Dose-saturable model for amoxicillin used to predict probability of response in normal and obese pediatrics
Maria Panselina[1], Elena Suarez[1], John C Lukas[2]
[1] University of the Basque Country, Leioa, Spain; [2] Dynakin SL, Derio, Spain
Objectives: Amoxicillin (“AMOX”), a beta-lactam hydrophilic antibiotic is used extensively against Streptococcus pneumoniae (“STREP”) in pediatric adult pneumonia and acute otitis. Five in 1000 persons each year contract pneumococcal pneumonia and incidence is increasing. Revised breakpoints for p.o. AMOX against resistant STREP are at minimum inhibitory concentration (MIC) ≥2 mg/L [1]. Due to the dose-saturable kinetics of AMOX [2] and increasing prevalence of obesity in children, efficacy between 6 and 12 year olds may be reduced. The %T>MIC efficacy is obtained for normal weight and obese (50% increase) children.
Methods: PK profiles in healthy normoweight adults were extracted from Sjovall [2] for four AMOX single oral adult doses and a combined first-order and dose saturation-impacted zero-order absorption model was developed for AMOX in NONMEM. Mono-compartmental AMOX parameters were within literature estimates, higher doses becoming infra-bioavailable and represented by an ellipsoid saturation function with a KD = 1500 mg. The model was used to simulate the standard regimen PK of 40 – 50 mg/kg/day AMOX in children of 6 to 12 yr. Allometry for volume of distribution was by weight. The GFR is mature at 6 yr so clearance was assumed unchanged. The total, by-weight, daily dose varied between 750 and 3000 mg/day. In obesity (BMI > 50), the increase in kidney size follows a ¾ law with increasing weight [3]. A 50% increase in nominal weight led to a 37% increase in CL and a similar increase in V due to increasing extracellular fluid. Simulations were performed for a Q3D multiple dose regimen for AMOX 750, 1200, 2250, 3000 mg daily, covering nominal to obese 6 and 12 yr-olds. The 3rd day profile was extracted and the %T>MIC efficacy across N=150 virtual subjects calculated (threshold taken as T>MIC = 50%). Protein binding for AMOX is 18%.
Results: The recommendation per weight AMOX dosing is expected to provide adequate coverage in resistant STREP for pediatric patients (6 to 12 yr) with near 70% T>MIC attainment at over 90% proportion of patients (given assumptions on pediatric PK parameters).
Conclusions: The 40-50 mg/kg/day plan seems likely to provide coverage of therapy even for obese children. However, the assumption of pediatric clearance been similar to the adult may not hold. According to bedside reports it possibly represents the lower limit for CL, then true coverage will be reduced yet remain efficacious for non-resistant strains.
References:
[1] Weinstein MP, Klugman KP, Jones RN. Rationale for Revised Penicillin Susceptibility Breakpoints versus Streptococcus pneumoniae: Coping with Antimicrobial Susceptibility in an Era of Resistance. Antimicrob Resist 2009; 48: 1596-1600.
[2] Sjövall J, Alván G, Westerlund D. Dose-dependent absorption of amoxycillin and bacampicillin. Clin Pharmacol Ther 1985; 38: 241-50.
[3] Payne KD, Hall RG. Dosing of antibacterial agents in obese adults: does one size fit all? Expert Rev Anti Infect Ther 2014; 12: 829–854.