086: Probing Gastric Emptying & Drug Metabolism Changes in Patients With Obesity Undergoing Weight-Loss Using a Cocktail Containing Acetaminophen, Caffeine & Omeprazole

Statement of Purpose: The prevalence of obesity is rapidly increasing around the world but pharmacokinetic (PK) data guiding dose selections for patients with obesity are deficient. Patients with obesity may exhibit delayed gastric emptying and higher drug clearance through uridine diphosphate glucuronosyltransferase (UGT), cytochrome P450 (CYP) 1A2, and CYP2C19, suggesting a requirement for higher doses compared to non-obese patients. There is a lack of studies comparing PK before and after weight loss by diet and exercise. This study was performed to fill the knowledge gap using a drug cocktail of over-the-counter (OTC) medicines including acetaminophen, caffeine, and omeprazole in patients with obesity undergoing weight loss.

Description of Methods & Materials: Adult patients with obesity entering the weight management program (WMP) (Clinicaltrials.gov-NCT02043457) at the University of Michigan were consented and enrolled (study ID HUM00210520). Before (Phase 1) and 12 – 16 weeks after starting WMP (Phase 2), a single-dose PK study was performed using a drug cocktail containing acetaminophen (probing gastric emptying and UGT1A1), caffeine (probing CYP1A2) and omeprazole (probing CYP2C19). The acetaminophen 500 mg/caffeine 65 mg as a single tablet and omeprazole 20 mg as a single tablet were administered orally. The study design is shown in Figure 1A. Blood samples were collected at 0.5, 1, 2, 3 and between 4 to 7 hours post-dosing. The concentrations of corresponding parent drugs and their major metabolites (acetaminophen/acetaminophen-glucuronide, caffeine/paraxanthine, omeprazole/5-hydroxyomeprazole) in plasma were assayed by LC-MS/MS for assessment of PK parameters: C_max, T_max, AUC_0-last, AUC_0-∞, and CL/F. The T_max of acetaminophen was used to estimate gastric emptying time. The UGT1A1, CYP1A2 and CYP2C19 activity defined as the ratio of the metabolite to parent plasma AUC_0-last served as the phenotyping indexes.

Data & Results: So far, 13 patients (23% male) with a median [min, max] weight and age of 117.6 [86.3, 167] kg and 45 [28, 63] years, respectively, have enrolled. Twelve patients completed Phase 1 and three have completed Phase 2. Weight loss of 7.6% to 15.6% (reduction of 8.9 to 26.1 kg) has been documented to date. No drug-related adverse events were reported. The PK parameters are summarized in Table 1. The gastric emptying time of our patients with obesity was around 2 times longer than healthy volunteers reported in the literature. Higher UGT1A1, CYP1A2, and CYP2C19 activities were seen in our patients compared to non-obese patients. A 95.2%, 51.3%, and 23.5% decrease in UGT1A1, CYP1A2 and CYP2C19 activity, respectively, was observed in one patient after a 26.1 kg weight loss (Figure 1B). No significant change in gastric emptying time was observed after weight loss.

Interpretation, Conclusion or Significance: Patients with obesity can have increased gastric emptying time, UGT1A1, CYP1A2 and CYP2C19 activities compared to non-obese patients. Furthermore, increased UGT1A1, CYP1A2 and CYP2C19 activities seem to be normalized by weight loss. The drug cocktail was safe, well-tolerated and an effective approach to establishing the PK of drugs in patients with obesity.

Disclosures: The authors have no conflicts of interest to declare.