Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency‐Guided First‐in‐Human Studies

Abstract

Many targeted therapies are administered at or near the maximum tolerated dose (MTD). With the advent of precision medicine, a larger therapeutic window is expected. Therefore, dose optimization will require a new approach to early clinical trial design. We analyzed publicly available data for 21 therapies targeting six kinases, and four poly (ADP‐ribose) polymerase inhibitors, focusing on potency and exposure to gain insight into dose selection. The free average steady‐state concentration (C ss ) at the approved dose was compared to the in vitro cell potency (half‐maximal inhibitory concentration (IC 50 )). Average steady‐state area under the plasma concentration‐time curve, the fraction unbound drug in plasma, and the cell potency were taken from the US drug labels, US and European regulatory reviews, and peer‐reviewed journal articles. The C ss was remarkably similar to the IC 50 . The median C ss /IC 50 value was 1.2, and 76% of the values were within 3‐fold of unity. However, three drugs (encorafenib, erlotinib, and ribociclib) had a C ss /IC 50 value > 25. Seven other therapies targeting the same 3 kinases had much lower C ss /IC 50 values ranging from 0.5 to 4. These data suggest that these kinase inhibitors have a large therapeutic window that is not fully exploited; lower doses may be similarly efficacious with improved tolerability. We propose a revised first‐in‐human trial design in which dose cohort expansion is initiated at doses less than the MTD when there is evidence of clinical activity and C ss exceeds a potency threshold. This potency‐guided approach is expected to maximize the therapeutic window thereby improving patient outcomes.

Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients

“…Although the absolute threshold level below which the activity of palbociclib may be affected is currently unknown, it has been reported that the free average steady-state concentration (C ss ) for palbociclib was similar to the in vitro cell potency (IC 50 ), with a C ss /IC 50 ratio of 0.94. 23 Findings of the current study support the hypothesis that long-term treatment with PPIs may reduce palbociclib plasma levels below the minimum effective concentration, thus affecting its efficacy to some degree. A limitation of our study is the lack of assessment of changes in palbociclib pharmacokinetics induced by PPIs.…”

“…Such a reduction in the ribociclib C trough is unlikely, however, to be clinically relevant due to its wide therapeutic index characterized by an average free C ss that largely exceeds the in vitro cell potency (C ss /IC 50 ratio >25). 23 Concerning abemaciclib, the drug shows similarities in pharmacokinetics compared with the other CDK4/6 inhibitors. Perhaps a feature that is worth mentioning is the saturable absorption which justifies, together with the shorter half-life and the smaller volume of distribution compared with ribociclib and palbociclib, a continuous, twice-daily administration.…”

Proton pump inhibitors may reduce the efficacy of ribociclib and palbociclib in metastatic breast cancer patients based on an observational study

“…When below the absolute threshold level, although it is not known at this time that the activity of palbociclib may be affected, palbociclib cell potency in vitro (IC 50 ) with free mean steady-state concentration (C ss ) is comparable with a C ss /IC 50 ratio of 0.94 [ 29 ]. The findings of the present study support the following hypothesis: prolonged treatment with PPIs may reduce palbociclib to plasma levels below the threshold of the minimum effective concentration, thus reducing its effectiveness to some extent.…”

Proton pump inhibitors may reduce the efficacy of ribociclib and palbociclib in metastatic breast cancer patients

“…When below the absolute threshold level, although it is not known at this time that the activity of palbociclib may be affected, palbociclib cell potency in vitro (IC50) with free mean steady-state concentration (Css) is comparable with a Css/IC50 ratio of 0.94 [23]. The ndings of the present study support the following hypothesis: prolonged treatment with PPIs may reduce palbociclib to plasma levels below the threshold of the minimum effective concentration, thus reducing its effectiveness to some extent.…”

“…Saman et al reported that trough concentration mean ribociclib values (C trough ) were 597 and 711 ng/ml in patients with or without PPI at 600 mg dose, respectively [14]. On average, free C ss expressing a broad therapeutic index a reduction in ribociclib C trough , is unlikely, as it greatly exceeds in vitro cell potency (C ss /IC50 ratio >25) [23]. But in real life, almost half of the patients use Ribociclib at a dose of 400 mg.…”