Publications

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

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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.

Dexmedetomidine Pharmacokinetics and a New Dosing Paradigm in Infants Supported With Cardiopulmonary Bypass

Posted on by Kayla Korzekwinski

Anesthesia & Analgesia • December 2019

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Zimmerman KO, Wu H, Laughon M, Greenberg RG, Walczack R, Schulman SR, Smith PB, Hornik CP, Cohen-Wolkowiez M, Watt KM

Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB.

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

Posted on by Kayla Korzekwinski

The Journal of Clinical Pharmacology • October 2019

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Balevic SJ, Cohen-Wolkowiez M

Almost half of recent pediatric trials failed to achieve labeling indications, due in large part to inadequate study design. Therefore, innovative study methods are crucial to optimize trial design while also reducing the potential harms inherent with drug investigation. New and innovative study designs are imperative to address current clinical pharmacology gaps and to ensure future therapeutics are safe and effective for children.

Rifampin Pharmacokinetics and Safety in Preterm and Term Infants

Posted on by Kayla Korzekwinski

Antimicrobial Agents and Chemotherapy • May 2019

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Smith PB, Cotten CM, Hudak ML, Sullivan JE, Poindexter BB, Cohen-Wolkowiez M, Boakye-Agyeman F, Lewandowski A, Anand R, Benjamin DK Jr, Laughon MM; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee.

Rifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We performed a multicenter, prospective pharmacokinetic (PK) and safety study of intravenous rifampin in infants of <121 days postnatal age (PNA). We enrolled 27 infants; the median (range) gestational age was 26 weeks (23 to 41 weeks), and the median PNA was 10 days (0 to 84 days). We collected 102 plasma PK samples from 22 of the infants and analyzed safety data from all 27 infants. We analyzed the data using a population PK approach.

Surfactant Administration in Preterm Infants: Drug Development Opportunities

Posted on by Kayla Korzekwinski

The Journal of Pediatrics • May 2019

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Taylor G, Jackson W, Hornik CP, Koss A, Mantena S, Homsley K, Gattis B, Kudumu-Clavell M, Clark R, Smith PB, Laughon MM

This study evaluated how frequently surfactant is used off-label in preterm infants. The majority of surfactant given to preterm infants is administered off-label. The uptrend in administration via INSURE coincides with increased supporting evidence. The gap between FDA labeling and current clinic practice exemplifies an opportunity for label expansion, which may require additional prospective or retrospective safety and/or effectiveness data for infants of older GA and higher birth weight.

Pharmacokinetics of ticarcillin-clavulanate in premature infants

Posted on by Kayla Korzekwinski

British Journal of Clinical Pharmacology • May 2019

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Watt KM, Hornik CP, Balevic SJ, Mundakel G, Cotten CM, Harper B, Benjamin DK, Anand R, Laughon M, Smith PB, Cohen-Wolkowiez M; Best Pharmaceuticals for Children Act Pediatric Trials Network Steering Committee

Ticarcillin-clavulanate covers a broad spectrum of pathogens that are common in premature infants. In infants <30 weeks gestational age, pharmacokinetic data to guide ticarcillin-clavulanate dosing are lacking. This study enrolled premature infants <30 weeks gestational age, determined pharmacokinetic parameters, and performed dosing simulations to determine optimal dosing for ticarcillin-clavulanate.

Furosemide Exposure and Prevention of Bronchopulmonary Dysplasia in Premature Infants

Posted on by Kayla Korzekwinski

The Journal of Pediatrics • May 2019

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Greenberg RG, Gayam S, Savage D, Tong A, Gorham D, Sholomon A, Clark RH, Benjamin DK, Laughon M, Smith PB

The goal of this study was to evaluate the association between furosemide exposure and risk of bronchopulmonary dysplasia (BPD) for premature infants. More days of furosemide exposure between postnatal day 7 and 36 weeks was associated with decreased risk of BPD and a combined outcome of BPD or death.

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.

Product Labeling of Drugs Commonly Administered to Children and Adults with Obesity

Posted on by Kayla Korzekwinski

Pharmaceutical Regulatory Affairs • April 2019

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Zimmerman KO, Benjamin DK ,Becker ML, Anand R, Hornik CP

Obesity is a major public health problem that can affect drug disposition and dosing, particularly in vulnerable pediatric populations. Despite potentially detrimental consequences from inappropriately dosed drugs in children with obesity, drug product labels largely fail to include dosing or guidance specific to this population. Using data from the PTN, this study explored possible ways to improve drug labeling in children with obesity.

Pharmacokinetics of Hydroxychloroquine in Pregnancies with Rheumatic Diseases

Posted on by Kayla Korzekwinski

Clinical Pharmacokinetics • April 2019

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Balevic SJ, Green TP, Clowse MEB, Eudy AM, Schanberg LE, Cohen-Wolkowiez M

 Hydroxychloroquine is an oral drug prescribed to pregnant women with rheumatic disease to reduce disease activity and prevent flares. Physiologic changes during pregnancy may substantially alter drug pharmacokinetics. However, the effect of pregnancy on hydroxychloroquine disposition and the potential need for dose adjustment remains virtually unknown. This study developed a one-compartment population-pharmacokinetic model for hydroxychloroquine in pregnant women with rheumatic disease.