Assessment of cytochrome P450 3A4-mediated drug-drug interactions for ipatasertib using a fit-for-purpose physiologically based pharmacokinetic model was written by Jing, Jing;Chen, Yuan;Musib, Luna;Jin, Jin Y.;Cheung, Kit Wun Kathy;Yoshida, Kenta;Sane, Rucha. And the article was included in Cancer Chemotherapy and Pharmacology in 2022.Electric Literature of C24H29N7O2 This article mentions the following:
Ipatasertib, a potent and highly selective small-mol. inhibitor of AKT, is currently under investigation for treatment of cancer. Ipatasertib is a substrate and a time-dependent inhibitor of CYP3A4. It exhibits non-linear pharmacokinetics at subclin. doses in the clin. dose escalation study. To assess the DDI risk of ipatasertib at the intended clin. dose of 400 mg with CYP3A4 inhibitors, inducers, and substrates, a fit-for-purpose physiol. based pharmacokinetic (PBPK) model of ipatasertib was developed. The PBPK model was constructed in Simcyp using in silico, in vitro, and clin. data and was optimized and verified using clin. data. The PBPK model described non-linear pharmacokinetics of ipatasertib and captured the magnitude of the observed clin. DDIs. Following repeated doses of 400 mg ipatasertib once daily (QD), the PBPK model predicted a 3.3-fold increase of ipatasertib exposure with itraconazole; a 2-2.5-fold increase with moderate CYP3A4 inhibitors, erythromycin and diltiazem; and no change with a weak CYP3A4 inhibitor, fluvoxamine. Addnl., in the presence of strong or moderate CYP3A4 inducers, rifampicin and efavirenz, ipatasertib exposures were predicted to decrease by 86% and 74%, resp. As a perpetrator, the model predicted that ipatasertib (400 mg) caused a 1.7-fold increase in midazolam exposure. This study demonstrates the value of using a fit-for-purpose PBPK model to assess the clin. DDIs for ipatasertib and to provide dosing strategies for the concurrent use of other CYP3A4 perpetrators or victims. In the experiment, the researchers used many compounds, for example, 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (cas: 571190-30-2Electric Literature of C24H29N7O2).
6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (cas: 571190-30-2) belongs to piperazine derivatives. Simple N-substituted piperazines have been found in many drug molecules. Outside the body, piperazine has a remarkable power to dissolve uric acid and producing a soluble urate, but in clinical experience it has not proved equally successful. Electric Literature of C24H29N7O2
Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics