Bioanalysis and clinical pharmacology of antiviral drugs

212 Pages·2013·3.89 MB·English

Bioanalysis and clinical pharmacology of antiviral drugs
-focus on HIV and influenza-
ISBN/EAN: 978-94-6108-422-4
© Wiete Kromdijk, Amsterdam
Cover design: Carlotte Mos – www.ocher.nl
Printed and layout by: Gildeprint Drukkerijen – www.gildeprint.nl
Printed on FSC certified paper
Bioanalysis and clinical pharmacology of antiviral drugs
-focus on HIV and influenza-
Bioanalyse en klinische farmacologie van antivirale middelen
- focus op HIV en Influenza -
(met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor aan de Universiteit Utrecht
op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan,
ingevolge het besluit van het college voor promoties in het openbaar te verdedigen
op woensdag 24 april 2013 des middags te 2.30 uur
door
Wiete Kromdijk
geboren op 27 augustus 1981
te Lochem
Promotor:
Prof.dr. J.H. Beijnen
co-promotoren:
Dr. A.D.R. Huitema
Dr. J.W. Mulder
The research described in this thesis was performed at the Department of Pharmacy &
Pharmacology of the Slotervaart Hospital / The Netherlands Cancer Institute, Amsterdam,
The Netherlands.
Publication of this thesis was financially supported by:
Abbvie bv., Hoofddorp, the Netherlands
Boehringer Ingelheim bv., Alkmaar, the Netherlands
Gilead Sciences Netherlands bv., Amsterdam, the Netherlands
Merck Sharp & Dohme bv., Haarlem, the Netherlands
Roche Nederland bv., Woerden, the Netherlands
Stichting Klinisch Wetenschappelijk Onderzoek Slotervaart Ziekenhuis (SKWOSZ),
Amsterdam, the Netherlands
The Netherlands Laboratory for Anticancer Drug Formulation (NLADF), Amsterdam, the
Netherlands
Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht, the Netherlands
ViiV Healthcare bv., Zeist, the Netherlands
CONtENtS
Preface 8
chapter 1: Dried blood spots for antiretroviral drug monitoring
1.1 Dried blood spots, a new era in antiretroviral drug monitoring 13
In preparation
1.2 Use of dried blood spots for the determination of plasma 25
concentrations of nevirapine and efavirenz
Journal of Antimicrobial Chemotherapy. 2012 May;67(5):1211-6
1.3 Therapeutic drug monitoring of antiretroviral drugs at home using 37
dried blood spots; a proof of concept study
Antiviral Therapy 2012 December; Epub ahead of print
1.4 Dried blood spots for therapeutic drug monitoring of antiretroviral 45
drugs in children and adolescents
Submitted for publication
1.5 Monitoring nevirapine exposure and virological efficacy in HIV 55
infected children on a fixed dose regimen using dried blood spots
In preparation

chapter 2: Antiretroviral nucleoside and nucleotide reverse transcriptase inhibitors
2.1 Clinical intracellular pharmacokinetics of antiretroviral nucleoside 67
and nucleotide reverse transcriptase inhibitors
Submitted for publication
2.2 Development and validation of an assay for the simultaneous 93
determination of zidovudine, abacavir, emtricitabine, lamivudine,
tenofovir and ribavirin in human plasma using LC-MS/MS
Journal of Chromatography B 2013; Epub ahead of print
2.3 Quantitative determination of the phosphorylated metabolites of 113
zidovudine, abacavir, emtricitabine, tenofovir and lamivudine in
human peripheral blood mononuclear cells using liquid
chromatography – tandem mass spectrometry
Submitted for publication
2.4 Intracellular concentrations of tenofovir and its phosphorylated 133
anabolites in HIV-infected patients
In preparation
chapter 3: oseltamivir
3.1 Quantitative determination of oseltamivir and oseltamivir 145
carboxylate in human fluoride EDtA plasma including the ex vivo
stability using high-performance liquid chromatography coupled
with electrospray ionization tandem mass spectrometry
Journal of Chromatography B 2012 April;891:57-63
3.2 Pharmacokinetics of oseltamivir carboxylate in critically ill patients; 165
each patient is unique
Intensive Care Medicine 2012 December; Epub ahead of print (shortened version)
3.3 Pharmacokinetics of oseltamivir in children; experience in clinical 173
practice and a concise review of the literature
Submitted for publication
3.4 Oseltamivir and its active metabolite cross the placenta at 187
significant levels
Clinical Infectious Disease (correspondence) 2012 June;54(11):1676-7

chapter 4: conclusions and perspectives
summary 199
samenvatting 202
Dankwoord 206
curriculum Vitae 209
List of publications 210
R1 PREFACE
R2
R3 Human immune deficiency virus (HIV) and respiratory infections are among the ten leading
R4 causes of death worldwide [1]. Since the beginning of the HIV epidemic in the early 1980s
R5 more than 60 million people have been infected with HIV and approximately 30 million
R6 people have died of acquired immune deficiency syndrome (AIDS) [2]. Annual influenza
R7 epidemics, one of the major causes of respiratory infections, may cause about 3 to 5 million
R8 cases of severe illness with about 250.000 to 500.000 annual deaths [3]. Adequate treatment of
R9 HIV and influenza is therefore of the utmost importance.
R10
R11 The aim of this thesis project was to develop bioanalytical methods and to implement these in
R12 clinical studies to improve current treatment strategies of HIV and influenza and to increase
R13 knowledge of the clinical pharmacology of antiviral drugs. Ultimately, this may improve
R14 treatment of these viral infections.
R15
R16 Since the introduction of the combination antiretroviral therapy, the morbidity and mortality
R17 of HIV infected patients has decreased dramatically. Currently, six different antiretroviral
R18 drug classes are available: nucleoside and nucleotide reverse transcriptase inhibitors (NRtIs),
R19 protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRtIs), integrase
R20 inhibitors, fusion inhibitors and entry inhibitors. The standard first line treatment in Europe
R21 consists of a backbone of two NRtIs combined with an NNRtI or PI [4].
R22 Plasma concentrations of NNRtIs and PIs have been related to virologic outcome and
R23 toxicity. As a consequence, therapeutic drug monitoring (tDM; individual dose optimization
R24 through measurement of drug plasma concentrations) can be used in special populations
R25 (children or pregnant women) and for selected indications (such as certain drug-drug
R26 interactions) to minimize toxicity and maximize virological outcome of the NNRtIs and
R27 PIs. tDM requires venous sampling which has the disadvantage of being painful, elaborate
R28 and expensive. chapter 1 introduces dried blood spot sampling for tDM, a patient friendly
R29 and easy alternative to venous sampling. The introduction of dried blood spots enables self-
R30 sampling by HIV-infected patients for tDM at home (chapter 1.3), allows a less painful
R31 tDM procedure for children (chapter 1.4) and most importantly, dried blood spots enable
R32 antiretroviral drug monitoring in resource limited settings where the HIV burden is highest
R33 (chapter 1.5).
R34 NRtIs are analogous of endogenous deoxynucleosides. After intracellular uptake, NRtIs
R35 are phosphorylated by endogenous kinases to their active triphosphate metabolite. Due to
R36 this intracellular activation pathway, intracellular NRtI triphosphates levels are generally
R37 considered to be a better predictor of antiviral activity than plasma concentrations. Knowledge
R38 of the clinical intracellular pharmacology of the NRtIs is still in its infancy due to difficulties
R39
8 | Preface
in analytical methodologies. chapter 2 gives an overview of the currently available data of the R1
intracellular NRtIs (chapter 2.1) and describes bioanalytical methods for the determination R2
of plasma and intracellular NRtIs (chapter 2.2 and 2.3). These methods can now be used in R3
clinical practice and preliminary data shows the usefulness of these methods (chapter 2.4). R4
The most recent pandemic influenza A (H1N1), also known as the Mexican flu or swine R5
flu, was resistant against adamantanes, whereas no initial resistance was observed against R6
neuramidase inhibitors. Oseltamivir is the only orally available neuramidase inhibitor. R7
Therefore, oseltamivir treatment was advised during the H1N1 pandemic influenza in R8
patients with an increased risk for complicated illness, like children less than 2 years old, R9
pregnant women and critically ill patients. However, knowledge of the optimal dosing in these R10
fragile populations was very limited. chapter 3.1 describes the development of a bioanalytical R11
method for the measurement of oseltamivir and its active metabolite oseltamivir carboxylate. R12
This method was used to investigate the current treatment strategies in critically ill patients R13
(chapter 3.2) and infants (chapter 3.3). R14
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REFERENCES R17
R18
1. World Health Report 2008: Primary health care, now more than ever. http://www.who.int/ R19
whr/2008/whr08_en.pdf (accessed January 2013)
R20
2. World Health Organization, Global Health Observatory HIV/AIDS, http://www.who.int/gho/
R21
hiv/en/index.html (accessed January 2013)
3. World Health Organization, Facts sheet Influenza, http://www.who.int/mediacentre/ R22
factsheets/2003/fs211/en/ (accessed January 2013) R23
4. Panel on Antiretroviral Guidelines for Adults and Adolescents, Department of Health and
R24
Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and
adolescents. http://www.aidsinfo.nih.gov/ (15 October 2012, date last accessed). R25
5. World Health Organization. WHO guidelines for pharmacological management of pandemic R26
(H1N1) 2009 influenza and other influenza viruses. 2010. Available from: http://www.who.int/ R27
csr/resources/publications/swineflu/h1n1_use_antivirals_20090820/en/index.html (accessed
R28
November 2011)
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