Drug disposition

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.

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.

Sildenafil Exposure in the Neonatal Intensive Care Unit

Posted on by Kayla Korzekwinski

American Journal of Perinatology • February 2019

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Thompson EJ, Perez K, Hornik CP, Smith PB, Clark RH, Laughon M; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee

Pulmonary hypertension causes substantial morbidity and mortality in infants. Although Food and Drug Administration approved to treat pulmonary arterial hypertension in adults, sildenafil is not approved for infants. This study sought to describe sildenafil exposure and associated diagnoses and outcomes in infants.

Systemic Timolol Exposure Following Topical Application to Infantile Hemangiomas

Posted on by Kayla Korzekwinski

Journal of the American Academy of Dermatology • February 2019

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Drolet BA, Boakye-Agyeman F, Harper B, Holland K, Lewandowski A, Stefanko N, Melloni C; Pediatric Trials Network Steering Committee.

Off-label ophthalmic timolol has been rapidly adopted for treatment of infantile hemangioma since topical application of beta-blockers was presumed to have an improved safety profile compared to oral administration. We examined timolol plasma concentrations in children receiving ophthalmic preparations applied to skin hemangiomas.

National Survey of Neonatal Intensive Care Unit Medication Safety Practices

Posted on by Kayla Korzekwinski

American Journal of Perinatology • November 2018

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Greenberg RG, Smith PB, Bose C, Clark RH, Cotten CM, DeRienzo C.

We conducted a detailed survey to identify medication safety practices among a large network of United States neonatal intensive care units (NICUs). We created a 53-question survey to assess 300 U.S. NICU’s demographics, medication safety practices, adverse drug event (ADE) reporting, and ADE response plans.

Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus

Posted on by Kayla Korzekwinski

CPT Pharmacometrics & Systems Pharmacology • November 2018

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Ku LC, Hornik CP, Beechinor RJ, Chamberlain JM, Guptill JT, Harper B, Capparelli EV, Martz K, Anand R, Cohen-Wolkowiez M, Gonzalez D; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.

Diazepam is labeled for status epilepticus (SE) in children, but there are limited data characterizing its disposition in pediatric patients. We developed a population pharmacokinetic (PK) model of i.v. diazepam in children with SE. We evaluated relationships between PK parameters and both safety and efficacy, and simulated exposures using dosing regimens from the product label and clinical practice.