Candidiasis

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

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.

Safety, Effectiveness, and Exposure-Response of Micafungin in Infants: Application of an Established Pharmacokinetics Model to Electronic Health Records

Posted on by Kayla Korzekwinski

The Pediatric Infectious Disease Journal • February 2020

Rivera-Chaparro ND, Ericson J, Wu H, Smith BP, Clark RH, Benjamin DK, Cohen-Wolkowiez M, Greenberg RG

 

Micafungin is used off-label in the United States to treat invasive candidiasis in neonates. This study used an established pharmacokinetic model to determine micafungin exposures for 46 courses in 39 hospitalized infants. In this small cohort of infants, micafungin exposure was not associated with laboratory markers of liver toxicity, death, or failure of microbiological clearance.

 

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

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

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.

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.

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

Posted on by Kayla Korzekwinski

Clinical Infectious Diseases • August 2016.

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.

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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.

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.

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

Posted on by Kayla Korzekwinski

JAMA • June 2014.

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.

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