Article pubs.acs.org/molecularpharmaceutics
Pharmacokinetics and Absorption of the Anticancer Agents Dasatinib and GDC-0941 under Various Gastric Conditions in Dogs − Reversing the Effect of Elevated Gastric pH with Betaine HCl Jodie Pang,† Gena Dalziel,‡ Brian Dean,† Joseph A. Ware,§ and Laurent Salphati*,† †
Department of Drug Metabolism and Pharmacokinetics, ‡Department of Small Molecule Pharmaceutical Sciences, and §Department of Small Molecule Clinical Pharmacology, Genentech, Inc., South San Francisco, California 94080, United States S Supporting Information *
ABSTRACT: Changes in gastric pH can impact the dissolution and absorption of compounds presenting pHdependent solubility. We assessed, in dogs, the effects of gastric pH-modifying agents on the oral absorption of two weakly basic anticancer drugs, dasatinib and GDC-0941. We also tested whether drug-induced hypochlorhydria could be temporarily mitigated using betaine HCl. Pretreatments with pentagastrin, famotidine, betaine HCl, or combinations of famotidine and betaine HCl were administered orally to dogs prior to drug dosing. The gastric pH was measured under each condition for up to 7 h, and the exposure of the compounds tested was calculated. The average gastric pH in fasted dogs ranged from 1.45 to 3.03. Pentagastrin or betaine HCl treatments lowered the pH and reduced its variability between dogs compared to control animals. In contrast, famotidine treatment maintained gastric pH at values close to 7 for up to 5 h, while betaine HCl transiently reduced the pH to approximately 2 in the famotidine-treated dogs. Famotidine pretreatment lowered GDC-0941 exposure by 5-fold, and decreased dasatinib measurable concentrations 30-fold, compared to the pentagastrin-treated dogs. Betaine HCl restored GDC-0941 AUC in famotidine-treated dogs to levels achieved in control animals, and increased dasatinib AUC to 1.5-fold that measured in control dogs. The results confirmed the negative impact of acid-reducing agents on the absorption of weakly basic drugs. They also suggested that betaine HCl coadministration may be a viable strategy in humans treated with acid-reducing agents in order to temporarily reduce gastric pH and restore drug exposure. KEYWORDS: dog, gastric pH, hypochlorhydria, pH-dependent solubility, absorption, pentagastrin, famotidine, betaine HCl, proton pump inhibitor, H2-receptor antagonist, dasatinib, GDC-0941
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exposing the patients to subtherapeutic levels,3,4 and precautions related to the coadministration of ARA are included in their prescribing information.5,6 Antifungal agents such as itraconazole and posaconazole, both weak bases, also presented reduced exposure under low intragastric acidity following administration of H2 RA or PPI.7,8 In addition, it was recently reported that up to 55% of cancer patients use drugs suppressing gastric acidity.2 The high prevalence of ARA use in cancer populations may be of concern when considering the weakly basic properties and pHdependent solubility of many of the molecular targeted anticancer agents.9 Thus, strategies designed to minimize the
INTRODUCTION Systemic bioavailability of orally administered drugs is impacted by numerous factors including intestinal metabolism, enterocytic efflux and uptake transport, gastrointestinal residence time, and hepatic metabolism and secretion. The dissolution of the compound is, however, the first step allowing the intestinal absorption and is dependent on the physicochemical properties of the drug. A major determinant of drug dissolution and absorption is gastric acidity. Thus, changes in stomach pH are expected to have marked effects on the solubility and dissolution of acidic or basic drugs; an increase in pH may lead to higher solubility and greater absorption of acidic drugs, while intestinal absorption of basic drugs may decrease under similar conditions. Acid-reducing agents (ARA), such as antacids, H2-receptor antagonists (H2RA) or proton pump inhibitors (PPI), are some of the most prescribed drugs in North America and are widely available as over-the-counter drugs.1,2Their concurrent use with the HIV protease inhibitors atazanavir, indinavir and nelfinavir leads to pronounced reduction in AUC and Cmax, potentially © XXXX American Chemical Society
Special Issue: Impact of Physical Chemical Drug-Drug Interactions from Drug Discovery to Clinic Received: June 19, 2013 Revised: August 12, 2013 Accepted: August 27, 2013
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dx.doi.org/10.1021/mp400356m | Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Molecular Pharmaceutics
Article
groups of four dogs (7.2 to 11.5 kg; Marshall Bioresources, Beijing, China) were used in each phase. There was at least a 3day washout period between each phase. The schedules of the pretreatments and pH measurements are presented in Figure 2 and described below. The first group of dogs received the following pretreatments in each phase, respectively: no pretreatment, one-tablet betaine HCl, famotidine plus onetablet betaine HCl, and pentagastrin. The second group of dogs received famotidine pretreatment, two-tablet betaine HCl, famotidine plus two-tablet betaine HCl, and no pretreatment, for each of the four phases, respectively. In the control group (no pretreatment), eight pH measurements were taken one hour apart. With famotidine pretreatment, the first pH measurement was taken immediately before famotidine administration, and each subsequent measurement was collected 1 h apart with a total of 8 pH measurements. In the one-tablet betaine HCl pretreatment group, one betaine HCl tablet was given 25 min following the initial pH measurement, and the second pH measurement was recorded 5 min following betaine HCl administration. All subsequent pH measurements were 1 h apart following the second pH measurement with a total of 6 pH measurements. In the twotablet betaine HCl pretreatment group, the first betaine HCl tablet was given 10 min after the first pH measurement, the second tablet was given 25 min after the first pH measurement, and the second pH measurement was taken 5 min following the second betaine HCl tablet administration. All subsequent pH measurements were 1 h apart following the second pH measurement with a total of 6 pH measurements. In the pentagastrin pretreatment group, pentagastrin was administered (im injection) immediately following the first pH measurement. The second pH measurement was taken 30 min later, and the rest of the measurements were recorded 1 h apart with a total of 6 measurements. Famotidine plus one-betaine HCl pretreatment started with a first pH measurement, immediately followed by famotidine administration. Betaine HCl administration occurred 2 h 55 min after the first pH measurement, and the second pH measurement at 3 h (5 min after the betaine HCl dose). Subsequent pH measurements were 1 h apart for a total of 8 pH measurements. Famotidine plus two-betaine HCl pretreatment started with the first pH measurement, followed by immediate famotidine administration, then first betaine HCl administration at 2 h and 40 min, and the second betaine HCl administration at 2 h 55 min. The second pH measurement occurred at 3 h, and subsequent pH measurements were 1 h apart, for a total of 8 pH measurements. A soft tube was inserted through the mouth into the stomach while the dog was maintained in a standing position. About 1 mL of gastric fluid was collected, and pH was measured using a pH meter (pHSpear; Thermo Fisher Scientific, Shanghai, China). Dasatinib Pharmacokinetic Study in Male Beagle Dogs. Twenty eight male Beagle dogs (6.9 to 10.5 kg; Marshall Bioresources, Beijing, China) were each given one 50 mg dasatinib tablet in a 7-group parallel-design study. Each group of four dogs, except the control group, was administered a different pretreatment prior to receiving dasatinib tablets. The second group of dogs received pentagastrin dissolved in saline (0.25 mg/mL) and administered intramuscularly (im) at 6 μg/ kg approximately 30 min before dasatinib administration. The third group received famotidine (40 mg tablet/dog), administered orally approximately 3 h before dasatinib administration. The fourth group of dogs received betaine
effects of variable gastric pH on these drugs are likely to provide more consistent therapeutic responses. The goal of our studies was to assess whether the decrease in exposure observed with weak bases under low gastric acidity could be mitigated or reversed. We selected dasatinib to investigate the impact of various gastric pH conditions on its absorption and pharmacokinetics in dogs. Dasatinib is a basic drug with three pKa values, 3.1, 6.8 and 10.8.9 It also exhibits a steep pH−solubility profile,10 where the solubility drops from approximately 18 mg/mL at pH 2.6 to 8 μg/mL at pH 6, and
