Optimal dosing of amoxicillin in obese and post-gastric bypass patients using a population pharmacokinetics-pharmacodynamics model approach.

Abstract

Aim: To characterize the impact of obesity and Roux-en-Y gastric bypass (RYGB) on systemic exposure to amoxicillin using population modeling approach. We also performed simulations to provide insights into optimising the dosing of amoxicillin against infectious bacteria in the respiratory tract.

Methods: Non-obese, obese, and post-RYGB patients, aged between 24 and 50 years, from two clinical studies, were evaluated. Sex, age, body size descriptors, history of bariatric surgery and renal function were assessed as potential covariates. The percentage of time of unbound amoxicillin plasma concentration above the minimum inhibitory concentration (%fT > MIC) of >40%, representing bactericidal activity, was used as a PK/PD target to calculate the probability of target attainment (PTA). The PTA threshold was defined as 90% of treated individuals achieving fT > MIC ≥ 40%.

Results: Amoxicillin PK was best characterized by a one-compartment model including a zero-order absorption with lag time followed by a first-order absorption and linear elimination. The relative oral bioavailability in post-RYGB patients was nearly halved compared with non-obese subjects. Age exhibited a negative correlation with clearance, consistent with amoxicillin being a hydrophilic drug primarily eliminated through the kidneys. For MIC ≤ 2 mg/L, the oral dosing regimen of 1000 mg q6h reached the therapeutic target for non-obese. For MIC ≤ 1 mg/L, 1000 mg q6h is needed in obese and post-RYGB subjects.

Conclusion: Amoxicillin doses of 1000 mg q6h were found to maximize the probability of attaining the PK/PD target with MIC ≤ 1 mg/L in obese and post-RYGB patients.