Combining "Bottom-up" and "Top-down" Approaches to Assess the Impact of Food and Gastric pH on Pictilisib (GDC-0941) Pharmacokinetics.

Pictilisib, a weakly basic compound, is an orally administered, potent, and selective pan-inhibitor of phosphatidylinositol 3-kinases for oncology indications. To investigate the significance of high-fat food and gastric pH on pictilisib pharmacokinetics (PK) and enable label recommendations, a dedicated clinical study was conducted in healthy volunteers, whereby both top-down (population PK, PopPK) and bottom-up (physiologically based PK, PBPK) approaches were applied to enhance confidence of recommendation and facilitate the clinical development through scenario simulations. The PopPK model identified food (for absorption rate constant (Ka )) and proton pump inhibitors (PPI, for relative bioavailability (Frel ) and Ka ) as significant covariates. Food and PPI also impacted the variability of Frel . The PBPK model accounted for the supersaturation tendency of pictilisib, and gastric emptying physiology successfully predicted the food and PPI effect on pictilisib absorption. Our research highlights the importance of applying both quantitative approaches to address critical drug development questions.

The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria.

Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug-induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib Cmax and AUC0-∞ by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib Cmax and AUC0-∞ by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions.

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.

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.

Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development.

Acid-reducing agents (ARAs) are the most commonly prescribed medications in North America and Western Europe. There are currently no data describing the prevalence of their use among cancer patients. However, this is a paramount question due to the potential for significant drug-drug interactions (DDIs) between ARAs, most commonly proton pump inhibitors (PPIs), and orally administered cancer therapeutics that display pH-dependent solubility, which may lead to decreased drug absorption and decreased therapeutic benefit. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility, but there are currently no data describing the potential for this ARA-DDI liability among targeted agents currently in clinical development. The objectives of this study were to (1) determine the prevalence of ARA use among different cancer populations and (2) investigate the prevalence of orally administered cancer therapeutics currently in development that may be liable for an ARA-DDI. To address the question of ARA use among cancer patients, a retrospective cross-sectional analysis was performed using two large healthcare databases: Thomson Reuters MarketScan (N = 1,776,443) and the U.S. Department of Veterans Affairs (VA, N = 1,171,833). Among all cancer patients, the total prevalence proportion of ARA use (no. of cancer patients receiving an ARA/total no. of cancer patients) was 20% and 33% for the MarketScan and VA databases, respectively. PPIs were the most commonly prescribed agent, comprising 79% and 65% of all cancer patients receiving a prescription for an ARA (no. of cancer patients receiving a PPI /no. of cancer patients receiving an ARA) for the MarketScan and VA databases, respectively. To estimate the ARA-DDI liability of orally administered molecular targeted cancer therapeutics currently in development, two publicly available databases, (1) Kinase SARfari and (2) canSAR, were examined. For those orally administered clinical candidates that had available structures, the pKa's and corresponding relative solubilities were calculated for a normal fasting pH of 1.2 and an "ARA-hypochlorhydric" pH of 4. Taking calculated pKa's and relative solubilities into consideration, clinical candidates were classified based on their risk for an ARA-DDI. More than one-quarter (28%) of the molecules investigated are at high risk for an ARA-DDI, and of those high risk molecules, nearly three-quarters (73%) are being clinically evaluated for at least one of five cancer types with the highest prevalence of ARA use (gastrointestinal, pancreatic, lung, glioblastoma multiforme, gastrointestinal stromal tumor (GIST)). These data strongly suggest that with the clinical development of ARA-DDI-susceptible cancer therapeutics will come continued challenges for drug-development scientists, oncologists, and regulatory agencies in ensuring that patients achieve safe and efficacious exposures of their cancer therapeutics and thus optimal patient outcomes.

Gastric reacidification with betaine HCl in healthy volunteers with rabeprazole-induced hypochlorhydria.

Previous studies have demonstrated that increased gastric pH from the use of acid-reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption of weakly basic drugs that exhibit pH-dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric reacidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 min, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 h. Betaine HCl significantly lowered gastric pH by 4.5 (± 0.5) units from 5.2 (± 0.5) to 0.6 (± 0.2) (P < 0.001) during the 30 min interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (± 4.3) min. The reacidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (± 33) and 77 (± 30) min, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH-dependent solubility when administered under hypochlorhydric conditions.

Light-activated regulation of cofilin dynamics using a photocaged hydrogen peroxide generator.

Hydrogen peroxide (H2O2) can exert diverse signaling and stress responses within living systems depending on its spatial and temporal dynamics. Here we report a new small-molecule probe for producing H2O2 on demand upon photoactivation and its application for optical regulation of cofilin-actin rod formation in living cells. This chemical method offers many potential opportunities for dissecting biological roles for H2O2 as well as remote control of cell behavior via H2O2-mediated pathways.