High-dose amoxicillin pharmacokinetics (PK) and pharmacodynamics (PD) in children
Michael Neely (1), Michael Reed (2), Roger Jelliffe (1)
(1) University of Southern California, Laboratory of Applied Pharmacokinetics, Los Angeles, CA; (2) Akron Children’s Hospital, Akron, OH
Objectives: We are unaware of any published PK data addressing oral amoxicillin (amox) dosages >25 mg/kg in children. Since amox absorption is saturable, we wished to estimate the percentages of the dosing interval that the plasma amox concentration would exceed newly updated pneumococcal breakpoint MICs (T>MIC), and the percent of children with the target T>MIC of ≥50%, after the commonly used dose of 45 mg/kg.
Methods: We used a published adult four-compartment model with delayed, saturable, time-limited amox absorption into a central compartment with linear elimination and transfer to/from a peripheral compartment.1,2 Parameters were log-transformed and allometrically scaled. Individual time-concentration data from the original study (6 adults, each given 500 and 3000 mg separated by ≥1 week) were used to fit the model using non-parametric methods implemented in MM-USCPACK, with standard visual/numerical checks. Upon comparison of simulated profiles with published Cmax and AUC ranges for doses ≤25 mg/kg in children,3 age multipliers were added to the allometric volume and elimination terms until the pediatric profiles could be accurately simulated. Single-dose T>MIC were simulated in 1000 representative 15 month, 12 kg children.
Results: For 500 mg in an adult, the Cmax mean (SD) of 1000 simulations was 8.4 (2.6) mg/L vs. 8.8 (1.8) in the study (P=0.71). Simulated AUC0-12 was 24.4 (6.1) mg*h/L vs. 25.0 (3.0) observed (P=0.24). For 3000 mg, Cmax was 29.5 (11.0) vs. 26.8 (3.9) (P=0.55) and AUC was 96.2 (28.8) vs. 91 (17) (P=0.44). For a child given 15 mg/kg, simulated Cmax was 6.6 (1.8) vs. observed 6.9 (3) (P=0.40) and AUC was 25.7 (6.5) vs. 24.9 (9.6) (P=0.53). For 25 mg/kg, Cmax was 10.7 (3.0) vs. 10.6 (5.1) (P=0.87). AUC was 42.6 (10.8) vs. 44.1 (24.6) (P=0.50). The geometric mean (interquartile range) amox dose at which absorption was 50% of maximum was 785 (337 - 2304) mg. Two further simulations are shown below.
|
|
45 mg/kg t=12 h |
30 mg/kg t=8h | ||
|
Cmax |
18.7 (5.1) |
12.8 (3.5) | ||
|
AUC0-t |
75.7 (18.9) |
51.0 (12.8) | ||
|
MIC |
T>MIC |
T>MIC ≥50% |
T>MIC |
T>MIC ≥50% |
|
2 (Susceptible) |
63 (12) % |
91% |
79 (14) % |
99% |
|
4 (Intermediate) |
48 (11) % |
41% |
58 (15) % |
75% |
|
8 (Resistant) |
32 (10) % |
3% |
33 (15) % |
10% |
Conclusion: This simulation suggests that amox plasma exposure after doses of 45 mg/kg (up to 540 mg) is proportional to lower doses, but requires confirmation. Even with the higher concentrations, treatment of intermediately susceptible pneumococcus should be with 90 mg/kg divided into 3, not 2, daily doses.
References:
[1]. Piotrovskij VK, Paintaud G, Alván G, Trnovec T. Modeling of the saturable time-constrained amoxicillin absorption in humans. Pharm. Res. 1994;11(9):1346-1351.
[2]. Paintaud G, Alván G, Dahl ML, et al. Nonlinearity of amoxicillin absorption kinetics in human. Eur. J. Clin. Pharmacol. 1992;43(3):283-288.
[3]. Fonseca W, Hoppu K, Rey LC, Amaral J, Qazi S. Comparing pharmacokinetics of amoxicillin given twice or three times per day to children older than 3 months with pneumonia. Antimicrob. Agents Chemother. 2003;47(3):997-1001.
