Clinical pharmacology of novel anticancer agents bioanalysis-clinical pharmacokinetics-mass ...

418 Pages·2016·15.14 MB·English

Clinical pharmacology of novel anticancer agents
bioanalysis - clinical pharmacokinetics - mass balance studies
ISBN/EAN: 978-94-028-0185-9
© 2016 Cynthia Nijenhuis, Den Haag
Cover design: Esther Ris – www.proefschriftomslag.nl
Printed by: Ipskamp Printing – www.proefschriften.net
Clinical pharmacology of novel anticancer agents
bioanalysis - clinical pharmacokinetics - mass balance studies
Klinische farmacologie van nieuwe antikankermiddelen
bioanalyse – klinische farmacokinetiek – massabalansstudies
(met een samenvating 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 15 juni 2016 des middags te 4.15 uur
door
Cynthia Marcella Nijenhuis
geboren op 18 februari 1987 te Hengelo (O)
Promotoren: Prof. dr. J.H. Beijnen
Prof. dr. J.H.M. Schellens
Copromotor: Dr. H. Rosing
The research described in this thesis was performed at the Department of Pharmacy &
Pharmacology of the Antoni van Leeuwenhoek - Netherlands Cancer Institute and MC
Slotervaart, Amsterdam, The Netherlands and the Department of Medical Oncology of the
Netherlands Cancer Institute, Amsterdam, The Netherlands
Printing of this thesis was financially supported by:
Boehringer Ingelheim
Chipsoft B.V.
Pfizer bv
PRA Health Sciences, Early Development Services, The Netherlands
Takeda Nederland bv
The Netherlands Cancer Institute
Utrecht Institute for Pharmaceutical Sciences

Preface
Cancer is currently the leading cause of death worldwide, accounting for 8.2 million
deaths in 2012 [1]. The first chemotherapy drug (nitrogen mustard) [2] approval in 1949
by the United States Food and Drug Administration (US FDA) was followed in 1958 by
the first cure of acute leukemia in children and adults by combination chemotherapy [3].
In the 1990s the landscape of cancer therapy started to shift with the US FDA approval of
rituximab in 1997 [4], which is a monoclonal antibody that specifically targets proteins of
immune cells interfering with the development of cancer. Since then many more therapies
targeting specific molecular abnormalities in cancer cells were successfully developed.
In addition to the efficacy of a new anticancer drug, drug safety always has to be evalua-
ted carefully before the drug can be approved [5]. Variability in efficacy and toxicity in
each patient can be related to drug exposure [6, 7]. It is therefore important to not only un-
derstand what the drug does to the body (pharmacodynamics), but also to understand
what the body does to the drug (pharmacokinetics). During clinical drug development it
is of pivotal importance to investigate the pharmacokinetics in an early stage, because it
may not only be predictive for therapeutic outcome, but it may also explain the toxicity
profiles of the drug.
This thesis describes the characterization and quantification of the pharmacokinetics of
(new) anticancer drugs. The first part of this thesis focuses on the development and vali-
dation of bioanalytical methods to quantify targeted cancer therapies in plasma and dried
blood spots (DBS), and their clinical application [6]. The second part of this thesis focu-
ses on human radiolabeled mass balance studies of which the aim is to characterize and
quantify the pharmacokinetics, including metabolism and excretion, of a drug in the
human body [8].
Outline of this thesis
As a short introduction to part Iof this thesis (Bioanalysis and clinical pharmacology of tar-
geted cancer therapies), chapter 1describes the current advances made in pharmacokinetic
monitoring of BRAF and MEK inhibitors in melanoma treatment.
To further investigate the pharmacokinetics of anticancer therapies bioanalytical methods
are needed. Vemurafenib is the first BRAF inhibitor that was approved for the treatment
of mutated BRAF V600 metastatic melanoma. Liquid chromatography coupled to tan-
dem mass spectrometry (LC-MS/MS) methods were developed for vemurafenib in plasma
and in dried blood spot (DBS) samples, which are presented in chapters 2 and 3, respecti-
vely. Chapter 4 describes the bioanalysis of MEK inhibitor cobimetinib in combination
with vemurafenib, since these two drugs are now given as combination treatment [9].
Another MEK inhibitor and BRAF inhibitor combination treatment is trametinib with da-
brafenib of which the simultaneous quantification and photodegradation of dabrafenib is
further explored in chapter 5. Chapter 6presents the bioanalysis of the targeted PARP in-
hibitor olaparib.
Resistance to BRAF inhibitors in melanoma treatment is quite common and the elucida-
tion of these resistance mechanisms resulted in the development of rational combination
therapies to overcome toxicity and resistance, which is discussed in chapter 7. Chapter 8fo-
cusses on the monitoring of toxicity and tumor response in patients using vemurafenib,
for which the relationship between plasma and DBS concentrations of vemurafenib was
established. In chapter 9the pharmacokinetics of melanoma patients using vemurafenib
was monitored in an outpatient seting.
In part II (Bioanalysis and metabolite identification of anticancer agents in mass balance studies)
the pharmacokinetics and metabolite profiling of three anticancer agents were investiga-
ted. As an introduction to part II, chapter 10provides a concise review of the regulatory
aspects of radiolabeled human mass balance studies in oncology.
Omacetaxine mepesuccinate is a reversible protein translation inhibitor. Chapter 11des-
cribes the development and validation of two LC-MS/MS methods to quantify omace-
taxine and its metabolites in plasma and urine. These assays were successfully applied to
support a clinical mass balance study with 14C-omacetaxine, which is described in chap-
ter 12. The samples collected in the mass balance study were used for metabolite profiling
of omacetaxine which is presented in chapter 13.
Vosaroxin is a non-anthracycline, first-in-class quinolone derivative. To support a clini-
cal mass balance study, assays for the quantification of vosaroxin and its metabolites were
developed, validated and successfully applied in chapter 14. The results from the clinical
mass balance study from 14C-vosaroxin and additional metabolite profiling are detailed
in chapter 15.
Lenvatinib is an oral, multiple receptor tyrosine kinase inhibitor. In a clinical mass ba-
lance study the pharmacokinetics and excretion of 14C-lenvatinib was studied and the re-
sults are presented in chapter 16. The samples collected in the mass balance study were
used for metabolite profiling in humans, which was compared to other species in chapter
17.
The conclusions of the studies described in this thesis are discussed and placed in a broa-
der perspective in the Conclusions and perspectiveschapter.
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