed; Sponsor: Takeda; Recruiting ➔ Completed; Trial primary completion date: Apr 2016 ➔ Apr 2015

Trial completion • Biosimilar

Phase I Open-label Study to Evaluate Pharmacokinetics of TAK-272 in Patients With Renal or Hepatic Impairment (clinicaltrials.gov) - P1; N=48; Recruiting; Sponsor: Takeda; Not yet recruiting -> Recruiting

Enrollment open • Biosimilar • Dyslipidemia

Benchmarking renin suppression and blood pressure reduction of direct renin inhibitor imarikiren through quantitative systems pharmacology modeling. (PubMed, J Pharmacokinet Pharmacodyn) - "Our analysis indicates that low doses (5-10 mg) of imarikiren are comparable to current RAAS therapies, and at higher doses (25-200 mg), RAAS suppression may be equivalent to existing dual-RAAS combinations (at registered doses). This study illustrates application of QSP modeling to predict phase II endpoints from phase I data."

Journal

Efficacy and Safety of Imarikiren in Patients with Type 2 Diabetes and Microalbuminuria: A Randomized, Controlled Trial. (PubMed, Clin J Am Soc Nephrol) - "Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria."

Clinical • Journal

Development of a novel murine heart failure model overexpressing human renin and angiotensinogen. (PubMed, FEBS Open Bio) - "Triple-tg mice treated with 10 mg/kg of TAK-272 (imarikiren / SCO-272), an orally active direct renin inhibitor, exhibited improvements in heart failure phenotypes, such as cardiac hypertrophy and survival rate; however, a dose of 300 mg/kg was required to improve symptoms in CSQ-tg mice. Our results suggest that this newly generated triple-tg heart failure model is useful to evaluate the cardioprotective effects of human renin inhibitors at clinically relevant doses, thereby minimizing the concerns of off-target effects related to much higher drug exposure than that achieved in clinical study."

Journal • Preclinical

A Randomized, Single-Center, Double-Blind, Placebo-Controlled Multiple-Dose Phase 1 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Imarikiren in Healthy Adult Nonelderly and Elderly Male Subjects. (PubMed, J Clin Pharmacol) - "Treatment-emergent adverse events were reported in 33.3% (elderly) and 22.2% (nonelderly) of imarikiren subjects. Multiple oral administrations of imarikiren for 7 days were safe and well tolerated with no drug accumulation and strong and sustained suppression of plasma renin activity."

Clinical • Journal • P1 data • PK/PD data

The effect of elevated α-acid glycoprotein on the pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor, in rats. (PubMed, Xenobiotica) - "3. These results strongly suggested that the pharmacokinetic of TAK-272 in humans would also be affected by the variation in the plasma AGP levels and should be discussed with not only the total concentrations but also the unbound concentrations in the clinical trial for patients with elevated plasma AGP levels."

Journal • PK/PD data • Preclinical