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Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants.

ABSTRACT: BACKGROUND:The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood. OBJECTIVES:The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants. METHODS:We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model. RESULTS:We identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration-time curve over 24 hours (AUC24,SS) and maximum concentration of sildenafil (Cmax,SS,SIL) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC24,SS; 1.19 (0.78, 1.82) for Cmax,SS,SIL. CONCLUSIONS:We found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil's safety profile in infants is warranted.

SUBMITTER: Hornik CP

PROVIDER: S-EPMC5720916 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants.

Hornik Christoph P CP Onufrak Nikolas J NJ Smith P Brian PB Cohen-Wolkowiez Michael M Laughon Matthew M MM Clark Reese H RH Gonzalez Daniel D

Cardiology in the young 20170808 1

<h4>Background</h4>The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood.<h4>Objectives</h4>The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants.<h4>Methods</h4>We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a populat ...[more]

PMID: 28784200

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Project description:PURPOSE:To characterize the population pharmacokinetics of cyclophosphamide, active 4-hydroxy-cyclophosphamide (4OH-CTX), and inactive carboxyethylphosphoramide mustard (CEPM), and their associations with hematologic toxicities in infants and young children with brain tumors. To use this information to provide cyclophosphamide dosing recommendations in this population. PATIENTS AND METHODS:Patients received four cycles of a 1-hour infusion of 1.5 g/m2 cyclophosphamide. Serial samples were collected to measure cyclophosphamide, 4OH-CTX, and CEPM plasma concentrations. Population pharmacokinetic modeling was performed to identify the patient characteristics influencing drug disposition. Associations between drug exposures and metrics reflecting drug-induced neutropenia, erythropenia, and thrombocytopenia were investigated. A Bayesian approach was developed to predict 4OH-CTX exposure using only cyclophosphamide and CEPM plasma concentrations. RESULTS:Data from 171 patients (0.07-4.9 years) were adequately fitted by a two-compartment (cyclophosphamide) and one-compartment model (metabolites). Young infants (<6 months) exhibited higher mean 4OH-CTX exposure than did young children (138.4 vs. 107.2 ?mol/L·h, P < 0.0001). No genotypes exhibited clinically significant influence on drug exposures. Worse toxicity metrics were significantly associated with higher 4OH-CTX exposures. Dosing simulations suggested decreased cyclophosphamide dosage to 1.2 g/m2 for young infants versus 1.5 g/m2 for children to attain similar 4OH-CTX exposure. Bayesian-modeled 4OH-CTX exposure predictions were precise (mean absolute prediction error 14.8% ± 4.2%) and had low bias (mean prediction error 4.9% ± 5.1%). CONCLUSIONS:A 4OH-CTX exposure-toxicity association was established, and a decreased cyclophosphamide dosage for young infants was suggested to reduce toxicity in this population. Bayesian modeling to predict 4OH-CTX exposure may reduce clinical processing-related costs and provide insights into further exposure-response associations.

Dataset Information

Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants.

Publications

Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants.

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