Dosing recommendations

Use of physiologically-based pharmacokinetic modeling to inform dosing of the opioid analgesics fentanyl and methadone in children with obesity

Posted on by Kayla Korzekwinski

CPT: Pharmacometrics & Systems Pharmacology • June 2022

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Gerhart JG, Carreno FO, Ford JL, Edginton AN, Perrin EM, Watt KM, Muller WJ, Atz AM, Al-Uzri A, Delmore P, Gonzalez D; on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee
Children with obesity are commonly prescribed the opioids fentanyl and methadone, and accurate dosing is critical to reducing the risk of serious adverse events associated with overexposure. However, there is limited information to guide fentanyl and methadone dosing in these children. This study addresses the clinical knowledge gap using physiologically-based pharmacokinetic models of fentanyl and methadone developed in adults and scaled to children with and without obesity to explore the interplay of obesity, age, and pharmacogenomics.

External Evaluation of Risperidone Population Pharmacokinetic Models Using Opportunistic Pediatric Data

Posted on by Kayla Korzekwinski

Frontiers in Pharmacology • March 2022

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Karatza E, Ganguly S, Hornik CD, Muller MJ, Al-Uzri A, James L, Balevic SJ, Gonzalez D; on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee
Risperidone is approved to treat schizophrenia in adolescents and autistic disorder and bipolar mania in children and adolescents. It is also used off-label in younger children for various psychiatric disorders. The objectives of this study were to assess whether opportunistically collected pediatric data can be used to evaluate risperidone population pharmacokinetic models externally and to identify a robust model for precision dosing in children. All the models had a modest predictive performance, potentially suggesting that sources of inter-individual variability were not entirely captured and that opportunistic data from a highly heterogeneous population are likely not the most appropriate data to evaluate risperidone models externally.

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.

Safety of sildenafil in extremely premature infants: a phase I trial

Posted on by Kayla Korzekwinski

Journal of Perinatology • January 2022

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Jackson W, Gonzalez D, Smith PB, Ambalavanan N, Atz A, Sokol GM, Hornik CD, Stewart D, Mundakel G, Poindexter BB, Ahlfeld SK, Mills M, Cohen-Wolkowiez M, Martz K, Hornik CP, Laughon MM; on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee
This study sought to characterize the safety of sildenafil in premature infants. Safety was evaluated based on adverse events (AEs), transaminase levels, and mean arterial pressure monitoring. There was one serious AE related to the study drug involving hypotension associated with a faster infusion rate than specified by the protocol. There were no AEs related to elevated transaminases. Sildenafil was well tolerated by the study population. Drug administration times and flush rates require careful attention to prevent infusion-related hypotension associated with faster infusions of IV sildenafil in premature infants.

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.

Population Pharmacokinetics of Metoclopramide in Infants, Children, and Adolescents

Posted on by Kayla Korzekwinski

Clinical and Translational Science • November 2020

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Ge S, Mendley SR, Gerhart JG, Melloni C, Hornik CP, Sullivan JE, Atz A, Delmore P, Tremoulet A, Poindexter BB, Harper B, Payne E, Lin S, Erinjeri J, Cohen-Wolkowiez M, Gonzalez D
Metoclopramide is commonly used for gastroesophageal reflux. The aims of the present study were to develop a pediatric population pharmacokinetic (PopPK) model, which was applied to simulate the metoclopramide exposure following dosing used in clinical practice. The study suggests that a metoclopramide dose as previously recommended for pediatric patients results in simulated exposure generally within suggested ranges for the treatment of gastroesophageal reflux.

Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019

Posted on by Kayla Korzekwinski

JAMA Pediatrics • October 2020

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Maharaj A, Wu H, Hornik CP, Balevic SJ, Hornik CD, Smith PB, Gonzalez D, Zimmerman KO, Benjamin DK Jr., Cohen-Wolkowiez M
This study sought to define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment. Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020).  Concerns were raised regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.

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 Milrinone in Infants, Children, and Adolescents

Posted on by Kayla Korzekwinski

Journal of Clinical Pharmacology • December 2019

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Hornik CP, Yogev R, Mourani PM, Watt KM, Sullivan JE, Atz AM, Speicher D, Al-Uzri A, Adu-Darko M, Payne E, Gelber C, Lin S, Harper B, Melloni C, Cohen-Wolkowiez M, Gonzalez D

Milrinone is a type 3 phosphodiesterase inhibitor used to improve cardiac output in critically ill infants and children. Milrinone is primarily excreted unchanged in the urine, raising concerns for toxic accumulation in the setting of renal dysfunction of critical illness. We developed a population pharmacokinetic model of milrinone using nonlinear mixed-effects modeling in NONMEM to perform dose-exposure simulations in children with variable renal function. Children below 21 years of age were included.

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.