Fluconazole

Physiologically-Based Pharmacokinetic Modeling Characterizes the CYP3A-Mediated Drug-Drug Interaction Between Fluconazole and Sildenafil in Infants

Posted on by Kayla Korzekwinski

Clinical Pharmacology & Therapeutics • January 2021

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Salerno SN, Edginton A, Gerhart JG, Laughon MM, Ambalavanan N, Sokol GM, Hornik CD, Stewart D, Mills M, Martz K, Gonzalez D; on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee
Infants being treated for pulmonary hypertension and prevention or treatment of invasive candidiasis may be given sildenafil with fluconazole concurrently. Physiologically-based pharmacokinetic (PBPK) modeling can potentially predict pediatric drug-drug interactions (DDIs) when clinical DDI data are limited. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters.

Population pharmacokinetics of sildenafil in extremely premature infants

Posted on by Kayla Korzekwinski

British Journal of Clinical Pharmacology • December 2019

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Gonzalez D, Laughon MM, Smith PB, Ge S, Ambalavanan N, Atz A, Sokol GM, Hornik CD, Stewart D, Mundakel G, Poindexter BB, Gaedigk R, Mills M, Cohen-Wolkowiez M, Martz K, Hornik CP

We performed a multicentre, open-label trial to characterize the pharmacokinetics (PK) of sildenafil in infants ≤28 weeks gestation and < 365 postnatal days (cohort 1) or < 32 weeks gestation and 3-42 postnatal days (cohort 2). We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study.

Physiologically-Based Pharmacokinetic Modeling of Fluconazole Using Plasma and Cerebrospinal Fluid Samples From Preterm and Term Infants

Posted on by Kayla Korzekwinski

CPT: Pharmacometrics & Systems Pharmacology • May 2019

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Gerhart JG, Watt KM, Edginton A, Wade KC, Salerno SN, Benjamin DK, Smith PB, Hornik CP, Cohen-Wolkowiez M, Duara S, Ross A, Shattuck K, Stewart DL, Neu N, Gonzalez D, on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee

Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically-based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children.

Antifungal Extraction by the Extracorporeal Membrane Oxygenation Circuit

Posted on by Kayla Korzekwinski

The Journal of ExtraCorporeal Technology • September 2017

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Watt KM, Cohen-Wolkowiez M, Williams DC, Bonadonna DK, Cheifetz IM, Thakker D, Benjamin DK Jr, Brouwer KLR

Invasive candidiasis is common and often fatal in patients supported with extracorporeal membrane oxygenation (ECMO), and treatment relies on optimal antifungal dosing. The ECMO circuit can extract drug and decrease drug exposure, placing the patient at risk of therapeutic failure. This ex vivo study determined the extraction of antifungal drugs by the ECMO circuit. Fluconazole and micafungin were studied separately in three closed-loop circuit configurations to isolate the impact of the oxygenator, hemofilter, and tubing on circuit extraction.

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

Posted on by Kayla Korzekwinski

Antimicrobial Agents and Chemotherapy • August 2016

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Momper JD, Capparelli EV, Wade KC, Kantak A, Dhanireddy R, Cummings JJ, Nedrelow JH, Hudak ML, Mundakel GT, Natarajan G, Gao J, Laughon M, Smith PB, Benjamin DK Jr.

Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly.

Fluconazole Prophylaxis for the Prevention of Candidiasis in Premature Infants: A Meta-analysis Using Patient-level Data

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Clinical Infectious Diseases • August 2016

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Ericson JE, Kaufman DA, Kicklighter SD, Bhatia J, Testoni D, Gao J, Smith PB, Prather KO, Benjamin DK Jr; Fluconazole Prophylaxis Study Team on behalf of the Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee.

Invasive candidiasis (IC) is an important cause of sepsis in premature infants and is associated with a high risk of death and neurodevelopmental impairment. Prevention of IC has become a major focus in very low birth weight infants, with fluconazole increasingly used as prophylaxis. We identified all randomized, placebo-controlled trials evaluating fluconazole prophylaxis in premature infants conducted in the United States.

Dosing in neonates: Special considerations in physiology and trial design

Posted on by Kayla Korzekwinski

Pediatric Research • January 2016

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Ku LC, Smith PB
Determining the right dose for drugs used to treat neonates is critically important. Neonates have significant differences in physiology affecting drug absorption, distribution, metabolism, and elimination that makes extrapolating dosages from adults and older children inappropriate. Fortunately, specialized analytical techniques, such as the use of dried blood spots, scavenged sampling, population pharmacokinetics analyses, and sparse sampling, have helped investigators better define doses that maximize efficacy and safety. Through the use of these methods, successful clinical trials have resulted in recent changes to drug dosing in this population.

Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation

Posted on by Kayla Korzekwinski

Antimicrobial Agents and Chemotherapy • June 2015

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Watt KM, Gonzalez D, Benjamin DK Jr, Brouwer KL, Wade KC, Capparelli E, Barrett J, Cohen-Wolkowiez M.

Candida infections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis.

Editorial commentary: Fluconazole therapeutic drug monitoring in children with cancer: not today

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Clinical Infectious Disease • December 2014

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Cohen-Wolkowiez M, Benjamin DK Jr.

This editorial focuses on insufficient fluconazole exposure in pediatric cancer patients and the need for therapeutic drug monitoring in critically ill children.

Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial

Posted on by Kayla Korzekwinski

JAMA • June 2014

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Benjamin DK Jr, Hudak ML, Duara S, Randolph DA, Bidegain M, Mundakel GT, Natarajan G, Burchfield DJ, White RD, Shattuck KE, Neu N, Bendel CM, Kim MR, Finer NN, Stewart DL, Arrieta AC, Wade KC, Kaufman DA, Manzoni P, Prather KO, Testoni D, Berezny KY, Smith PB; Fluconazole Prophylaxis Study Team.

Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown. This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days.