Population pharmacokinetics and dosing simulations of amoxicillin in obese adults receiving co-amoxiclav. (5th September 2020)

• Record Type: Journal Article
• Authors: Mellon, G; Hammas, K; Burdet, C; Duval, X; Carette, C; El-Helali, N; Massias, L; Mentré, F; Czernichow, S; Crémieux, A -C
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 75:Number 12(2020)
• Page Start: 3611
• Page End: 3618
• Publication Date: 2020-09-05
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkaa368
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: Background: Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav. Materials and methods: Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC–tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix. Results: Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m 2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin C max after oral administration significantly reduced with weight ( P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT >MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral). Conclusions: Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.