Schedule-dependent modulation of the pharmacokinetics of MK-2206, an oral pan-AKT inhibitor: perspectives

Excerpt

In a well-planned and well-executed clinical Phase I study, Doi et al. describe the safety, tolerability, and pharmacokinetics of MK-2206 in Japanese patients with advanced solid tumors [1]. The selection of the two dose regimens, every other day drug administration (QOD) and once weekly administration (QW) in a 28-day repeating treatment cycle, needs to be commended because the pharmacokinetics of MK-2206 derived from the two regimens would enable further fine-tuning of either the dose or the regimen of MK-2206 [1]. The intent of this note is to provide some perspectives on the topic. In order to be concise and have objectivity, the ensuing discussion would be limited to the pharmacokinetics derived from the 60-mg QOD and 200-mg QW dose schedules of MK-2206. Moreover, there is a comparability of total MK-2206 dose administered to patients from the above two dose schedules: 840 mg (60 mg × 14 doses) and 800 mg (200 mg × 4 doses) from QOD and QW schedules, respectively [1]. Given the relatively long half-life of MK-2206 (75 h) [2], it would be expected that QOD dosing schedule would show much higher accumulation of MK-2206 on repeated dosing relative to the QW dosing schedule. …