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Pharmaceutics
Special Issues
Pharmacokinetics of Pediatric Drugs
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Pharmacokinetics of Pediatric Drugs

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 13171

Special Issue Editor

Prof. Dr. Stephanie L. Läer

E-Mail Website
Guest Editor
Heinrich-Heine-Universität Düsseldorf, Dusseldorf, Germany
Interests: clinical trials; pediatric research; cardiovascular treatment; heart failure; pharmacokinetics; pharmacodynamics

Special Issue Information

Dear Colleagues,

Pediatric drug therapy has stimulated ground-breaking research in pharmacokinetics and drug metabolism undertaken by all kinds of scientists working in pharmaceutical and medical research facilities as well as the pharmaceutical and biotechnology industry. Important pediatric drug regulations have paved the way for even more research in the pediatric field. The principle of drug absorption, distribution, metabolism and excretion (ADME) is the foundational basis of rational drug design and pharmacotherapy in children. The effect of maturation on ADME and its descriptive quantitative analysis is the basis of pediatric pharmacokinetics are fundamental in the drug development process. Pharmacokinetics in pediatric clinical trials facilitates an understanding of organ-based functionality and is essential for dosing regimens according to age in this special population. Population pharmacokinetic analysis and modeling of drug concentrations have a significant impact in understanding the variability of the heterogeneous pediatric patient groups.

This Special Issue serves to highlight and capture the contemporary progress and current landscape of pharmacokinetics and drug metabolism within the pediatric patient population. We invite articles on all aspects of pharmacokinetics and drug metabolism highlighting the world-class research currently undertaken in the field of pediatric research for this Special Issue.

Prof. Dr. Stephanie L. Läer
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • children
  • pharmaceutics
  • formulation
  • ontogeny and drug development
  • pharmacokinetics
  • clinical trials and ethical considerations
  • dosing in children
  • organ function and maturation
  • population pharmacokinetics
  • modeling and simulation
  • laboratory parameters

Published Papers (5 papers)

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Research

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19 pages, 2529 KiB  
Article
Pharmacogenetic Analysis of Voriconazole Treatment in Children
by Romy Tilen, Paolo Paioni, Aljoscha N. Goetschi, Roland Goers, Isabell Seibert, Daniel Müller, Julia A. Bielicki, Christoph Berger, Stefanie D. Krämer and Henriette E. Meyer zu Schwabedissen
Pharmaceutics 2022, 14(6), 1289; https://doi.org/10.3390/pharmaceutics14061289 - 17 Jun 2022
Cited by 5 | Viewed by 2148
Abstract
Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually [...] Read more.
Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually the therapeutic outcome. To investigate the impact of these genetic variants and other covariates on voriconazole trough concentrations, we performed a retrospective data analysis, where we used medication data from 36 children suffering from invasive fungal infections treated with voriconazole. Data were extracted from clinical information systems with the new infrastructure SwissPKcdw, and linear mixed effects modelling was performed using R. Samples from 23 children were available for DNA extraction, from which 12 selected polymorphism were genotyped by real-time PCR. 192 (49.1%) of 391 trough serum concentrations measured were outside the recommended range. Voriconazole trough concentrations were influenced by polymorphisms within the metabolizing enzymes CYP2C19 and CYP3A4, and within the drug transporters ABCC2 and ABCG2, as well as by the co-medications ciprofloxacin, levetiracetam, and propranolol. In order to prescribe an optimal drug dosage, pre-emptive pharmacogenetic testing and careful consideration of co-medications in addition to therapeutic drug monitoring might improve voriconazole treatment outcome of children with invasive fungal infections. Full article
(This article belongs to the Special Issue Pharmacokinetics of Pediatric Drugs)
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22 pages, 877 KiB  
Article
Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies)
by Stephanie Laeer, Willi Cawello, Bjoern B. Burckhardt, László Ablonczy, Milica Bajcetic, Johannes M. P. J. Breur, Michiel Dalinghaus, Christoph Male, Saskia N. de Wildt, Jörg Breitkreutz, Muhammed Faisal, Anne Keatley-Clarke, Ingrid Klingmann and Florian B. Lagler
Pharmaceutics 2022, 14(6), 1163; https://doi.org/10.3390/pharmaceutics14061163 - 30 May 2022
Cited by 4 | Viewed by 2692
Abstract
Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric [...] Read more.
Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric patients with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) in five participating European countries. Children were treated for 8 weeks with ODMTs according to an age-appropriate dosing schedule. The primary objective was to describe PK parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (t-max)) of enalapril and its active metabolite enalaprilat. Of 102 patients, 89 patients (n = 26, DCM; n = 63 CHD) were included in the primary PK endpoint analysis. Rate and extent of enalapril and its active metabolite enalaprilat were described and etiology and age could be identified as potential PK modifying factors. The dosing schedule appeared to be tolerated well and did not result in any significant drug-related serious adverse events. The PK analysis and the lack of severe safety events supports the applied age-appropriate dosing schedule for the enalapril ODMTs. Full article
(This article belongs to the Special Issue Pharmacokinetics of Pediatric Drugs)
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16 pages, 2138 KiB  
Article
Scaling Approaches for Pediatric Dose Selection: The Fremanezumab (AJOVY®) Journey to Select a Phase 3 Dose Using Pharmacokinetic Data from a Phase 1 Study
by Aksana Jones, Orit Cohen-Barak, Andrijana Radivojevic and Jill Fiedler-Kelly
Pharmaceutics 2021, 13(6), 785; https://doi.org/10.3390/pharmaceutics13060785 - 24 May 2021
Cited by 2 | Viewed by 2468
Abstract
Fremanezumab, a fully humanized IgG2Δa/kappa monoclonal antibody, selectively targets the calcitonin-gene-related peptide (CGRP) and prevents it from binding to the CGRP receptor. The safety, tolerability, pharmacokinetics (PK), and efficacy of fremanezumab for treating migraines administered as a once monthly 225 mg dose or [...] Read more.
Fremanezumab, a fully humanized IgG2Δa/kappa monoclonal antibody, selectively targets the calcitonin-gene-related peptide (CGRP) and prevents it from binding to the CGRP receptor. The safety, tolerability, pharmacokinetics (PK), and efficacy of fremanezumab for treating migraines administered as a once monthly 225 mg dose or a once quarterly 675 mg dose have been well characterized in adults. The fremanezumab exposure and body weight relationship supported the use of the approved 225 mg monthly adult dose for pediatric patients weighing ≥45 kg. In the pediatric Phase 3 program, a 120 mg dose for patients weighing <45 kg was determined using the results of an open-label study and a population PK modeling and simulation strategy. A thorough evaluation was conducted to further characterize the population PK of fremanezumab and assess the predictive performance of the adult population PK model when applied to the Phase 1 pediatric data, the predictive performance of alternative pediatric population PK models, and the predictive performance of the selected pediatric population PK model via a noncompartmental-based approach. This latter comparison to noncompartmental results provided additional evidence that the pediatric population PK model predicts the observed data well and supports the 120 mg monthly dose in patients weighing <45 kg. Full article
(This article belongs to the Special Issue Pharmacokinetics of Pediatric Drugs)
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12 pages, 1511 KiB  
Article
Umbilical Cord, Maternal Milk, and Breastfed Infant Levetiracetam Concentrations Monitoring at Delivery and during Early Postpartum Period
by Ivana Kacirova, Milan Grundmann and Hana Brozmanova
Pharmaceutics 2021, 13(3), 398; https://doi.org/10.3390/pharmaceutics13030398 - 17 Mar 2021
Cited by 8 | Viewed by 1595
Abstract
(1) To obtain objective information about levetiracetam transplacental passage and its transport into colostrum, mature milk, and breastfed infants, we analyzed data from women treated for epilepsy between October 2006 and January 2021; (2) in this cohort study, maternal, umbilical cord, milk, and [...] Read more.
(1) To obtain objective information about levetiracetam transplacental passage and its transport into colostrum, mature milk, and breastfed infants, we analyzed data from women treated for epilepsy between October 2006 and January 2021; (2) in this cohort study, maternal, umbilical cord, milk, and infant serum concentrations were measured at delivery, 2–4 days postpartum (colostrum) and 7–31 days postpartum (mature milk). Paired umbilical cord serum, maternal serum, breastfed infant serum, and milk concentrations were used to assess the ratios of umbilical cord/maternal serum, milk/maternal serum, and infant/maternal serum concentrations. The influence of combined treatment with enzyme-inducing antiseizure medication carbamazepine was assessed; (3) the umbilical cord/maternal serum concentration ratio ranged between 0.75 and 1.78 (mean 1.10 ± 0.33), paired maternal and umbilical cord serum concentrations were not significantly different, and a highly significant correlation was found between both concentrations. The mean milk/maternal serum concentration ratio was 1.14 ± 0.27 (2–4 days postpartum) and 1.04 ± 0.24 (7–31 days postpartum) while the mean infant/maternal serum concentration ratio was markedly lower (0.19 ± 0.13 and 0.14 ± 0.05, respectively); (4) levetiracetam was found in the umbilical cord at a concentration similar to those in maternal serum. All of the breastfed infant serum concentrations were below the reference range used for the general epileptic population. Full article
(This article belongs to the Special Issue Pharmacokinetics of Pediatric Drugs)
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Review

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14 pages, 589 KiB  
Review
What Is the Best Predictor of Phenobarbital Pharmacokinetics to Use for Initial Dosing in Neonates?
by Martin Šíma, Danica Michaličková and Ondřej Slanař
Pharmaceutics 2021, 13(3), 301; https://doi.org/10.3390/pharmaceutics13030301 - 25 Feb 2021
Cited by 3 | Viewed by 3269
Abstract
Phenobarbital is a first-line treatment of various seizure types in newborns. Dosage individualization maximizing the proportion of patients with drug levels in therapeutic range or sufficient treatment response is still challenging. The aim of this review was to summarize the available evidence on [...] Read more.
Phenobarbital is a first-line treatment of various seizure types in newborns. Dosage individualization maximizing the proportion of patients with drug levels in therapeutic range or sufficient treatment response is still challenging. The aim of this review was to summarize the available evidence on phenobarbital pharmacokinetics in neonates and to identify its possible covariates suitable for individualization of initial drug dosing. Several covariates have been considered: body weight and height, body surface area, gestational and postnatal age, laboratory parameters of renal and hepatic functions, asphyxia, therapeutic hypothermia, extracorporeal membrane oxygenation (ECMO), drug interactions, and genetic polymorphisms. The most frequently studied and well-founded covariate for the estimation of phenobarbital dosing is actual body weight. Loading dose of 15–20 mg/kg followed by a maintenance dose of 3–5 mg/kg/day seems to be accurate. However, the evidence for the other covariates with respect to dosing individualization is not sufficient. Doses at the lower limit of suggested range should be preferred in patients with severe asphyxia, while the upper limit of the range should be targeted in neonates receiving ECMO support. Full article
(This article belongs to the Special Issue Pharmacokinetics of Pediatric Drugs)
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