Population Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Children

Abstract

Liposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited pharmacokinetic (PK) data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults. Our objective was to describe the pharmacokinetics of LAmB in children aged 1 to 17 years with suspected or documented IFD. Thirty-five children were treated with LAmB at doses of 2.5 to 10 mg kg ؊1 daily. Samples were taken at baseline and at 0.5-to 2.0-h intervals for 24 h after receipt of the first dose (n ‫؍‬ 35 patients) and on the final day of therapy (n ‫؍‬ 25 patients). LAmB was measured using high-performance liquid chromatography (HPLC). The relationship between drug exposure and development of toxicity was explored. An evolution in PK was observed during the course of therapy, resulting in a proportion of patients (n ‫؍‬ 13) having significantly higher maximum serum concentrations (C max ) and areas under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) later in the course of therapy, without evidence of drug accumulation (trough plasma concentration accumulation ratio of <1.2). The fit of a 2-compartment model incorporating weight and an exponential decay function describing volume of distribution best described the data. There was a statistically significant relationship between mean AUC 0 -24 and probability of nephrotoxicity (odds ratio, 2.37; 95% confidence interval, 1.84 to 3.22; P ‫؍‬ 0.004). LAmB exhibits nonlinear pharmacokinetics. A third of children appear to experience a time-dependent change in PK, which is not explained by weight, maturation, or observed clinical factors. The small unilamellar liposomal formulation of amphotericin B (LAmB; AmBisome) is widely used for the treatment of invasive fungal disease (IFD) in adults and children. This compound has been available for over 2 decades and is a first-line agent in the treatment of serious opportunistic diseases that include invasive aspergillosis, invasive candidiasis, cryptococcal meningoencephalitis, and mucormycosis (1-4).Despite extensive clinical experience, many of the details relating to the underlying pharmacological properties of LAmB remain unclear. A limited number of data sets and population pharmacokinetic (PK) models have been reported for LAmB (5-7). These analyses were based on data gathered from patients receiving relatively low doses and exclusively sampled early in the course of therapy. There are very limited data reporting the PK of LAmB in pediatric populations.A better understanding of the pharmacological properties of LAmB remains a priority and would enable optimal dosing, particularly for special populations, such as infants and children. Doses ranging from 2.5 to 10 mg kg Ϫ1 per day were studied, and each patient was intensively sampled. The individual PK profiles for a subpopulation of participants (n ϭ 25) were compared at the commencement and end of therapy. MATERIALS AND METHODSPatients and antifungal regimen. This stud...

Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis

“…Inspection of the PK data of liposomal amphotericin B in rabbits suggested that the volume of distribution contracted with time, as recently described by us in children (19). with output equation where X 1 and X 2 are the amounts of liposomal amphotericin B in the central and peripheral compartments, respectively.…”

Minimum concentration of Amphotericin B in serum according to the formulation, dose, and daily or prolonged intermittent therapeutic regimen

“…In the non-daily regimen of L-AmB, the patient had measurable amphotericin B in serum even when 50 mg was infused for the seven prior days, although, mean trough serum concentration was found to decrease with a reduction in the dose and number of weekly infusions. This observation agrees with the results of the Cmin obtained in a few days after the discontinuation of L-AmB treatment, which revealed more reduced levels in patients who had received lower doses of the drug 15,16 . The blood concentrations of amphotericin B were markedly reduced 24 to 48 h after infusion, and despite the administration of a high dose of 10 mg/kg weight/ week, a Cmin of less than 1 µg/mL was observed after 168 h 9 .…”

“…The Cmin values for D-Amph and L-AmB were comparable to those detected in the initial studies on the pharmacokinetics of the daily administration of L-AmB 2,14 . The increase in Cmin with the increase in the daily dose of L-AmB was observed previously, despite the lack of a directly proportional relationship 15 . The blood trough levels of L-Amb were higher than those obtained with the tolerated daily doses of D-Amph; however, a significantly higher Cmin relative to that with D-Amph was only achieved with a daily dose of 100 mg (~2 mg/kg weight).…”

Safety, Tolerability, and Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Pediatric Patients

“…The differences in the mean last-day AUC 0 -24 and AUC 0 -∞ values for a dose of 10 mg/kg/day, being higher in adults than in pediatric patients, may be related to interpatient variability. A population pharmacokinetic model, which was developed from these data, demonstrated nonlinear pharmacokinetics as well as a time-dependent change that was not explained by any of the covariates monitored in this study (19).…”