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

Abstract

Changes in gastric pH can impact the dissolution and absorption of compounds presenting pH-dependent 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.

Pharmacokinetics of Dasatinib

“…There was another interaction study in dogs with famotidine (40 mg, orally, 3 h prior to dasatinib), pentagastrin (6 μg/kg, im, 30 min prior to dasatinib) and betaine HCl (750 mg, orally, either 5 min, or 5 and 20 min prior to dasatinib), in which probably due to administration only 30 min before dasatinib, pentagastrin led to a doubling of dasatinib AUC (measured gastric pH was also lower than in control group). Two tablets of betaine HCl (1,500 mg in total) had the same effect on absorption as pentagastrin while when dasatinib was given with famotidine and petagastrin the negative effect of famotidine was mitigated (Pang et al, 2013).…”

Combining “Bottom‐up” and “Top‐down” Approaches to Assess the Impact of Food and Gastric pH on Pictilisib (GDC‐0941) Pharmacokinetics

“…Due to the steep pH‐dependent solubility profile ( Figure a ), and the pH‐dependent absorption in hypochlorhydric dog, a phase I randomized study was conducted in healthy volunteers to investigate the effect of food and PPI on pictilisib PK. This was a single‐center, four‐period, two‐sequence, open‐label, randomized, crossover study conducted using a 40‐mg dose of pictilisib (NCT00999128).…”

Using pH Gradient Dissolution with In-Situ Flux Measurement to Evaluate Bioavailability and DDI for Formulated Poorly Soluble Drug Products

“…Dogs are the most common species for preclinical PK studies; however, they have different gastrointestinal (GI) physiology compared to humans, with gastric pH being most significant and impactful (8). Therefore, animal studies often require pre-medication of each animal to adjust stomach pH to more human-like conditions (4,(9)(10).…”

“…Other drugs were BCS Class IIb with in vivo data available. The first one, GDC-0941, exhibited significant DDI with ARAs in vivo (9). The second drug, compound A, had significant DDI with ARAs that was largely overcome by formulation with acidic excipients (22).…”