Physiologically-based pharmacokinetic modeling to predict the exposure and to assess pharmacodynamics of daptomycin in infants within 1 year old

Abstract

Daptomycin is widely used in pediatric patients for serious infections caused by Gram-positive bacteria, however, studies regarding its safety and efficacy in infants within 1 year old are very limited. A physiologically-based pharmacokinetic (PBPK) model of daptomycin was built for children aged 1–17 years old and extrapolated to infants within 1 year old to evaluate pharmacodynamics (PD) based on efficacy and safety considerations. Monte Carlo Simulations (MCSs) were conducted to determine the probabilities of target attainment (PTA) and cumulative fractions of response (CFR) of daptomycin. The pharmacokinetic (PK) of daptomycin did not differ much in the population of infants within 1 year of age, with peak plasma concentration (C_max) and area under the curve (AUC) maintained at an approximate level at all months of age, while the average trough concentration of daptomycin was 3.49 μg/mL when 10 mg/kg daptomycin was given, and 4.98 ug /mL at 15 mg/kg. According to the results of the MCSs, 10mg/kg daptomycin provides good antimicrobial effect for S.pneumoniae and MSSA. With the increase of dosage, the CFR value of daptomycin against MRSA, E.faecalis and E.faecium also gradually reached >90 %, except for E.faecalis with an average CFR of only 82.94 % at 12mg/kg. This is a daptomycin PBPK model in infants within 1 year of age, dose regimen higher than 10 mg/kg should be recommended for this population in the treatment of MRSA, E. faecalis, and E. faecalis.