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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01398046.

Figures

Figure 1. Sample gastric pH data of two subjects captured by the Heidelberg pH Capsule

Gastric pH measurements at 1-minute intervals were plotted versus time to produce the following curves. Vertical dashed lines (- - -) mark the following study events: (i) administration of 20 mg oral rabeprazole with 90 mL of water, (ii) administration of 1500 mg oral BHCl with 250 mL of water, and (iii) study end. The left curve represents a “best-case scenario,” where a subject began the study day with a gastric pH > 4 after pre-treatment with rabeprazole for 4 days. In contrast, the right curve represents a “worst-case scenario,” where a subject began the study with pH < 4. In these instances, BHCl was not administered until gastric pH remained above 4 for at least 15 minutes.

Figure 2. Potency of BHCl administration in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria

Gastric pH was compared at equal time intervals (15 and 30 minutes) before and after BHCl administration. In both time intervals, gastric pH ranged from 4.5–5.9 before BHCl, with a mean pH of 5.1 (±0.5) and 5.2 (±0.5) for the 15- and 30-minute intervals, respectively. After BHCl administration, the mean gastric pH was dropped to 0. 9 (±0.4) and 0.6 (±0.2), ranging between 0.5–1.6 and 0.5–1.1, for the 15- and 30-minute intervals, respectively. Means of 6 subjects are represented by horizontal bars. (*** : P<0.001)

Figure 3. Serum Gastrin Levels Measured at Major Study Events and the Corresponding Observed Gastric pH

Serum gastrin levels (pg/mL) were measured three-times on each study day: before rabeprazole dosing, before BHCl dosing, and at the end of the study day. No significant relationships were observed between serum gastrin and gastric pH with respect to the artificial changes in pH due to rabeprazole and BHCl.