Publications by authors named "Gregory L Kearns"

98 Publications

Clearance of buprenorphine during pregnancy and neonatal outcomes.

Arch Womens Ment Health 2021 Apr 16. Epub 2021 Apr 16.

Department of Psychiatry, University of Wisconsin, Madison, WI, USA.

Buprenorphine is emerging as the preferred pharmacologic treatment for opioid use disorder during pregnancy. We examined the relative plasma clearance of buprenorphine (BUP) across pregnancy. Pregnant women with opioid use disorder participating in a prospective, observational study from 2013 to 2016 on stress in pregnancy who were receiving BUP for opioid use disorder were included. Women with an active eating disorder or suicidal ideation were excluded. Research visits occurred at 4-6-week intervals across pregnancy and the early postpartum period and included medication exposure history and blood samples. All assays for BUP serum concentrations at steady state were completed. Relative weight-adjusted clearance (Cl) was calculated using Cl = (daily dose [mg]/ body weight [kg])/serum concentration [ng/ml]. We collected 112 maternal blood samples from 29 women throughout pregnancy and the postpartum period. Serum concentrations for BUP ranged from < 0.2 to 15.8 ng/ml. Eleven women, with greater than three collected samples, increased their daily dose of BUP during pregnancy; however, there were no significant differences in relative clearance of BUP across this same period. This data suggests that women with opioid use disorder receiving BUP did not demonstrate a significant increase in BUP clearance across pregnancy despite increase in dosages during pregnancy. When selecting an appropriate BUP dosage for management of perinatal opioid use disorder, gestational stage appears not to be an important covariate and should be based on an individualized approach.
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http://dx.doi.org/10.1007/s00737-021-01128-1DOI Listing
April 2021

Adolescents and Drug Development: Commentary on a Dawning Paradigm Shift.

J Clin Pharmacol 2021 Jun 20;61(6):740-743. Epub 2021 Apr 20.

Departments of Pediatrics, Pharmacology and Physiology and Genomics & Precision Medicine, George Washington University School of Medicine and Health Sciences and Children's National Hospital, Washington, District of Columbia, USA.

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http://dx.doi.org/10.1002/jcph.1862DOI Listing
June 2021

A Pilot Comparison of High- Versus Low-Tech Palatability Assessment Tools in Young Children.

Paediatr Drugs 2021 Jan 25;23(1):95-104. Epub 2020 Nov 25.

Texas Christian University and UNTHSC School of Medicine, Fort Worth, TX, USA.

Background: Medication refusal in children is largely driven by aversive taste profiles, which in turn influence adherence and therapeutic outcomes. However, there are no standardized methods for evaluating taste in young children. This study compares facial recognition technology with three hedonic visual scales in this population.

Methods: Children, 3-7 years of age, were enrolled with informed parental permission into an institutional review board-approved, double-blind, randomized investigation. Each child received three test articles: prednisone (bitter), simple syrup (sweet), and filtered water (neutral), with an appropriate washout. Facial recognition software (Noldus FaceReader 7) recorded facial expression and intensity for 30-60 s after administration. Participants subsequently rated taste using three hedonic scales (5-point Sjövall and 5- and 3-point TASTY) and responded to simple questions on their perception of the test article. Repeated measures analysis of variance and multiple regression analysis were used to explore associations between palatability measures.

Results: Twelve children (seven males: ten white and two black) completed the study without adverse effects. There were no significant differences in participant characteristics by randomization sequence. The three hedonic scales tracked similarly for each test substance, with correlations between the 5-point scales (r = 0.899) comparable to those between the 3- and 5-point scales (r = 0.860-0.903). Hedonic scales appeared more reliable in assessing taste response than facial recognition, which did not effectively discriminate positive and negative responses.

Conclusions: Our experience suggests that the TASTY scales appear to offer the greatest promise for assessing palatability in future clinical use.
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http://dx.doi.org/10.1007/s40272-020-00430-2DOI Listing
January 2021

Bioavailability testing of a newly developed clindamycin oral suspension in a pediatric porcine model.

Pharm Dev Technol 2019 Oct 21;24(8):1038-1043. Epub 2019 Jun 21.

b Department of Pharmaceutical Sciences , University of Tennessee Health Science Center , Memphis , TN , USA.

Clindamycin's bitter taste and odor is known to affect treatment adherence in children. Recently, a formulation of clindamycin HCl complexed with ion exchange resin IRP 69 was shown to mask the bitter taste. Because of the potential benefit of this formulation for children, a pilot study using a porcine model was conducted to evaluate its relative bioavailability. A randomized two-way crossover study design using six ( = 6) healthy male piglets 10-12 kg was used to evaluate the absorption profiles and pharmacokinetic parameters of clindamycin from the resinate complex formulation (Test) compared to a commercialized reference suspension. A dose of 15 mg/kg was administered orally by gastric gavage to each piglet followed by repeated blood sampling over 12 h. A wash-out period of 48 h occurred between treatments. Plasma concentration vs. time data was analyzed by non-compartmental analysis. The mean relative bioavailability of clindamycin from the resinate formulation was 78.8%. A two-tailed, paired Student t test yielded a  < 0.05 for and parameters. A two one-sided test (TOST) suggested a difference in and for the Test formulation compared to the reference formulation according to the FDA's criteria for bioequivalence. The bioavailability of clindamycin from this novel oral formulation supports continued evaluation of the drug in humans for potential pediatric applications.
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http://dx.doi.org/10.1080/10837450.2019.1624771DOI Listing
October 2019

Evaluating metronidazole as a novel, safe CYP2A6 phenotyping probe in healthy adults.

Br J Clin Pharmacol 2019 05 12;85(5):960-969. Epub 2019 Mar 12.

Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Kansas City, MO, USA.

Aims: CYP2A6 is a genetically polymorphic enzyme resulting in differential substrate metabolism and health behaviours. Current phenotyping probes for CYP2A6 exhibit limitations related to procurement (deuterated cotinine), toxicity (coumarin), specificity (caffeine) and age-appropriate administration (nicotine, NIC). In vitro, CYP2A6 selectively forms 2-hydroxymetronidazole (2HM) from metronidazole (MTZ). The purpose of this study was to evaluate MTZ as a CYP2A6 phenotyping probe drug in healthy adults against the well-established method of measuring trans-3-hydroxycotinine (3HC)/cotinine (COT).

Methods: A randomized, cross-over, pharmacokinetic study was completed in 16 healthy, nonsmoking adults. Separated by a washout period of at least 2 weeks, MTZ 500 mg and NIC gum 2 mg were administered and plasma was sampled over 48 hours and 8 hours, respectively. Correlations of plasma metabolite/parent ratios (2HM/MTZ; 3HC/COT) were assessed by Pearson coefficient. CYP2A6 genotyping was conducted and incorporated as a variable of plasma ratio response.

Results: Correlations between the plasma ratio 2HM/MTZ and 3HC/COT were ≥ 0.9 at multiple time points (P < 0.001), demonstrating a wide window during which 2HM/MTZ can be queried post-MTZ dose. CYP2A6 genotype had significant impacts on both MTZ and NIC phenotyping ratios with decreased activity predicted phenotypes demonstrating 2HM/MTZ ratios ≤58% and 3HC/COT ratios ≤56% compared with extensive activity predicted phenotypes at all time points examined in the study (P < 0.05). No adverse events were reported in the MTZ arm while 38% (n = 6) of participants reported mild adverse events in the NIC arm.

Conclusions: Metronidazole via 2HM/MTZ performed well as a novel, safe phenotyping probe for CYP2A6 in healthy adults.
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http://dx.doi.org/10.1111/bcp.13884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475679PMC
May 2019

How to Conduct Clinical Trials in Children: A Tutorial.

Clin Transl Sci 2019 05 18;12(3):218-230. Epub 2019 Mar 18.

Children's Mercy Kansas City, Kansas City, Missouri, USA.

Despite a growing interest in, and commitment to, implementing pediatric clinical trials, approximately one in every five trials in children fails because of inappropriate study design, suboptimal experiment planning, or inadequate participant enrollment. This tutorial, presented from the perspectives of seasoned pediatric investigators, an experienced research coordinator, and an established pediatric clinical trials network, is designed to provide practical guidance for successfully implementing pediatric clinical trials at an academic center or another comparable institution.
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http://dx.doi.org/10.1111/cts.12615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510379PMC
May 2019

Developmental Changes in Pharmacokinetics and Pharmacodynamics.

J Clin Pharmacol 2018 10;58 Suppl 10:S10-S25

Arkansas Children's Research Institute, Little Rock, AR, USA.

Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In pediatrics, age is a continuum that can and does add variability in drug disposition and effect. This article addresses the many important factors that influence drug disposition and effect relative to age. What is known about the influence of maturation on the processes of drug absorption, distribution, metabolism, excretion, and drug receptor dynamics are outlined. Our state of understanding of many of these factors remains in flux, however, and only with additional study will we be able to better anticipate and model drug-response relationships across the age continuum. Being able to continuously improve our care of the ill pediatric patient while simultaneously being able to accurately determine the utility of new drugs and chemical entities in this population requires our enhanced understanding of these disposition characteristics.
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http://dx.doi.org/10.1002/jcph.1284DOI Listing
October 2018

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

Paediatr Drugs 2018 Oct;20(5):483-495

Duke Clinical Research Institute, Durham, NC, USA.

Background And Aims: 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. Subsequently, we developed a population-based pharmacokinetic (PopPK) model to characterize pantoprazole disposition and evaluated appropriate pantoprazole dosing strategies for obese pediatric patients, using simulation.

Methods: Pharmacokinetic data from the only prospective study of PPIs in obese children (aged 6-17 years; n = 40) included 273 pantoprazole and 256 pantoprazole-sulfone plasma concentrations, after single oral-dose administration, and were used for pantoprazole model development and covariate analysis (NONMEM). Model evaluation was performed via bootstrapping and predictive checks, and the final model was applied to simulate systemic pantoprazole exposures for common dosing scenarios.

Results: A two-compartment PopPK model, which included CYP2C19 genotype and total body weight, provided the best fit. Resultant, typical, weight-normalized pantoprazole parameter estimates were different than previously reported for children or adults, with significantly reduced pantoprazole CL/F for obese children. Of the dosing scenarios evaluated, the weight-tiered approach, approved by the US Food and Drug Administration, achieved pantoprazole exposures [area under the curve (AUC)] within ranges previously reported as therapeutic, without over- or under-prediction for obese children.

Conclusions: Our data argue against empiric dose escalation of PPIs for obese children and support current FDA-approved pediatric weight-tiered dosing for pantoprazole; however, 3- to 5-fold inter-individual variability in pantoprazole AUC remained using this dosing approach.
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http://dx.doi.org/10.1007/s40272-018-0305-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178956PMC
October 2018

Reply.

J Pediatr 2018 07 18;198:327-328. Epub 2018 Apr 18.

Department of Pediatrics University of Arkansas for Medical Sciences Section of Clinical Pharmacology and Toxicology Arkansas Children's Hospital Little Rock, Arkansas.

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http://dx.doi.org/10.1016/j.jpeds.2018.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704112PMC
July 2018

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

J Pediatr 2018 02;193:102-108.e1

Department of Pediatrics, University of Arkansas for Medical Sciences Section of Clinical Pharmacology and Toxicology, Arkansas Children's Hospital, Little Rock, AR.

Objective: 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.

Study Design: 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. Ten post-dose pantoprazole plasma concentrations were measured, and PK variables generated via noncompartmental methods (WinNonlin). Linear and nonlinear regression analyses and analyses of variance were used to explore obesity, age, and CYP2C19 genotype contribution to pantoprazole PK. PK variables of interest were compared with historic nonobese peers treated with pantoprazole.

Results: Independent of genotype, when normalized to dose per kg total body weight, pantoprazole apparent clearance and apparent volume of distribution were significantly lower (P < .05) and systemic exposure significantly higher (P < .01) in obese vs nonobese children. When normalized per kg LBW, these differences were not evident in children ≥12 years of age and markedly reduced in children <12 years of age.

Conclusions: LBW dosing of pantoprazole led to pantoprazole PK similar to nonobese peers. Additional factors, other than body size (eg, age-related changes in CYP2C19 activity), appear to affect pantoprazole PK in children <12 years of age.

Trial Registration: ClinicalTrials.gov: NCT02186652.
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http://dx.doi.org/10.1016/j.jpeds.2017.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806153PMC
February 2018

Targeted metabolomic profiling indicates structure-based perturbations in serum phospholipids in children with acetaminophen overdose.

Toxicol Rep 2016 23;3:747-755. Epub 2016 Aug 23.

Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.

Phospholipids are an important class of lipids that act as building blocks of biological cell membranes and participate in a variety of vital cellular functions including cell signaling. Previous studies have reported alterations in phosphatidylcholine (PC) and lysophosphatidylcholine (lysoPC) metabolism in acetaminophen (APAP)-treated animals or cell cultures. However, little is known about phospholipid perturbations in humans with APAP toxicity. In the current study, targeted metabolomic analysis of 180 different metabolites including 14 lysoPCs and 73 PCs was performed in serum samples from children and adolescents hospitalized for APAP overdose. Metabolite profiles in the overdose group were compared to those of healthy controls and hospitalized children receiving low dose APAP for treatment of pain or fever (therapeutic group). PCs and lysoPCs with very long chain fatty acids (VLCFAs) were significantly decreased in the overdose group, while those with comparatively shorter chain lengths were increased in the overdose group compared to the therapeutic and control groups. All ether linked PCs were decreased in the overdose group compared to the controls. LysoPC-C26:1 was highly reduced in the overdose group and could discriminate between the overdose and control groups with 100% sensitivity and specificity. The PCs and lysoPCs with VLCFAs showed significant associations with changes in clinical indicators of drug metabolism (APAP protein adducts) and liver injury (alanine aminotransferase, or ALT). Thus, a structure-dependent reduction in PCs and lysoPCs was observed in the APAP-overdose group, which may suggest a structure-activity relationship in inhibition of enzymes involved in phospholipid metabolism in APAP toxicity.
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http://dx.doi.org/10.1016/j.toxrep.2016.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5616013PMC
August 2016

The Need for Pediatric Drug Development.

J Pediatr 2018 01 21;192:13-21. Epub 2017 Sep 21.

Department of Pediatrics, University of Utah, School of Medicine, Salt Lake City, UT.

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http://dx.doi.org/10.1016/j.jpeds.2017.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942021PMC
January 2018

Pharmacokinetics of two 6-mercaptopurine liquid formulations in children with acute lymphoblastic leukemia.

Pediatr Blood Cancer 2017 Aug 10;64(8). Epub 2017 Mar 10.

Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Background: A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation.

Methods: Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts. Group 1 (n = 11; five males) received a 5 mg/ml liquid formulation and the marketed 50 mg 6-MP tablet on separate occasions, and Group 2 (n = 11; five males) received a 50 mg/ml liquid formulation and the marketed tablet. The usual prescribed 6-MP dose (25-115 mg/m ) was given after an 8-hr fast. Serial blood samples were collected over 8 hr postdose. Plasma 6-MP concentrations were determined using a good laboratory practice (GLP)-validated liquid chromatography-tandem mass spectrometry method. PK parameters were calculated using noncompartmental analysis and compared within and between cohorts, and thiopurine methyltransferase (TPMT) genotype was analyzed.

Results: No patient had a TPMT genotype reflective of a poor metabolizer phenotype. Comparison of PK parameters between 5 and 50 mg/ml treatments revealed significant differences (P <0.05) in AUC (where AUC is area under the curve), C , and T . Comparisons within each group revealed significant differences in AUC and T in the 5 mg/ml group.

Conclusions: Pharmacokinetic profiles of 6-MP established in healthy adults with the approved liquid formulation may not reflect the PK profile in children with ALL. Formulation-specific differences in PK may significantly impact the dose-exposure profile in these children and must be considered.
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http://dx.doi.org/10.1002/pbc.26465DOI Listing
August 2017

Palatability of a novel oral formulation of prednisone in healthy young adults.

J Pharm Pharmacol 2017 Apr 8;69(4):489-496. Epub 2017 Mar 8.

Arkansas Children's Research Institute, Little Rock, AR, USA.

Objectives: Prednisone is a widely used anti-inflammatory for a variety of conditions. While oral liquid formulations of prednisone enable weight-based dosing, children frequently find them to be objectionable due to bitter taste. This limitation of prednisone can adversely impact patient acceptance and may result in non-compliance. Efforts to mask flavours often result in poorly controlled, heterogeneous particle distributions and can provide ineffective taste masking. The present work utilized a novel drug delivery technology developed by Orbis Biosciences, Inc., to create an oral taste-masked formulation of prednisone.

Methods: The study examined the palatability of Orbis' microsphere prednisone formulation in healthy young adults (n = 24). Four test articles were used in the study including a reference formulation (Roxanne Laboratories), a control and the test formulation (Orbis) prepared in two different ways. Study participants were randomized in a crossover design.

Key Findings: Results indicated that the test prednisone formulation was indistinguishable from the control, and both were preferable to the reference formulation in every category of palatability assessed using a validated 9-point Hedonic Scale. The data also suggested that preparing the microsphere suspension immediately before administration results in the most ideal palatability properties.

Conclusions: In conclusion, the novel microsphere formulation technology was effective in taste-masking prednisone.
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http://dx.doi.org/10.1111/jphp.12710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360468PMC
April 2017

Decreased Pregnane X Receptor Expression in Children with Active Crohn's Disease.

Drug Metab Dispos 2016 07 24;44(7):1066-9. Epub 2016 Mar 24.

The Children's Mercy Hospital, Kansas City, Missouri (V.S., C.V., C.F., V.S., J.D., J.S.L.) University of California San Diego, San Diego, California (A.H.); Arkansas Children's Hospital Research Institute, Little Rock, Arkansas (G.L.K.). Laboratory of origin: The Children's Mercy Hospital.

Expression of the pregnane X receptor (PXR) has been reported to be decreased in animal models of inflammatory bowel disease (IBD). To investigate the differential expression of PXR in children with Crohn's disease, a type of IBD, RNA was extracted from archived intestinal biopsies from 18 children with Crohn's disease (CD) and 12 age- and sex-matched controls (aged 7-17yrs). The aim of this investigation was to compare the relative mRNA expression of PXR, cytochrome p450 3A4 (CYP3A4), and villin 1 (VIL1) (a marker of epithelial cell integrity) in the inflamed terminal ileum (TI) versus noninflamed duodenum of children with CD. Relative expression was determined via reverse transcription real-time quantitative polymerase chain reaction, data normalized to glyceraldehyde 3-phosphate dehydrogenase, and differences in gene expression explored via paired t tests. PXR expression was decreased in the inflamed TI versus noninflamed duodenum (TI = 1.88 ± 0.89 versus duodenum = 2.5 ± 0.67; P < 0.001) in CD, but not controls (TI = 2.11 ± 0.41 versus duodenum = 2.26 ± 0.61; P = 0.52). CYP3A4 expression was decreased in CD (TI = -0.89 ± 3.11 versus duodenum = 1.90 ± 2.29; P < 0.05), but not controls (TI = 2.46 ± 0.51 versus duodenum = 2.60 ± 0.60; P = 0.61), as was VIL1 (CD TI = 3.80 ± 0.94 versus duodenum = 4.61 ± 0.52; P < 0.001; controls TI = 4.30 ± 0.35 versus duodenum = 4.47 ± 0.40; P = 0.29). PXR expression correlated with VIL1 (r = 0.78, P = 0.01) and CYP3A4 (r = 0.52, P = 0.01) expression. In conclusion, PXR, CYP3A4, and VIL1 expression was decreased only in the actively inflamed small intestinal tissue in children with CD. Our findings suggest that inflammation has the potential to influence expression of genes, and potentially intestinal proteins, important to drug disposition and response. The observed differential patterns of gene expression support further investigation of the role of PXR in the pathogenesis and/or treatment of pediatric Crohn's disease.
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http://dx.doi.org/10.1124/dmd.115.068742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931888PMC
July 2016

Clinical and Pharmacologic Considerations for Guanfacine Use in Very Young Children.

J Child Adolesc Psychopharmacol 2016 08 19;26(6):498-504. Epub 2016 Feb 19.

3 Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Hospital , Kansas City, Missouri.

Objective: Guanfacine, in the immediate release form, remains a commonly used medication for the treatment of clinically significant hyperactivity, impulsivity, or disruptive behaviors. This article reviews the available literature regarding guanfacine use in very young children (<6 years of age), and explores some of the factors that may uniquely impact the clinical pharmacology of guanfacine in very young children and that deserve consideration when it is used in this patient population.

Methods: The authors performed electronic literature searches in PubMed through October 2015 using the terms attention-deficit/hyperactivity disorder, guanfacine, and alpha agonists. We also performed an informal review of the literature and used selected articles from relevant reference lists. The result was a broad, qualitative review of the literature, with a focus on specific factors regarding guanfacine use in very young children.

Results: Despite the fact that guanfacine is commonly used in very young children, there is a paucity of published studies that looked specifically at its use in this population. In reviewing the pharmacology of guanfacine, there are specific factors that may play a unique role in its disposition in very young children.

Conclusions: Guanfacine is an important medication option in very young children; however, there is a significant pharmacologic "information gap," and further research is needed to help establish appropriate, safe, and effective dosing of guanfacine in this population.
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http://dx.doi.org/10.1089/cap.2014.0159DOI Listing
August 2016

Functional Biomarkers: an Approach to Bridge Pharmacokinetics and Pharmacodynamics in Pediatric Clinical Trials.

Curr Pharm Des 2015 ;21(39):5636-42

Arkansas Children's Hospital Research Institute and the Department of Pediatrics at the University of Arkansas for Medical Sciences.

Over the past 30 years, much has been learned about the impact of development on drug disposition (i.e., pharmacokinetics). This is not true concerning drug action (i.e., pharmacodynamics). As a consequence, in clinical therapeutics and the drug development process, assumptions are often times made that a specific systemic drug exposure that is associated with desired drug action in adults will produce the same response in children. A review of the literature would suggest that this assumption may, in some cases, be an errant one. The relative paucity of information concerning developmental pharmacodynamics is associated with the challenge of assessing and quantitating drug response in vivo in infants and children. An approach to overcome these difficulties has been the evolution of biomarkers that are functional in nature in that they are capable of measuring drug response in both a time and age dependent fashion. The purpose of this review is to illustrate how functional biomarkers capable of assessing drug response/ effect in the developing child are developed and being evaluated for their clinical utility.
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http://dx.doi.org/10.2174/1381612821666150901105337DOI Listing
September 2016

Availability of Oral Formulations Labeled for Use in Young Children in Serbia, Germany and the USA.

Curr Pharm Des 2015 ;21(39):5668-73

Department of Pharmacology, School of Medicine, University of Belgrade, P.O. Box 38, 11129 Belgrade 102, Serbia.

Background: The paucity of marketed drug products that have been adequately studied in infants and children and subsequently, licensed (or labeled) for pediatric use has caused abundant use of off-label and unauthorized products in this patient population. In those instances where insufficient pharmacologic or therapeutic information exists for children, the potential for off-label use of medicines to result in therapeutic misadventure does as well. In the USA, a series of regulatory measures have been introduced since 1997 which have increased both the number and scope of pediatric drug trials and also, fostered the development of ageappropriate drug formulations by pharmaceutical companies. Provisions of these regulations for previously marketed drugs include the potential for a company to be granted 6 months of marketing exclusivity, thereby providing them with a financial incentive. For new drugs being developed that have potential pediatric use, the regulations mandate the inclusion of children in the drug development process. In the EU comparable measures have been very recently (Jan 2007) signed into European law to overcome the therapeutic orphan status of the infants and children of Europe.

Method: The aims of this study was to compare the availability of age-appropriate oral formulations labeled for use in children less than 12 years of age in Serbia, Germany and USA in 2007, and to investigate if certain drug groups of therapeutic importance to children had fewer medicines appropriately labeled for pediatric patients available. The primary sources of information for determining the ageappropriate oral dosage forms, and their licensing and labeling status were the official manuals on drug information and national formularies in 2007.

Finding: The general availability of oral drugs was the highest in the USA (304), followed by Germany (235) and Serbia (156). From all these oral drugs the availability of labeled age-appropriate pediatric dosage formulations was only between 21.2% and 47.7%. Moreover, there were striking differences between the three countries in the availability of labeled age-appropriate formulations for certain drug groups such as cardiovascular (absent in Serbia) and antiparasitic drugs (absent in Serbia and Germany).

Interpretation: Our data suggest that significant country-to-country differences continue to exist in both the number and type of oral drug formulations that have pediatric labeling. Potential contributing factors include country-specific differences in the drug regulatory process, capacity for pharmaceutical development and the regulatory lag time associated with the implementation of drug regulation specifically addressing pediatric product development and labeling. We hypothesize that the new European regulation concerning medicines and children will improve the current unacceptable situation.
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http://dx.doi.org/10.2174/1381612821666150901105925DOI Listing
September 2016

Systemic exposure to menthol following administration of peppermint oil to paediatric patients.

BMJ Open 2015 Aug 12;5(8):e008375. Epub 2015 Aug 12.

Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA Division of Pediatric Gastroenterology, Texas Children's Hospital, Houston, Texas, USA Children's Nutrition Research Center, Houston, Texas, USA.

Objective: Peppermint oil (PMO) has been used to treat abdominal ailments dating to ancient Egypt, Greece and Rome. Despite its increasing paediatric use, as in irritable bowel syndrome (IBS) treatment, the pharmacokinetics (PK) of menthol in children given PMO has not been explored.

Design And Setting: Single-site, exploratory pilot study of menthol PK following a single 187 mg dose of PMO. Subjects with paediatric Rome II defined (IBS; n=6, male and female, 7-15 years of age) were enrolled. Blood samples were obtained before PMO administration and at 10 discrete time points over a 12 h postdose period. Menthol was quantitated from plasma using a validated gas chromatography mass spectrometry technique. Menthol PK parameters were determined using a standard non-compartmental approach.

Results: Following a dose of PMO, a substantial lag time (range 1-4 h) was seen in all subjects for the appearance of menthol which in turn, produced a delayed time of peak (Tmax=5.3 ± 2.4 h) plasma concentration (Cmax=698.2 ± 245.4 ng/mL). Tmax and Tlag were significantly more variable than the two exposure parameters; Cmax, mean residence time and total area under the curve (AUC=4039.7 ± 583.8 ng/mL × h) which had a coefficient of variation of <20%.

Conclusions: Delayed appearance of menthol in plasma after oral PMO administration in children is likely a formulation-specific event which, in IBS, could increase intestinal residence time of the active ingredient. Our data also demonstrate the feasibility of using menthol PK in children with IBS to support definitive studies of PMO dose-effect relationships.
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http://dx.doi.org/10.1136/bmjopen-2015-008375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538270PMC
August 2015

Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design.

Clin Pharmacokinet 2015 Dec;54(12):1273-85

Sino-French Pediatric Research Center, Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012, Jinan, China.

Background And Objective: The use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation, as well as dose prediction, and compare this strategy with a predetermined pharmacokinetic sampling approach.

Methods: Three population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), predetermined (i.e. scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients.

Results: Pharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at predetermined times and 165 that were scavenged from those obtained as part of clinical care. All datasets were fit using a two-compartment model with first-order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady-state volume of distribution) compared with the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation, and showed similar results. Monte Carlo simulation based on area under the concentration-time curve from zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) using either the SC or the TR model gave similar dose prediction for ciprofloxacin.

Conclusion: Blood samples scavenged in the course of caring for neonates can be used to estimate ciprofloxacin pharmacokinetic parameters and therapeutic dose requirements.
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http://dx.doi.org/10.1007/s40262-015-0291-1DOI Listing
December 2015

The challenge of obesity in paediatric leukaemia treatment: it is not just size that matters.

Arch Dis Child 2015 Jan 21;100(1):101-5. Epub 2014 Oct 21.

Department of Pediatrics and Pharmacology, University of Missouri Kansas City, Kansas City, Missouri, USA Center for Children's Healthy Lifestyles and Nutrition, The Children's Mercy Hospital, Kansas City, Missouri, USA.

In the last two decades, tremendous advances have been made in the treatment of acute lymphocytic leukaemia (ALL) in children with 5 year 'cure' rates in excess of 90%. The maintenance of remission is due, in part, to individualisation of therapy which must consider age, body size, genetic constitution and the impact of disease on drug disposition and action. This review, focused on treatment of ALL and one of the therapeutic mainstays, 6-mercaptopurine, illustrates the importance of obesity as a modulating factor in dose individualisation.
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http://dx.doi.org/10.1136/archdischild-2014-307147DOI Listing
January 2015

Pupillometry: a non-invasive technique for pain assessment in paediatric patients.

Arch Dis Child 2014 Dec 3;99(12):1125-31. Epub 2014 Sep 3.

Departments of Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri, USA Divisions of Clinical Pharmacology, The Children's Mercy Hospital, Kansas, Missouri, USA Department of Pharmacology, The University of Missouri, Kansas, Missouri, USA Department of Hematology and Oncology, The Children's Mercy Hospital, Kansas, Missouri, USA.

Objective: Pupillometry has been used to assess pain intensity and response to analgesic medications in adults. The aim of this observational study was to explore proof of concept for the use of this technique in paediatric patients. Changes in pupil parameters before and after opioid exposure also were evaluated.

Design And Setting: This was a single-centre, prospective study conducted at an academic paediatric medical centre.

Patients: Children 9-17 years of age undergoing elective surgical correction of pectus excavatum were enrolled into a protocol approved by the human ethical committee (institutional review board).

Interventions: Pupil size and reactivity were measured using a handheld pupillometer. Pain was assessed using age-appropriate, validated pain self-report scales.

Results: Thirty patients were enrolled. Each point change on a 10 cm visual analogue pain intensity scale was associated with a statistically significant mean change of 0.11 mm/s in maximum pupil constriction velocity, and of approximately 0.4% in pupil diameter. As expected, there was an association between total opioid dose (expressed as morphine equivalents) and pupil diameter. Age, sex and baseline anxiety scores did not correlate significantly with pupillary response.

Conclusions: The association of maximum pupillary constriction velocity and diameter with pain scores illustrates the potential for using pupillometry as a non-invasive method to objectively quantitate pain response/intensity in children. The technique holds promise as a pharmacodynamic 'tool' to assess opioid response in paediatric patients.
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http://dx.doi.org/10.1136/archdischild-2014-306286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395877PMC
December 2014

Population pharmacokinetics of ciprofloxacin in neonates and young infants less than three months of age.

Antimicrob Agents Chemother 2014 Nov 25;58(11):6572-80. Epub 2014 Aug 25.

Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France Clinical Investigation Center CIC1426, INSERM, Paris, France EA7323, Université Paris Diderot-Université Paris Descartes, Paris, France

Ciprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.
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http://dx.doi.org/10.1128/AAC.03568-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249352PMC
November 2014

Rifapentine Pharmacokinetics and Tolerability in Children and Adults Treated Once Weekly With Rifapentine and Isoniazid for Latent Tuberculosis Infection.

J Pediatric Infect Dis Soc 2014 Jun 16;3(2):132-45. Epub 2014 Jan 16.

Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults.

Methods: Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentration-time curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME).

Results: There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed.

Conclusions: A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults.
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http://dx.doi.org/10.1093/jpids/pit077DOI Listing
June 2014

Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease.

J Clin Pharmacol 2014 Sep 11;54(9):1016-22. Epub 2014 Apr 11.

Department of Biopharmaceutics and Pharmacokinetics, Medical University of Gdansk, Gdansk, Poland.

The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222 hour. The typical apparent volume of distribution was 21.8 L and the apparent systemic clearance was 6.88 L/h for an average weight patient of 30.7 kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6 hours post-dose and AUC with the most significant (R(2)  = 0.71) observed at 1.5 hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 hours after an oral dose of the drug were highly predictive of systemic drug exposure.
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http://dx.doi.org/10.1002/jcph.303DOI Listing
September 2014

Estimation of body weight in children in the absence of scales: a necessary measurement to insure accurate drug dosing.

Arch Dis Child 2014 Jun 26;99(6):570-4. Epub 2014 Feb 26.

Department of Pediatrics, The University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA The Division of Pediatric Pharmacology and Therapeutic Innovation, The Children's Mercy Hospital, Kansas City, Missouri, USA.

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http://dx.doi.org/10.1136/archdischild-2013-305211DOI Listing
June 2014

Targeted liquid chromatography-mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children.

Biomark Med 2014 ;8(2):147-59

Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA and Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA.

Aim: Long-chain acylcarnitines have been postulated to be sensitive biomarkers of acetaminophen (APAP)-induced hepatotoxicity in mouse models. In the following study, the relationship of acylcarnitines with other known indicators of APAP toxicity was examined in children receiving low-dose (therapeutic) and high-dose ('overdose' or toxic ingestion) exposure to APAP.

Materials & Methods: The study included three subject groups: group A (therapeutic dose, n = 187); group B (healthy controls, n = 23); and group C (overdose, n = 62). Demographic, clinical and laboratory data were collected for each subject. Serum samples were used for measurement of APAP protein adducts, a biomarker of the oxidative metabolism of APAP and for targeted metabolomics analysis of serum acylcarnitines using ultra performance liquid chromatography-triple-quadrupole mass spectrometry.

Results: Significant increases in oleoyl- and palmitoyl-carnitines were observed with APAP exposure (low dose and overdose) compared with controls. Significant increases in serum ALT, APAP protein adducts and acylcarnitines were observed in overdose children that received delayed treatment (time to treatment from overdose >24 h) with the antidote N-acetylcysteine. Time to peak APAP protein adducts in serum was shorter than that of the acylcarnitines and serum ALT.

Conclusion: Perturbations in long-chain acylcarnitines in children with APAP toxicity suggest that mitochrondrial injury and associated impairment in the β-oxidation of fatty acids are clinically relevant as biomarkers of APAP toxicity.
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http://dx.doi.org/10.2217/bmm.13.150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125006PMC
October 2014

Adverse events associated with meropenem versus imipenem/cilastatin therapy in a large retrospective cohort of hospitalized infants.

Pediatr Infect Dis J 2013 Jul;32(7):748-53

Duke Clinical Research Institute and Department of Pediatrics, Duke University, Durham, NC 27715, USA.

Background: Carbapenems are commonly used in hospitalized infants despite a lack of complete safety data and associations with seizures in older children. We compared the incidence of adverse events in hospitalized infants receiving meropenem versus imipenem/cilastatin.

Methods: We conducted a retrospective cohort study of 5566 infants treated with meropenem or imipenem/cilastatin in neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. Multivariable conditional logistic regression was performed to evaluate the association between carbapenem therapy and adverse events, controlling for infant factors and severity of illness.

Results: Adverse events were more common with use of meropenem compared with imipenem/cilastatin (62.8/1000 infant days versus 40.7/1000 infant days, P < 0.001). There was no difference in seizures with meropenem versus imipenem/cilastatin (adjusted odds ratio 0.96; 95% confidence interval: 0.68, 1.32). The incidence of death, as well as the combined outcome of death or seizure, was lower with meropenem use-odds ratio 0.68 (0.50, 0.88) and odds ratio 0.77 (0.62, 0.95), respectively.

Conclusion: In this cohort of infants, meropenem was associated with more frequent but less severe adverse events when compared with imipenem/cilastatin.
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http://dx.doi.org/10.1097/INF.0b013e31828be70bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708263PMC
July 2013

The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst.

Drug Metab Dispos 2013 Sep 27;41(9):1686-94. Epub 2013 Jun 27.

Section of Developmental Pharmacology and Experimental Therapeutics, Division of Pediatric Clinical Pharmacology and Therapeutic Innovation, The Children's Mercy Hospitals, Kansas City, MO 64108, USA.

Despite metronidazole's widespread clinical use since the 1960s, the specific enzymes involved in its biotransformation have not been previously identified. Hence, in vitro studies were conducted to identify and characterize the cytochrome P450 enzymes involved in the formation of the major metabolite, 2-hydroxymetronidazole. Formation of 2-hydroxymetronidazole in human liver microsomes was consistent with biphasic, Michaelis-Menten kinetics. Although several cDNA-expressed P450 enzymes catalyzed 2-hydroxymetronidazole formation at a supratherapeutic concentration of metronidazole (2000 μM), at a "therapeutic concentration" of 100 μM only CYPs 2A6, 3A4, 3A5, and 3A7 catalyzed metronidazole 2-hydroxylation at rates substantially greater than control vector, and CYP2A6 catalyzed 2-hydroxymetronidazole formation at rates 6-fold higher than the next most active enzyme. Kinetic studies with these recombinant enzymes revealed that CYP2A6 has a Km = 289 μM which is comparable to the Km for the high-affinity (low-Km) enzyme in human liver microsomes, whereas the Km values for the CYP3A enzymes corresponded with the low-affinity (high-Km) component. The sample-to-sample variation in 2-hydroxymetronidazole formation correlated significantly with CYP2A6 activity (r ≥ 0.970, P < 0.001) at substrate concentrations of 100 and 300 μM. Selective chemical inhibitors of CYP2A6 inhibited metronidazole 2-hydroxylation in a concentration-dependent manner and inhibitory antibodies against CYP2A6 virtually eliminated metronidazole 2-hydroxylation (>99%). Chemical and antibody inhibitors of other P450 enzymes had little or no effect on metronidazole 2-hydroxylation. These results suggest that CYP2A6 is the primary catalyst responsible for the 2-hydroxylation of metronidazole, a reaction that may function as a marker of CYP2A6 activity both in vitro and in vivo.
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http://dx.doi.org/10.1124/dmd.113.052548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876806PMC
September 2013