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Therapeutic Drug Monitoring of HIV Treatment
Bridging Laboratory and Clinical Practice
Publication of this thesis was financially supported by Stichting Klinisch Farmaceutische
Cover design and photography: André Olthaar
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© 2006 J.A.H. Droste
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Therapeutic Drug Monitoring of HIV Treatment
Bridging Laboratory and Clinical Practice
een wetenschappelijke proeve
op het gebied van de Medische Wetenschappen
ter verkrijging van de graad van doctor
aan de Radboud Universiteit Nijmegen
op gezag van de Rector Magnificus Prof. Dr. C.W.P.M. Blom,
volgens besluit van het College van Decanen
in het openbaar te verdedigen op donderdag 1 juni 2006
des namiddags om 1.30 uur precies
JACQUELINE ADRIANA HENRICA DROSTE
Geboren op 21 december 1962 te Nijmegen
Prof. Dr. Y.A. Hekster
Dr. D.M. Burger
Dr. P.P. Koopmans
Prof. Dr. C.G.J. Sweep
Prof. Dr. J.L. Willems
Prof. Dr. I.M. Hoepelman, Universitair Medisch Centrum Utrecht
Voor André en Stijn
Simultaneous Determination of the HIV Drugs Indinavir, Amprenavir,
Saquinavir, Ritonavir, Lopinavir, Nelfinavir, the Nelfinavir
Hydroxymetabolite M8, and Nevirapine in Human Plasma by Reversed-
Phase High-Performance Liquid Chromatography
Ther Drug Monit 2003; 25: 393-399
Long Term Stability of Protease Inhibitors in Human Plasma of HIV-
False-Positive Results in Urine Drug-Screening in Healthy Volunteers
Participating in Phase I Studies with Efavirenz and Rifampin
Accepted for publication in Ther Drug Monit
Quality of TDM services
Evaluation of Antiretroviral Drug Measurements by an Interlaboratory
Quality Control Program
J Acquir Immune Defic Syndr 2003; 32: 287-291
TDM: Therapeutic Drug Measuring or Therapeutic Drug Monitoring?
Ther Drug Monit 2005; 27: 412-416
Limited Penetration of Lopinavir into Seminal Plasma of HIV-1-Infected
AIDS 2002; 16(12): 1698-1700
Pharmacokinetic Study of Tenofovir Disoproxil Fumarate Combined with
Rifampin in Healthy Volunteers
Antimicrob Agents Chemother 2005; 49(2): 680-684
Assessment of Drug-Drug Interactions Between Tenofovir Disoproxil
Fumarate and the Nonnucleoside Reverse Transcriptase Inhibitors
Nevirapine and Efavirenz in HIV-Infected Patients
J Acquir Immune Defic Syndr 2006; 41: 37-43
Nevirapine Plasma Concentrations are Still Detectable After More Than 2
Weeks in the Majority of Women Receiving Single-Dose Nevirapine
Implications for Intervention Studies
J Acquir Immune Defic Syndr 2005; 39: 419-421
List of publications
HUMAN IMMUNODEFICIENCY VIRUS / ACQUIRED IMMUNE DEFICIENCY SYNDROME
The first patients with the acquired immunodeficiency syndrome (AIDS) were identified in
19811, and in early 1983 a virus that caused AIDS was isolated2. At the end of 1984 it was
proved that the new virus (called human immunodeficiency virus; HIV) belonged to the
subfamily of lentitretroviruses and that it was a retrovirus.
Like any virus, HIV must use the cells of another organism -its host- to survive and
reproduce. HIV is adapted to using the cells of the human immune system, the CD4 cells.
Retroviruses are unique in biology. Unlike other viruses, retroviruses carry their genetic code
as RNA and they produce a unique enzyme called reverse transcriptase, which converts
their RNA into DNA. Next the cellular machinery of the host is used for reproduction.
At the end of 2004, 39.4 million people were living with HIV; the majority of these people are
living in Sub-Saharan Africa: 25.4 million. About 14,000 new HIV infections a day occurred in
TREATMENT OF HIV/AIDS AND ANTIRETROVIRAL DRUGS
Treatment with antiretroviral drugs has been proven to prolong survival in persons with AIDS
and with asymptomatic HIV infection4. Furthermore, the use of highly active antiretroviral
therapy (HAART) is associated with a decline in morbidity and mortality in HIV-infected
persons5. HAART is an intensive therapy in which antiretroviral drugs from different groups
There are four main groups of antiretroviral drugs (Table 1). Each of these groups attacks
HIV in a different way.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
The first group of antiretroviral drugs to treat HIV has become available in 1987 with the
introduction of zidovudine6. These drugs inhibit the enzyme reverse transcriptase, which is
produced by HIV and needed to reproduce itself in cells. These drugs are taken up by target
cells and phosphorylated to triphosphate metabolites by cellular enzymes to produce active
Nonnucleoside Reverse Transcriptase inhibitors (NNRTIs)
The second group of antiretroviral drugs is the NNRTIs and started to be approved in 1996.
Nevirapine was the first NNRTI approved6. These drugs work slightly different from the
NRTIs in that they bind in a different way to the reverse transcriptase enzyme.
Protease Inhibitors (PIs)
The third type of antiretroviral drugs are PIs, of which the first (indinavir) was approved in
19956. PIs, as the name says, inhibit protease, an enzyme that breaks down protein and is
one of the main enzymes that HIV uses to reproduce itself.
Fusion or Entry Inhibitors
The fourth group of antiretroviral drugs is called fusion or entry inhibitors. The first fusion
inhibitor is enfuvirtide, which has been approved since 20038. This drug inhibits the
attachment of HIV to the cell and in this way inhibits the reproduction of viral particles.
NRTIs NNRTIs PIs Fusion Inhibitors
THERAPEUTIC DRUG MONITORING
The role of therapeutic drug monitoring (TDM) in the management of antiretroviral agents is
a topic of increasing interest9-14. TDM may be used when a number of important criteria are
met14. First a more direct intermediate measure of patient response is not available; second
a large interindividual variability in pharmacokinetic parameters should exist; furthermore,
there should be a good relationship between plasma drug concentrations and therapeutic or
toxic effect and a narrow range of concentrations that are effective and well tolerated. Finally
drug assays should be available. TDM for protease inhibitors, nevirapine, and efavirenz is
useful since there is a relationship between exposure and response14, a large inter-patient
variability exists, and the therapeutic ranges are known. Furthermore, pharmacokinetic
parameters may be altered by the many drug interactions that have been described for
antiretroviral drugs15, hepatic dysfunction, and non-compliance; TDM may also be useful for
NRTIs in these cases.
The practice of TDM is based on several disciplines, including pharmacodynamics,
pharmacokinetics, and chemical analysis. Pharmacodynamics is the study of the
biochemical and physiologic effects of drugs and their mechanisms of action.
Pharmacokinetics is the study of the time course of a drug and its metabolites in the body
after administration by any route and therefore analysis of drugs and metabolites is needed.
Chemical analysis is the basic stone. Drugs and metabolites should be determined
specifically and sensitively. This is particular difficult when large amounts of different drugs
OBJECTIVE OF THIS THESIS
The objective of the studies in this thesis is to make a contribution to therapeutic drug
monitoring of HIV treatment by bringing information from the laboratory into the clinical
The second part of the thesis is devoted to the chemical analysis. Chapter 1 describes the
simultaneous determination of the protease inhibitors and nevirapine in human plasma. A
bio-analytical method is a prerequisite for therapeutic drug monitoring. In chapter 2 the
stability of protease inhibitors in plasma of HIV-infected patients was studied because long-
term stability may be needed for retrospective studies. Chapter 3 describes the cross-
reactivity of efavirenz and rifampin with a urine drug-screening assay.
The third part of this thesis focuses on the quality of therapeutic drug monitoring services.
The studies in chapters 4 and 5 present the results of an international quality control
program, which was initiated to alert laboratories to deviating plasma levels of protease
inhibitors and the nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine.
Furthermore, the quality of the recommendations given by the participants of the quality
control program, concerning adjustments of doses or regimen and possible interactions was
In part IV of this thesis pharmacokinetic studies are described. In chapter 6 the penetration
of lopinavir into seminal plasma is studied.
In chapter 7 and 8 the possible drug-drug interaction of tenofovir disoproxil fumarate with
rifampin, efavirenz, and nevirapine was studied. Chapter 9 describes the results of a single-
dose nevirapine study.
Finally, in the general discussion the results of this thesis are brought in a wider perspective
and recommendations for further research are presented.
1. Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, Saxon A. Pneumocystis
carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of
a new acquired cellular immunodeficiency. N Engl J Med 1981;305:1425-31.
2. Gallo RC, Montagnier L. The discovery of HIV as the cause of AIDS. N Engl J Med
3. Anonymous. http://www.unaids.org/en/resources/epidemiology.asp. 2004.
4. Hogg RS, Heath KV, Yip B, Craib KJ, O'Shaughnessy MV, Schechter MT, Montaner JS.
Improved survival among HIV-infected individuals following initiation of antiretroviral therapy.
5. Palella FJJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten JE, Aschman DE,
Holmberg SD. Declining morbidity and mortality among patients with advanced human
immunodeficiency virus infection. New England Journal of Medicine 1998;338:853-60.
6. www.fda.gov/oashi/aids/virals.html. Website . 2005.
7. St Clair MH, Richards CA, Spector T, Weinhold KJ, Miller WH, Langlois AJ, Furman PA. 3'-
Azido-3'-deoxythymidine triphosphate as an inhibitor and substrate of purified human
immunodeficiency virus reverse transcriptase. Antimicrob Agents Chemother 1987;31:1972-77.
8. Fuzeon® Summary of Product Characteristics. Roche Registration Limited, Hertfordshire,
United Kingdom . 2003.
9. John L, Marra F, Ensom MH. Role of therapeutic drug monitoring for protease inhibitors. Ann
10. Becker S, Luber AD. Therapeutic Drug Monitoring for Antiretrovirals: Uses and Misuses in
Clinical Practice. Medscape HIV/AIDS eJournal 8(2) 2002 2003.
11. Back DJ, Gibbons SE, Khoo SH. Therapeutic drug monitoring of antiretrovirals: ready for the
clinic. Journal of the International Association of physicians in AIDS care 2000;34-37.
12. Back DJ, Khoo SH, Gibbons SE, Merry C. The role of therapeutic drug monitoring in treatment
of HIV infection. British Journal of Clinical Pharmacology 2001;51:301-8.
13. Burger DM, Aarnoutse RE, Hugen PW. Pros and cons of therapeutic drug monitoring of
antiretroviral agents. Curr Opin Infect Dis 2002;15:17-22.
14. Aarnoutse RE, Schapiro JM, Boucher CA, Hekster YA, Burger DM. Therapeutic drug
monitoring: an aid to optimising response to antiretroviral drugs? DRUGS 2003;63:741-53.
General introduction Download full-text
15. De Maat MM, Ekhart GC, Huitema AD, Koks CH, Mulder JW, Beijnen JH. Drug interactions
between antiretroviral drugs and comedicated agents. Clin Pharmacokinet 2003;42:223-82.