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Population pharmacokinetics and pharmacodynamics of caspofungin in pediatric patients.

ABSTRACT: We describe the pharmacokinetics (PKs) of caspofungin, an echinocandin antifungal, administered once daily as a 1-hour intravenous infusion in children and adolescents (ages, 3 months to 17 years), based on pooled data from four prospective pediatric studies. Caspofungin dosing was body-surface-area (BSA) based (50 mg/m2 daily after 70 mg/m2 on day 1). The area under the concentration-time curve from time zero to 24 h (AUC0-24), the concentration at the end of infusion (1 h after the start of infusion; C1), and the trough concentration (24 h after the start of infusion; C24) were obtained for 32 pediatric patients with invasive candidiasis, 10 with invasive aspergillosis, and 82 in the setting of empirical therapy with fever and neutropenia. Exposures were modestly higher (93 to 134% for C1, 45 to 78% for C24, ?40% for AUC0-24) in pediatric patients than in adults receiving the standard 50-mg daily dose. The potential for covariates (age, gender, weight, race, renal status, serum albumin level, and disease state) to alter PKs was evaluated with a multiple-linear-regression model. Weight and disease state had statistically significant (P<0.05) yet small effects on caspofungin PKs in pediatric patients. Concomitant use of dexamethasone (a cytochrome p450 inducer) was associated with a statistically significant reduction (44%) in C24 in a limited number of patients (n=4). Odds ratios were estimated for the association between log-transformed PKs and treatment outcome or adverse events. No PK parameter or hybrid parameter (AUC/MIC, C1/MIC, and C24/MIC) was significantly correlated with treatment outcome or adverse events in the setting of similar response levels as adults, which suggests that the concentrations examined fall within the therapeutic window for caspofungin in pediatric patients. These results support a 50-mg/m2 daily dosing regimen (after a 70-mg/m2 loading dose) in children ages 3 months to 17 years.

SUBMITTER: Li CC

PROVIDER: S-EPMC3088186 | biostudies-other | 2011 May

REPOSITORIES: biostudies-other

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Population pharmacokinetics and pharmacodynamics of caspofungin in pediatric patients.

Li Chi-Chung CC Sun Peng P Dong Yingwen Y Bi Sheng S Desai Rajesh R Dockendorf Marissa Fallon MF Kartsonis Nicholas A NA Ngai Angela L AL Bradshaw Susan S Stone Julie A JA

Antimicrobial agents and chemotherapy 20110207 5

We describe the pharmacokinetics (PKs) of caspofungin, an echinocandin antifungal, administered once daily as a 1-hour intravenous infusion in children and adolescents (ages, 3 months to 17 years), based on pooled data from four prospective pediatric studies. Caspofungin dosing was body-surface-area (BSA) based (50 mg/m2 daily after 70 mg/m2 on day 1). The area under the concentration-time curve from time zero to 24 h (AUC0-24), the concentration at the end of infusion (1 h after the start of in ...[more]

PMID: 21300834

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Project description:• Population pharmacokinetics and pharmacodynamics of rivaroxaban have been characterized in healthy subjects and in patients with total venous thromboembolism, deep vein thrombosis or atrial fibrillation.• This article is the first description of the population pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in patients with acute coronary syndrome (ACS). It is the largest population pharmacokinetic and pharmacodynamic study on rivaroxaban conducted to date (n= 2290). The PK and PK-PD relationship of rivaroxaban in patients with ACS were similar to those in other patient populations. In addition, model-based simulations showed that the influence of renal function and age on the exposure to rivaroxaban in the ACS population were similar to the findings from Phase 1 special population studies. These findings suggest that rivaroxaban has highly predictable PK-PD and may provide a consistent anticoagulant effect across the studied patient populations, which allows an accurate prediction of the dose to control anticoagulation optimally.The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS. METHODS A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated.The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h(-1) (interindividual variability, 139%), 6.48 l h(-1) (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients.The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure-prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied.

Dataset Information

Population pharmacokinetics and pharmacodynamics of caspofungin in pediatric patients.

Publications

Population pharmacokinetics and pharmacodynamics of caspofungin in pediatric patients.

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