Genentech needed to characterize the pharmacokinetics (PK) and exposure-response relationship of cobimetinib and vemurafenib to optimize dosing. It also needed to assess whether co-administration of the drugs could cause a clinically significant CYP3A-mediated drug-drug interaction (DDI).

A population PK model was developed to characterize cobimetinib’s PK. Then an exposure-response analysis was conducted using data from another Phase 3 study of cobimetinib with vemurafenib in BRAF V600E mutation-positive patients. A concentration-QT analysis was also performed to determine whether the drug combination could cause cardiotoxicity. This modeling showed that administration of cobimetinib with vemurafenib did not produce any clinically significant changes in the safety or efficacy endpoints.

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A few clinical DDI studies were conducted with healthy volunteers. Co-administration of itraconazole (a strong CYP3A inhibitor) with cobimetinib produced a significant increase in cobimetinib exposure. These clinical results were used, together with cobimetinib in vitro data, to build and verify a Simcyp Simulator physiologically-based PK (PBPK) model. That model was used to predict the potential changes in cobimetinib exposure in the presence of other CYP3A inhibitors and inducers. In fact, it provided insight into 16 potential DDIs without needing to perform clinical studies. It was also used to determine the optimal dosing for different patient groups. The cobimetinib label advises against concurrent use of strong or moderate CYP3A inhibitors and strong or moderate CYP3A inducers.

The PBPK model built in the Simcyp Simulator provided insight into 16 potential DDIs without needing to perform clinical studies.

Headquartered in South San Francisco, California, Genentech, a member of the Roche Group, is a leading biotechnology company that discovers, develops, manufactures, and commercializes medicines to treat patients with serious and life-threatening medical conditions.

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