Impact of Food and the Proton Pump Inhibitor Rabeprazole on the Pharmacokinetics of GDC-0941 in Healthy Volunteers: Bench to Bedside Investigation of pH-Dependent Solubility

Abstract

GDC-0941 is an orally administered potent, selective pan-inhibitor of phosphatidylinositol 3-kinases (PI3Ks) with good preclinical antitumor activity in xenograft models and favorable pharmacokinetics and tolerability in phase 1 trials, and it is currently being investigated in phase II clinical trials as an anti-cancer agent. In vitro solubility and dissolution studies suggested that GDC-0941, a weak base, displays significant pH-dependent solubility. Moreover, preclinical studies conducted in famotidine-induced hypochlorhydric dog suggested that the pharmacokinetics of GDC-0941 may be sensitive to pharmacologically induced hypochlorhydria. To investigate the clinical significance of food and pH-dependent solubility on GDC-0941 pharmacokinetics a four-period, two-sequence, open-label, randomized, crossover study was conducted in healthy volunteers. During the fasting state, GDC-0941 was rapidly absorbed with a median Tmax of 2 h. The presence of a high-fat meal delayed the absorption of GDC-0941, with a median Tmax of 4 h and a modest increase in AUC relative to the fasted state, with an estimated geometric mean ratio (GMR, 90% CI) of fed/fasted of 1.28 (1.08, 1.51) for AUC0-∞ and 0.87 (0.70, 1.06) for Cmax. The effect of rabeprazole (model PPI) coadministration on the pharmacokinetics of GDC-0941 was evaluated in the fasted and fed state. When comparing the effect of rabeprazole + GDC-0941 (fasted) to baseline GDC-0941 absorption in a fasted state, GDC-0941 median Tmax was unchanged, however, both Cmax and AUC0-∞ decreased significantly after pretreatment with rabeprazole, with an estimated GMR (90% CI) of 0.31 (0.21, 0.46) and 0.46 (0.35, 0.61), respectively for both parameters. When rabeprazole was administered in the presence of the high-fat meal, the impact of food did not fully reverse the pH effect; the overall effect of rabeprazole on AUC0-∞ was somewhat attenuated by the high-fat meal (estimate GMR of 0.57, with 90% CI, 0.50, 0.65) but unchanged for the Cmax (estimate of 0.43, with 90% CI, 0.37, 0.50). The results of the current investigations emphasize the complex nature of physicochemical interactions and the importance of gastric acid for the dissolution and solubilization processes of GDC-0941. Given these findings, dosing of GDC-0941 in clinical trials was not constrained relative to fasted/fed states, but the concomitant use of ARAs was restricted. Mitigation strategies to limit the influence of pH on exposure of molecularly targeted agents such as GDC-0941 with pH-dependent solubility are discussed.

Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

“…The measured solubility and dissolution properties of LY3023414 were favorable for absorption if compared with published data for other PI3K/mTOR inhibitors (2,30,43). The compound was quite soluble near pH 2, which corresponds to the initial pH encountered by LY3023414 in the stomach, and remained soluble in simulated gastric and intestinal fluids.…”

Impact of Acid‐Reducing Agents on the Pharmacokinetics of Palbociclib, a Weak Base With pH‐Dependent Solubility, With Different Food Intake Conditions

“…Administration of a drug product with food may change the bioavailability in different ways, including changes in gastrointestinal pH, delay in gastric emptying, stimulation of bile flow, and changes in luminal metabolism of the studied drug. 17,[28][29][30] In an open-label, randomized crossover study, a high-fat meal did not mitigate the decrease in exposure of a weak base drug GDC-0941 caused by rabeprazole, as observed by the similar AUC 0-inf and C max reduction under a fed condition relative to a fasted condition. 29 Thus, food intake may not always be able to mitigate the decrease in drug exposure caused by ARAs.…”

“…17,[28][29][30] In an open-label, randomized crossover study, a high-fat meal did not mitigate the decrease in exposure of a weak base drug GDC-0941 caused by rabeprazole, as observed by the similar AUC 0-inf and C max reduction under a fed condition relative to a fasted condition. 29 Thus, food intake may not always be able to mitigate the decrease in drug exposure caused by ARAs. It can also depend on the pH-solubility profile, extent of intestinal absorption, and other PK characteristics of the study drug.…”

Breast Cancer Resistance Protein (ABCG2) in Clinical Pharmacokinetics and Drug Interactions: Practical Recommendations for Clinical Victim and Perpetrator Drug-Drug Interaction Study Design

“…As such, although using a PPI may minimize the safety risks, other drugs are expected to offer a superior in vivo inhibition profile, rendering data interpretation more straightforward. Finally, any observed DDIs with PPIs are fundamentally confounded by increased gastrointestinal pH (Ware et al, 2013), and a separate intestinal pH control arm must be incorporated into the clinical study with a PPI that is not a BCRP inhibitor to control for this effect (Adkison et al, 2010). Natural Products.…”