Making things easier. How to improve antiviral drug treatment for children

234 Pages·2017·10.09 MB·English

PDF hosted at the Radboud Repository of the Radboud University
Nijmegen

The following full text is a publisher's version.

For additional information about this publication click this link.
http://hdl.handle.net/2066/160820

Please be advised that this information was generated on 2023-02-07 and may be subject to
change.
Making things easier
How to improve antiviral drug treatment for children
Diane Bastiaans
Making things easier –
How to improve antiviral drug treatment for children
Thesis, Radboud University, Nijmegen, the Netherlands
ISBN
978-94-028-0347-1
Cover design
Johan ter Haar (painting)
Merijn Roest | TychoMerijn.com (photography)
Sanneke Bastiaans (lay-out)
Lay-out manuscript
Martin Bastiaans
Printing
Ipskamp Printing, Enschede
(cid:13)c 2016 Diane Bastiaans
Financial support for the printing of this thesis was provided by the Department
of Pharmacy of the Radboud university medical center.
All rights are reserved. No part of this book may be reproduced, distributed, stored in
a retrieval system, or transmitted in any form or by any means, without prior written
permission of the author.
Making things easier
How to improve antiviral drug treatment for children
Proefschrift
ter verkrijging van de graad van doctor
aan de Radboud Universiteit Nijmegen
op gezag van de rector magnificus
prof. dr. J.H.J.M. van Krieken,
volgens besluit van het college van decanen
in het openbaar te verdedigen
op maandag 7 november 2016
om 16:30 uur precies
door
Diane Elisabeth Theodora Bastiaans
geboren op 14 augustus 1976
te Geldrop
Promotoren
Prof. dr. D.M. Burger
Prof. dr. A. Warris (University of Aberdeen, Verenigd Koninkrijk)
Manuscriptcommissie
Prof. dr. S.N. de Wildt
Dr. D.A. van Riet–Nales (College ter Beoordeling van Geneesmiddelen, Utrecht)
Prof. dr. A.J.A.M. van der Ven

6 Making things easier
Contents
General introduction 9
Part 1 Dosing regimen – pharmacokinetics 15
1 Once- vs. twice-daily lopinavir/ritonavir in HIV-1-infected children 17
2 Sustained viral suppression in HIV-infected children on once-daily
lopinavir/ritonavir in clinical practice 41
3 Administration of the approved darunavir once-daily dosage in
children results in lower than predicted exposure 57
4 DoseevaluationoflamivudineinHIV-infectedchildrenaged5months
– 18 years based on a population pharmacokinetics analysis 69
Part 2 Paediatric formulations 91
5 The role of formulation on the pharmacokinetics of antiretroviral drugs 93
6 Pharmacokinetics of pediatric lopinavir/ritonavir tablets in children
when administered twice daily according to FDA weight bands 137
7 A new paediatric formulation of valaciclovir: development and
bioequivalence assessment 153
8 Invivoandinvitropalatabilitytestingofanewpaediatricformulation
of valaciclovir 165
9 General discussion 185
Summary 199
Nederlandse samenvatting 209
List of abbreviations and acronyms 219
List of co-authors with affiliation at time of research 223
List of publications 229
Dankwoord 231
Curriculum vitae 233
How to improve antiviral drug treatment for children 7
General introduction
8 Making things easier
General introduction
Medicines for children
Paediatric patients cannot simply use the same drug formulations and
dosages as adult patients. The appropriateness of a formulation is deter-
mined by the characteristics of the patient to be treated with the drug, the
specific drug and the dose to be used, and the environment in which it has
to be administered. Children are characterized by gaining in height and
weightuntiltheygrowupbeyondadolescence, andbythesizeandfunction
of their organs changing over time [1]. The right dose has to be determined
for children taking into account the disease they suffer from, their age and
stage of development. This often results in the need for different amounts
of drugs relative to their weight, body surface area or maturation of organ
functions, and different formulations depending on their age and devel-
opment. Oral administration of drugs is generally considered the most
convenient method to administer drugs, also for children. For paediatric
oral drug therapy several aspects have to be considered [2]. Since the dose
might have to be changed while children grow and develop, drug formula-
tions with the possibility of flexible dosing are preferred. Different aspects
determine acceptability, such as food restrictions, size of tablets, amount of
drug to be taken and the palatability [2,3]. Palatability is determined by
the taste, texture and smell of the formulation [4]. It can be expected that
the lower the acceptability of the drug formulation, the more important
also the dosing frequency is. Which type of formulation is appropriate for
a child changes during its growth and development [5]. Liquid formulations
are generally considered most appropriate for the youngest children, slowly
changing to the use of solid formulations, such as tablets and capsules, for
older children.
When no appropriate paediatric formulations are available, (hospital)
pharmacists can attempt to make medicines more child friendly, such
as preparing capsules or a liquid out of tablets with the ‘inappropriate’
strength, or by compounding using the pure active pharmaceutical ingre-
dient [6,7]. Excipients have to be used to be able to develop such a new
formulation. For use in children, certain excipients used in adult drug
formulations should be avoided, if possible [4,8]. For example excipi-
ents as alcohol and propylene glycol can have serious adverse effects in
children [4,9,10]. Not all drug formulations can be changed into a child
friendly formulation. For example, some active pharmaceutical ingredients
have to be protected from degradation in the gastrointestinal tract or can
How to improve antiviral drug treatment for children 9