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Population Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Children

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Lestner, Jodi M, Groll, Andreas H, Aljayyoussi, Ghaith, Seibel, Nita L, Shad, Aziza, Gonzalez, Corina, Wood, Lauren V, Jarosinski, Paul F, Walsh, Thomas J and Hope, William W (2016) 'Population Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Children'. Antimicrobial Agents and Chemotherapy, Vol 60, Issue 12, pp. 7340-7346.

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Abstract

BACKGROUND
Liposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited PK data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults.

OBJECTIVES
To describe the pharmacokinetics of LAmB in children aged 1-17 years with suspected or documented IFD.

METHODS
Thirty-five children were treated with LAmB at dosages of 2.5-10 mg kg(-1) daily. Samples were taken at baseline and at 0.5-2.0 hourly intervals for twenty-four hours 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.

RESULTS
An evolution in PK was observed during the course of therapy resulting in a proportion of patients (n=13) having significantly higher maximum serum concentration (Cmax) and area under the concentration time curve (AUC0-24) later in the course of therapy, without evidence of drug accumulation (Cmin accumulation ratio, AR < 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 AUC0-24 and probability of nephrotoxicity (OR 2.37; 95% CI 1.84-3.22, p=0.004).

CONCLUSIONS
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.

Item Type: Article
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 252 Antifungal agents. Antifungal antibiotics
QV Pharmacology > QV 38 Drug action.
QW Microbiology and Immunology > Immune Responses > QW 700 Infection. Mechanisms of infection and resistance.
QW Microbiology and Immunology > Immunotherapy and Hypersensitivity > QW 920 Immunosuppression. Immunosuppressive agents
WS Pediatrics > By Age Groups > WS 460 Adolescence (General)
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1128/AAC.01427-16
Depositing User: Jessica Jones
Date Deposited: 07 Oct 2016 15:04
Last Modified: 06 Feb 2018 13:13
URI: http://archive.lstmed.ac.uk/id/eprint/6248

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