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 Joseph A. Ware,* ,† Gena Dalziel, ‡ Jin Y. Jin, † Jackson D. Pellett, ‡ Gillian S. Smelick, † David A. West, † Laurent Salphati, § Xiao Ding, § Rebecca Sutton, ∥ Jane Fridyland, ⊥ Mark J. Dresser, † Glenn Morrisson, ⊥ and Scott N. Holden ⊥ † Small Molecule Clinical Pharmacology, ‡ Small Molecule Pharmaceutical Sciences, § Drug Metabolism and Pharmacokinetics, ∥ Clinical Project Management, and ⊥ Early Clinical Development, Genentech Research and Early Development, 1 DNA Way, South San Francisco, California 94080, United States 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 T max of 2 h. The presence of a high-fat meal delayed the absorption of GDC-0941, with a median T max 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 AUC 0−∞ and 0.87 (0.70, 1.06) for C max . 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 T max was unchanged, however, both C max and AUC 0−∞ 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 AUC 0−∞ was somewhat attenuated by the high-fat meal (estimate GMR of 0.57, with 90% CI, 0.50, 0.65) but unchanged for the C max (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. KEYWORDS: gastric pH, acid-reducing agents (ARA), proton pump inhibitor (PPI), H2-receptor antagonists (H2RA), drug absorption, physicochemical, drug−drug interaction (DDI), oral anti-cancer therapy, molecular targeted agents, drug development ■ INTRODUCTION A key objective of drug development is to build an integrated and comprehensive understanding of the determinants of human pharmacokinetics (PK), pharmacodynamics (PD), and drug−drug interaction (DDI) potential. As phase I studies of anti-cancer agents are typically conducted in patients taking up to 20 concomitant prescribed drugs for comorbidities, evaluation of DDI risk early in clinical development is especially important. In particular, in vitro assays, preclinical studies, and computational models are used to predict the likelihood that a small molecule will have favorable PK after oral administration. Data from in vitro and preclinical studies are also used to construct physiologically based PK models to predict human PK and DDI potential involving drug metabolizing enzymes and/or drug transporters. 1−3 For orally administered drugs, the first step in the drug absorption process is tablet disintegration followed by drug dissolution and membrane permeability. Both Special Issue: Impact of Physical Chemical Drug-Drug Interactions from Drug Discovery to Clinic Received: September 19, 2013 Revised: October 4, 2013 Accepted: October 7, 2013 Published: October 7, 2013 Article pubs.acs.org/molecularpharmaceutics © 2013 American Chemical Society 4074 dx.doi.org/10.1021/mp4005595 | Mol. Pharmaceutics 2013, 10, 4074−4081