Population pharmacokinetics of micafungin in neonates and young infants

Abstract

Micafungin is an echinocandin with potent activity against Candida spp. Hematogenous Candida meningoencephalitis (HCME) is a frequent complication of disseminated Candida infection in premature infants. A preclinical model of HCME suggests that micafungin may be an effective agent for this syndrome, but relatively high weight-based dosages are required. This prompted the further study of the safety and pharmacokinetics (PK) of micafungin in infants. Here, we describe the population pharmacokinetics of micafungin in 47 infants with a proven or presumptive diagnosis of disseminated candidiasis, who received 0.75, 1.5, 3, 7, 10, and 15 mg/kg of micafungin. The drug was infused daily, and samples were taken in the first dosing interval and at steady state. Serum concentrations were measured using high-performance liquid chromatography (HPLC). Data were modeled using an allometric pharmacokinetic model using a three-fourths scaling exponent for clearance and parameters normalized to a 70-kg adult. Drug exposures were estimated using Monte Carlo simulation. Optimal sampling times were determined using D-optimal design theory. The fit of the allometric model to the data was highly acceptable. The pharmacokinetics of micafungin were linear. The weight-normalized estimates of clearance and volume of distribution approximated those previously described for adults. The original population parameter values could be recapitulated in the Monte Carlo simulations. A dosage of 10 mg/kg/day resulted in 82.6% of patients with areas under the concentration-time curve (AUCs) that are associated with near-maximal decline in fungal burden within the central nervous system (CNS).

FIG. 1.

The observed-versus-predicted values from the allometric population pharmacokinetic model after the Bayesian step.

FIG. 2.

The Bayesian estimates for absolute estimates for clearance (A) and the volume of distribution (B) for each of the 47 neonates. The solid line represents the fit of the model to the data.

FIG. 3.

Monte Carlo simulations for 9,999 patients receiving micafungin. (A) Neonates receiving 8 mg/kg; (B) neonates receiving 10 mg/kg; (C) neonates receiving 12 mg/kg; (D) adults receiving 100 mg. The simulations in panel D were performed using the mean population parameter estimates from Gumbo et al. (10).

FIG. 4.

Target attainment rates as a function of the MIC. The distribution of MICs for Candida albicans is shown (solid circles). The target attainment rates for the 9,999 simulated neonates for each MIC value is represented by open circles. Target attainment rates fall dramatically with MICs of >0.0625 mg/liter.

FIG. 5.

Optimal sampling times for neonates weighing 0.5 and 1.5 kg receiving micafungin at 10 mg/kg.