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 weightnormalized 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).

Population Pharmacokinetics of Micafungin and Its Metabolites M1 and M5 in Children and Adolescents

“…As a result, body weight was directly incorporated into a structural model using an allometric scaling term. This approach was used previously for micafungin (for both neonates and children [6,7]) and enables the nonlinear relationship between size (approximated using body weight) and the structural parameters to be estimated.…”

“…Previous studies described the population PK of micafungin in 72 children aged 2 to 17 years with febrile neutropenia (6) and 47 infants aged Ͻ120 days with suspected or proven invasive candidiasis (7). In this analysis, we describe the population PK of micafungin in 229 children aged 4 months to Ͻ17 years with a range of different diseases.…”

“…These studies enrolled patients across different age groups and have led to the development of a variety of population PK models (6,7). The overriding goal has been the identification of regimens that produce drug exposures comparable with those observed in adults, for whom the efficacy has been established in a number of phase II and III clinical trials (2,(8)(9)(10).…”

Antifungal Pharmacokinetics and Pharmacodynamics

“…Monte Carlo simulation has been very helpful to define dosing regimens for difficult-tostudy populations, such as children and neonates, and for certain infections in which the study of different dosing regimens is impractical based on the number of possible regimens or unethical because the study would include suboptimal regimens that cannot be justified (Hope et al 2007b(Hope et al , 2008(Hope et al , 2010Ikawa et al 2009;Warn et al 2012). Forexample, studies using the bridging technique of Monte Carlo simulation were performed for neonates and children with hematogenous Candida meningoencephalitis, a rare but well-recognized and potentially lethal infection, with micafungin and anidulafungin (Hope et al 2010;Warn et al 2012).…”

“…Forexample, studies using the bridging technique of Monte Carlo simulation were performed for neonates and children with hematogenous Candida meningoencephalitis, a rare but well-recognized and potentially lethal infection, with micafungin and anidulafungin (Hope et al 2010;Warn et al 2012). In both cases, the recommended dosing strategy would be expected to lead to suboptimal outcome, and therefore higher dosing regimens are recommended.…”