The patient matters
Jessica van der Bol
The patient matters
Jessica van der Bol
The work described in this thesis was conducted at the Department of Medical
Oncology, Daniel den Hoed Cancer Center, Erasmus MC, Rotterdam.
Printing of this thesis was supported by:
Pfi zer bv, Merck Sharp & Dohme BV, Janssen-Cilag B.V., Amgen B.V.,
Boehringer Ingelheim bv and Novartis Oncology.
Personalized Irinotecan Treatment: The patient matters.
Cover picture: Bert Letwory
Cover design, layout and printing: Optima Grafi sche Communicatie, Rotterdam
All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system
of any nature, or transmitted in any form or by any means, without permission of the
author, or when appropriate, of the publishers of the publications.
Copyright 2011 JM van der Bol, Rotterdam, The Netherlands
Personalized Irinotecan Treatment:
The pati ent matt ers
Geïndividualiseerde irinotecan behandeling:
De pati ënt prominent
ter verkrijging van de graad van doctor aan de
Erasmus Universiteit Rotterdam
op gezag van de rector magnifi cus
Prof.dr. H.G. Schmidt
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
vrijdag 17 juni 2011 om 13:30 uur
Jessica Margaretha van der Bol
geboren te Wenen, Oostenrijk
Prof.dr. J. Verweij
Overige leden: Prof.dr. T. van Gelder
Prof.dr. S. Rodenhuis
Prof.dr. P. Sonneveld
Copromotor: Dr. A.H.J. Mathijssen
Ik dacht dat het leven veel exacter in elkaar stak,
maar het blijkt één grote improvisatie te zijn.
Ter nagedachtenis aan Leo Biemans
22 juni 1959 - 26 juli 2001
Chapter 2Cigarette smoking and irinotecan treatment: pharmacokinetic
interaction and eff ects on neutropenia.
Journal of Clinical Oncology 2007; 25(19): 2719-26.
Chapter 3 Eff ects of mannose-binding lectin polymorphisms on
irinotecan-induced febrile neutropenia.
The Oncologist 2010; 15(10): 1063-72.
Chapter 4Renal function as a predictor of irinotecan-induced
Clinical Pharmacology & Therapeutics 2008; 84(2): 254-62.
Chapter 5Eff ect of omeprazole on the pharmacokinetics and toxicities
of irinotecan in cancer patients: A prospective cross-over
drug-drug interaction study.
European Journal of Cancer 2011; 47(6): 831-8.
Chapter 6Eff ects of methimazole on the elimination of irinotecan.
Cancer Chemotherapy and Pharmacology 2011; 67(1): 231-6.
Chapter 7A CYP3A4 phenotype-based dosing algorithm for
individualized treatment of irinotecan.
Clinical Cancer Research 2010; 16(2): 736-42.
Chapter 8 Summary and conclusion128
Appendix Samenvatting en conclusie
Curriculum Vitae/About the author
Ch apter 1
In the early sixties of the last century, camptothecin (CPT) was isolated from the Chinese
plant Camptotheca acuminata (Nyssaceae family),1 and was found to be a very potent
antitumor agent in vitro.2 However, its clinical development was hindered by a relatively
limited clinical activity and severe and unpredictable toxicities,3-6 most problematic be-
ing hemorrhagic cystitis and enteritis. These turned out to be partially related to the poor
hydrophilicity of the drug and the initial administration of camptothecin in the inactive
carboxylate form.7,8 Once the mechanism of action of camptothecin was discovered,9
there was renewed interest in the drug. Eff orts were made to develop water-soluble
camptothecin analogues with improved antitumor activity and decreased toxicity. Irino-
tecan, also known as CPT-11, was developed as a water-soluble prodrug of SN-38, a very
potent camptothecin analogue,6,10 which has a 100-1000 fold higher cytotoxic activity
in vitro than the parent compound.11,12 Camptothecins, including irinotecan and SN-38,
inhibit the enzyme topoisomerase-I by binding to it and forming a stable complex
between topoisomerase-I and DNA. This induces single-strand breaks in chromosomal
DNA, ultimately leading to cytotoxicity and apoptosis.9,13
Irinotecan has a highly complex metabolism, involving multiple metabolizing phase
I and phase II enzymes and several drug transporters (Figure 1). Irinotecan itself is not
the active substance, but needs to be hydrolyzed by carboxylesterases into its active
metabolite SN-38.14 These carboxylesterases are predominantly localized in the liver, but
also in the lungs and in the mucosa of the gastrointestinal tract.15 However, only a small
fraction of irinotecan is directly converted into SN-38. Competing with the formation
of SN-38 is the CYP3A-mediated oxidation of irinotecan into the inactive metabolites
NPC and APC, and the structurally unresolved metabolite M4. NPC and APC both also
can be converted into SN-38 by carboxylesterases; NPC has the same affi nity as irino-
tecan, but APC is a very poor carboxylesterase-substrate.16 SN-38 is mainly eliminated
via glucuronidation into SN-38 glucuronide (SN-38G), which involves several UGT1A
enzymes;17 UGT1A1 being the most important.18 After biliary excretion, SN-38G can be
re-activated into SN-38 by β-glucuronidase-producing bacteria in the intestines. This
reactivation is thought to have a causative role in irinotecan’s intestinal toxicity.19 In
addition, several drug-transporting proteins are involved in the cellular uptake (Organic
Anion Transporting Polypeptides; OATP1B1 and OATP1B3)20,21 and the hepatobiliary and
renal elimination of irinotecan and its metabolites (ATP Binding Cassette transporters;
ABCB1 (P-glycoprotein), ABCC1 (MRP), ABCC2 (cMOAT), and ABCG2 (BCRP)).22-27 To make
it even more complex, both irinotecan and SN-38 exist in an active lactone form and an
inactive carboxylate form. There is a pH-dependent equilibrium between the two; an
acidic pH promotes the formation of the lactone form, while a physiological pH favors
the carboxylate form.28,29
Figure 1. Metabolism of irinotecan
After intravenous infusion, irinotecan is distributed throughout the body. It is metabolized into the
active metabolite SN-38 by carboxylesterases (CES), which are predominantly localized in the liver, but
also in the lungs and the mucosa of the gastrointestinal tract. In addition, irinotecan is being oxidized
by CYP3A enzymes into the inactive metabolites APC, M4, and NPC; the latter also being a substrate
for CES-mediated conversion into SN-38. SN-38 is inactivated by UGT1A enzymes, UGT1A1 being the
most important, into its glucuronide-conjugate SN-38G. After hepatobiliary excretion, SN-38G can be
reactivated into SN-38 by β-glucuronidase (β-GLUC) producing bacteria. Several uptake (Solute Carrier
Organic Anion (SLCO) transporter family) and effl ux transporters (ATP-binding cassette (ABC) transporter
family) are involved in the elimination of irinotecan.
Copyright PharmGKB. Re-published with permission from PharmGKB and Stanford University.
Early clinical studies with irinotecan were performed in the nineties and showed
responses in patients with colorectal cancer, and several other solid and hematological
malignancies, such as lung, breast, esophageal, head and neck, pancreatic, renal cell,
cervical, and ovarian cancer, leukemia and lymphoma.6,30 In 1996, irinotecan received
accelerated approval in the USA for the treatment of metastatic colorectal cancer after
failure of fl uorouracil (5-FU)-based therapy. Two years later it was approved in the Neth-
erlands. Currently, irinotecan is used in combination therapy and as single agent in the
fi rst-line and second-line treatment of colorectal cancer, as it prolongs life and improves
the quality of life.31-33
Although irinotecan is an active drug, it is notorious in clinical practice because of
its unpredictable and severe toxicities, mainly diarrhea and neutropenia. Many years
of research have given some more insight in the pathophysiology and predictors of
these toxicities.34 However, until now there is no clear explanation for the interpatient
variability in exposure and effi cacy of irinotecan. Body surface area (BSA)-based dosing
of irinotecan does not reduce this variability,35 which makes BSA-based dosing useless
in the case of irinotecan, as it is for many other anticancer drugs.36 Although fl at-fi xed
dosing seems a good alternative because it is simpler and safer (as no calculation errors
can be made),37 the interpatient variability in pharmacokinetics and toxicities remains
the same. Therefore, a new dosing algorithm on the basis of patient characteristics that
are known to infl uence the pharmacokinetics, toxicities and effi cacy of irinotecan, is
necessary to truly personalize irinotecan therapy.
In general, interpatient variability in drug exposure and effi cacy can be explained by
several factors, both inherited (genetic) and environmental (Figure 2). Since the start of
the Human Genome Project in which all human genes and base pairs were analyzed,38
much focus has been put on polymorphisms in metabolizing enzymes and drug trans-
porters to explain the large interpatient variability that is seen with many anticancer
drugs. In the case of irinotecan, much focus was put on the UGT1A1*28 polymorphism, a
promoter repeat in the TATA-box of the UGT1A1 gene, that results in a reduced formation
of the enzyme UGT1A1.39,40 In addition, several other polymorphisms in the metabolic
pathway of irinotecan and their role in the variability of pharmacokinetics and toxici-
ties were investigated.41-46 However, although UGT1A1*28 and other polymorphisms do
explain a part of the interpatient variability of the pharmacokinetics and toxicities of
irinotecan, it is not the holy grail.47,48
As already mentioned, not only genetic but also environmental factors play a role in
pharmacokinetic variability. In the case of irinotecan, the eff ect of several concomitant
drugs and herbal products has already been investigated, such as combinations of
irinotecan with ketoconazole, valproic acid, St John’s wort, medical cannabis, and milk
thistle.49-53 However, the eff ect of other environmental factors, such as comorbidity and
lifestyle is scarcely investigated and other drug-drug interactions could also play a role.
In addition to indirect ways of reducing toxicities by reducing the variability in phar-
macokinetics, direct ways to decrease irinotecan’s toxicities also have been explored,
especially for diarrhea. Although nowadays diarrhea is manageable by using high-dose
loperamide and antibiotics, prediction and more importantly prevention of the occur-
rence of diarrhea remains diffi cult. Strategies for reducing intestinal toxicity have mainly
been aimed on preventing the reactivation of SN-38 by β-glucuronidase producing
bacteria and the absorption of unbound intestinal SN-38. These include the adminis-
tration of neomycin, cholestyramine/levofl oxacin, activated charcoal, budesonide and
compounds that promote intestinal alkalization.54-60
•Route of Administration
•Ascites •Schedule •Body Size
Organ functiongBehavior Unknown factors
•Bone Marrow•Bone Marrow
Figure 2. Factors aff ecting the interpatient variability of drug therapy
Abbreviations: OTC, over the counter; PK, pharmacokinetics; PD, pharmacodynamics.
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AIMS OF THE THESIS
This thesis describes research that was performed in order to add new tools into the
toolbox of personalized irinotecan treatment. We set out to fi nd new factors that explain
the relatively large interpatient variability in pharmacokinetics and toxicity of irinote-
can. Several factors were taken into consideration, such as life style factors (smoking)
in Chapter 2, genetic factors (mannose-binding lectin polymorphisms) in Chapter 3;
comorbidity (renal failure) in Chapter 4 and co-medication in Chapter 5 (omeprazole)
and Chapter 6 (strumazole). Finally, Chapter 7 describes a new individualized dosing
model for irinotecan based on the most predictive patient characteristics. The aim of
this research was to gain knowledge with respect to interpatient variability in pharma-
cokinetics and toxicities of irinotecan, with the ultimate aim to personalize treatment for
each single patient on the basis of his/her characteristics.