Obesity

Development and Evaluation of a Virtual Population of Children with Obesity for Physiologically Based Pharmacokinetic Modeling

Posted on by Kayla Korzekwinski

Clinical Pharmacokinetics • February 2022

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Gerhart JG, Carreno FO, Edginton AN, Sinha J, Perrin E, Kumar KR, Rikhi A, Hornik CP, Harris V, Ganguly S, Cohen-Wolkowiez M, Gonzalez D; on behalf of the Best Pharmaceuticals for Children Act — Pediatric Trials Network Steering Committee
A virtual population of children with obesity was developed using national survey, electronic health record, and clinical trial data, as well as data extracted from the literature. The objective of this study was to develop a virtual population of children with obesity to enable physiologically based pharmacokinetic modeling, then use the novel virtual population in conjunction with previously developed models of clindamycin and trimethoprim/sulfamethoxazole to better understand dosing of these drugs in children with obesity. Model simulations supported current recommended weight-based dosing in children with obesity for clindamycin and trimethoprim/sulfamethoxazole, as they met target exposure despite these changes in clearance and volume of distribution.

Estimation of Body Fat Percentage for Clinical Pharmacokinetic Studies in Children

Posted on by Kayla Korzekwinski

Clinical and Translational Science • March 2021

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Green TP, Binns HJ, Wu H, Ariza AJ, Perrin EM, Quadri M, Hornik CP, Cohen-Wolkowiez M

Obesity is a prevalent childhood condition and the degree of adiposity is likely to be an important covariate in the pharmacokinetics (PKs) of many drugs. The goal of these studies was to facilitate the evaluation and, where appropriate, quantification of the covariate effect of body fat percentage (BF%) on PK parameters in children. Researchers examined two large databases to determine the values and variabilities of BF% in children with healthy body weights and in those with obesity, comparing the accuracy and precision of BF% estimation by both clinical methods and demographically derived techniques. They also conducted simulation studies to evaluate the utility of the several methods for application in clinical trials. The estimation of BF% from sex and obesity stage can routinely be applied to PK clinical trials to evaluate the contribution of BF% as a potential covariate.

Pharmacokinetics of Hydrochlorothiazide in Children: A Potential Surrogate for Renal Secretion Maturation

Posted on by Kayla Korzekwinski

The Journal of Clinical Pharmacology • March 2021

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Commander SJ, Wu H, Boakye-Agyeman F, Melloni C, Hornik CD, Zimmerman K, Al-Uzri A, Mendley SR, Harper B, Cohen-Wolkowiez M, Hornik CP
Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment of hypertension and edema. The pharmacokinetic (PK) properties of HCTZ in children are not well characterized, particularly among children with obesity who frequently suffer from hypertension and may, therefore, benefit from HCTZ therapy. Simulated exposure decreased with age and was likely due to older children receiving the maximum absolute doses of HCTZ. Further studies with more patients in each age group are required to confirm these PK findings of HCTZ in the children.

Dosing of Continuous Fentanyl Infusions in Obese Children: A Population Pharmacokinetic Analysis

Posted on by Kayla Korzekwinski

The Journal of Clinical Pharmacology • December 2019

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Maharaj AR, Wu H, Zimmerman KO, Speicher D, Sullivan JE, Watt K, Al-Uzri A, Payne E, Erinjeri J, Lin S, Harper B, Melloni C, Hornik CP; on behalf of the Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee
The impact of childhood obesity on fentanyl PK is relatively unknown. We developed a population pharmacokinetic (PopPK) model using opportunistically collected samples from a cohort of predominately obese children receiving fentanyl per the standard of care. Use of an allometric relationship between weight and clearance was appropriate for describing the PK of intravenous fentanyl in our cohort. Our proposed model-derived continuous infusion strategy maximized the probability of achieving target steady-state concentrations in children of varying weights.

Population Pharmacokinetics of Doxycycline in Children

Posted on by Kayla Korzekwinski

Antimicrobial Agents and Chemotherapy • September 2019

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Thompson EJ, Wu H, Melloni C, Balevic S, Sullivan JE, Laughon M, Clark KM, Kalra R, Mendley S, Payne E, Erinjeri J, Gelber C, Harper B, Cohen-Wolkoweiz M, Hornik CP

Doxycycline is a tetracycline-class antimicrobial labeled by the United States (U.S.) Food and Drug Administration for children >8 years of age for many common childhood infections. Doxycycline is not labeled for children ≤8 years of age, due to the association between tetracycline class antibiotics and tooth staining. We leveraged opportunistically-collected plasma samples after intravenous (IV) and oral doxycycline doses received per standard of care to characterize the pharmacokinetics (PK) of doxycycline in children of different ages between 0 and 18 years.

Low Etanercept Concentrations in Children With Obesity and Juvenile Idiopathic Arthritis

Posted on by Kayla Korzekwinski

The Journal of Pediatric Pharmacology and Therapeutics • November 2021

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Balevic SJ, Becker ML, Gonzalez D, Funk RS

This study evaluated the impact of obesity on etanercept (ETN) drug exposure in children with juvenile idiopathic arthritis (JIA). The data suggest that children who are obese may be routinely under-dosed using current dosing strategies. As a result, characterizing adequate drug exposure in children of all sizes is an important step toward precision dosing.

Pharmacokinetics of Ceftazidime in Children and Adolescents with Obesity

Posted on by Kayla Korzekwinski

Paediatric Drugs • September 2021

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Maharaj AR, Wu H, Zimmerman KO, Muller WJ, Sullivan JE, Sherwin CMT, Autmizguine J, Rathore MH, Hornik CD, Al-Uzri A, Payne EH, Hornik CP, on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee

The aim of this study was to evaluate ceftazidime pharmacokinetics (PK) in a cohort that includes a predominate number of children and adolescents with obesity and assess the efficacy of competing dosing strategies.

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.

A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents

Posted on by Kayla Korzekwinski

Pediatric Drugs • October 2018

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Shakhnovich V, Brian Smith P, Guptill JT, James LP, Collier DN, Wu H, Livingston CE, Zhao J, Kearns GL, Cohen-Wolkowiez M; Best Pharmaceuticals for Children Act–Pediatric Trials Network.

Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers.

Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures

Posted on by Kayla Korzekwinski

The Journal of Pediatrics • February 2018

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Shakhnovich V, Smith PB, Guptill JT, James LP, Collier DN, Wu H, Livingston CE, Zhao J, Kearns GL; Best Pharmaceuticals for Children Act – Pediatric Trials Network.

To assess appropriate pantoprazole dosing for obese children, we conducted a prospective pharmacokinetics (PK) investigation of pantoprazole in obese children, a patient population that is traditionally excluded from clinical trials. A total of 41 obese children (6-17 years of age), genotyped for CYP2C19 variants *2, *3, *4, and *17, received a single oral dose of pantoprazole, ~1.2 mg/kg lean body weight (LBW), with LBW calculated via a validated formula.