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http://informahealthcare.com/xenISSN: 0049-8254 (print), 1366-5928 (electronic)
Xenobiotica, Early Online: 115! 2014 Informa UK Ltd. DOI: 10.3109/00498254.2014.941964
Metabolism, excretion and pharmacokinetics of [14C]crizotinib followingoral administration to healthy subjects
Theodore R. Johnson1, Weiwei Tan2, Lance Goulet1*, Evan B. Smith1*, Shinji Yamazaki1, Gregory S. Walker3,Melissa T. OGorman4, Gabriella Bedarida5, Helen Y. Zou6, James G. Christensen6*, Leslie N. Nguyen1*,Zhongzhou Shen1*, Deepak Dalvie1, Akintunde Bello7, and Bill J. Smith1
1Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., San Diego, CA, USA, 2Department of Clinical Pharmacology,
Pfizer Inc., San Diego, CA, USA, 3Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT, USA, 4Department of
Clinical Pharmacology, Pfizer Inc., Groton, CT, USA, 5Clinical Research Unit, Pfizer Inc., New Haven, CT, USA, 6Oncology Research, Pfizer Inc.,
San Diego, CA, USA, and 7Department of Clinical Pharmacology, Pfizer Inc., New York, NY, USA
1. Crizotinib (XALKORI), an oral inhibitor of anaplastic lymphoma kinase (ALK) andmesenchymal-epithelial transition factor kinase (c-Met), is currently approved for thetreatment of patients with non-small cell lung cancer that is ALK-positive.
2. The metabolism, excretion and pharmacokinetics of crizotinib were investigated followingadministration of a single oral dose of 250mg/100 mCi [14C]crizotinib to six healthy malesubjects.
3. Mean recovery of [14C]crizotinib-related radioactivity in excreta samples was 85% of the dose(63% in feces and 22% in urine).
4. Crizotinib and its metabolite, crizotinib lactam, were the major components circulating inplasma, accounting for 33% and 10%, respectively, of the 096 h plasma radioactivity.Unchanged crizotinib was the major excreted component in feces (53% of the dose).In urine, crizotinib and O-desalkyl crizotinib lactam accounted for 2% and 5% of the dose,respectively. Collectively, these data indicate that the primary clearance pathway forcrizotinib in humans is oxidative metabolism/hepatic elimination.
5. Based on plasma exposure in healthy subjects following a single dose of crizotinib andin vitro potency against ALK and c-Met, the crizotinib lactam diastereomers are notanticipated to contribute significantly to in vivo activity; however, additional assessment incancer patients is warranted.
Crizotinib, excretion, human, metabolism,oncology, pharmacokinetics
Received 9 May 2014Revised 1 July 2014Accepted 2 July 2014Published online 18 July 2014
Lung cancer is the most common and lethal cancer worldwide
(Janku et al., 2010), and the majority of lung cancers (85%)
are non-small cell lung cancer (NSCLC) (Tyczynski et al.,
2003). Recently, advances in the understanding and treatment
of NSCLC have been made based on the identification of
molecular alterations specific to tumor cells (Herbst et al.,
2008). Rearrangements of anaplastic lymphoma kinase
(ALK), a receptor tyrosine kinase (RTK), in NSCLC were
reported in 2007, primarily as fusions to echinoderm micro-
tubule-like protein 4 (EML4) (Soda et al., 2007). The potent
oncogenic activity of the EML4-ALK fusion kinase was
confirmed when expressed in the lungs of transgenic mice
(Soda et al., 2008). These fusion proteins are found in 37%of NSCLC patients overall, frequently in younger patients and
in never or light smokers (Gandhi & Janne, 2012).
Collectively, these findings suggested that a pharmacotherapy
specifically targeting ALK may prove beneficial in treatment
of patients with advanced NSCLC.
Crizotinib (XALKORI, PF-02341066) is a potent small-
molecule inhibitor of ALK and its oncogenic variants
(i.e. ALK fusion events and selected ALK mutations)
(Figure 1) (Cui et al., 2011). It is also a potent inhibitor of
the RTK mesenchymal-epithelial transition (c-Met), also
known as hepatocyte growth factor receptor, as well as
ROS1 (c-ros) and Recepteur dOrigine Nantais RTKs
(Cui et al., 2008; Zou et al., 2007). In mice bearing NSCLC
*Present addresses: Lance Goulet, PharmAkea Therapeutics, San Diego,CA, USA. Evan B. Smith, Neurocrine Pharmaceuticals, San Diego, CA,USA. James G. Christensen, Mirati Therapeutics, San Diego, CA, USA.Leslie N. Nguyen, Johnson & Johnson Pharmaceutical Research &Development, San Diego, CA, USA. Zhongzhou Shen, DartNeuroScience, San Diego, CA, USA.
Address for correspondence: Theodore R. Johnson, Ph.D.,Pharmacokinetics, Dynamics and Metabolism, La Jolla Laboratories,Pfizer Worldwide Research and Development, 10646 Science CenterDrive, San Diego, CA 92121, USA. Tel: +858-622-7988.Fax: +484-323-8332. E-mail: firstname.lastname@example.org
tumor xenografts that expressed ALK fusion protein,
crizotinib demonstrated marked, dose-dependent antitumor
efficacy, which correlated to pharmacodynamic inhibition of
phosphorylation of ALK fusion proteins (including
EML4-ALK) in tumors in vivo (Yamazaki et al., 2012; Zou
et al., 2011). Crizotinib is approved globally for the treatment
of patients with locally advanced or metastatic NSCLC that is
ALK-positive. The recommended dose schedule of crizotinib
is 250 mg taken orally twice daily. Results from a phase III
trial demonstrated that crizotinib was superior to standard
chemotherapy (pemetrexed or docetaxel) in patients with
previously treated, advanced ALK-positive NSCLC (Shaw
et al., 2013). In 347 patients who had previously been treated
with platinum-based chemotherapy, crizotinib prolonged
progression-free survival to a median of 7.7 months compared
with 3.0 months in the chemotherapy group. Likewise,
objective response rate was significantly higher in those
treated with crizotinib (65% versus 20%).
The disposition of crizotinib has been evaluated in rats and
dogs to support safety assessment and the pharmacokinetics
(PK) of crizotinib have been characterized in healthy subjects
and cancer patients in a number of clinical studies. The major
metabolic pathways in rats and dogs were oxidation of the
piperidine ring, with direct sulfation and O-dealkylation
also observed in rat (Smith et al., 2011; Zhong et al., 2010).
In nonclinical mass balance studies, recovery of total
radioactivity was essentially complete (>89%), and fecal/biliary excretion was the major route of elimination.
Crizotinib is primarily metabolized by CYP3A and is also a
time-dependent inhibitor and inducer of CYP3A in vitro
(Johnson et al., 2011; Mao et al., 2013). In vivo, crizotinib is a
moderate CYP3A inhibitor, with a 3.7-fold increase in the
area under the plasma concentrationtime curve (AUC) of
oral midazolam observed following 28 days of crizotinib
dosing at 250 mg BID (Tan et al., 2010). In cancer patients,
peak plasma concentrations of crizotinib were reached 4 h
after a single 250-mg oral dose and declined with an apparent
terminal half-life of 42 h (Li et al., 2011; Tan et al., 2010).
Oral bioavailability of crizotinib in healthy volunteers was
43% following a single 250-mg oral dose (Xu et al., 2011a).
Crizotinib exhibits time-dependent PK, as reflected by a
40% decrease in oral clearance with repeat-dose adminis-
tration, likely due to auto-inhibition/inactivation of CYP3A
(Li et al., 2011).
Given the complex pharmacokinetic profile of crizotinib in
humans, a more thorough understanding of its disposition was
warranted. Herein, we report the findings from a study of the
metabolism, excretion and PK of [14C]crizotinib in
healthy human subjects following a single 250-mg oral dose
as well as exploratory assessments of the PK and pharmaco-
logical activity of the primary oxidative metabolites of
Materials and methods
Chemicals and reference compounds
Crizotinib (PF-02341066) was synthesized by Medicinal
Chemistry and Pharmaceutical Sciences, Pfizer Worldwide
Research and Development (San Diego, CA and Sandwich,
UK, respectively) (Cui et al., 2011). Synthetic standards of
crizotinib metabolites, crizotinib lactam (PF-06260182), the
constituent diastereomers of crizotinib lactam (PF-06270079
and PF-06270080), O-desalkyl crizotinib (PF-03255243) and
O-desalkyl crizotinib lactam (PF-06268935), were synthe-
sized by Medicinal Chemistry, Pfizer Worldwide Research
and Development (San Diego, CA). The absolute configur-
ation of the crizotinib lactam constituent diastereomers,
PF-06270079 and PF-06270080, were not determined.
[14C]Crizotinib (specific activity 0.407mCi/mg; radiochem-ical purity >99%) and [2H5]crizotinib (PF-03623192) weresynthesized by Radiochemistry, Pfizer Worldwide Research
and Development (Groton, CT). Perma Fluor, Carbo-Sorb and
Ultima Gold liquid scintillation fluid was obtained from
PerkinElmer (Waltham, MA). Reagents and solvents of
analytical or high pressure liquid chromatography (HPLC)
grade were purchased from commercial manufacturers.
Subjects were healthy males between the ages of 18 and 55