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Absorption, Metabolism And Excretion Of [14C]pomalidomide In Humans Following Oral Administration

Matthew C. Hoffmann, Claudia Kasserra, Josephine F Reyes, Peter H. Schafer, Jolanta Kosek, Lori Capone, Anastasia Parton, Heasook Kim-Kang, Sekhar Surapaneni, Gondi Kumar
Published 2012 · Medicine
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PurposeTo investigate the pharmacokinetics and disposition of [14C]pomalidomide following a single oral dose to healthy male subjects.MethodsEight subjects were administered a single 2 mg oral suspension of [14C]pomalidomide. Blood (plasma), urine and feces were collected. Mass balance of radioactivity and the pharmacokinetics of radioactivity, pomalidomide and metabolites were determined. Metabolite profiling and characterization was performed. The enzymes involved in pomalidomide metabolism and the potential pharmacological activity of metabolites were evaluated in vitro.ResultsMean recovery was 88 %, with 73 and 15 % of the radioactive dose excreted in urine and feces, respectively, indicating good oral absorption. Mean Cmax, AUC0−∞ and tmax values for pomalidomide in plasma were 13 ng/mL, 189 ng*h/mL and 3.0 h. Radioactivity and pomalidomide were rapidly cleared from circulation, with terminal half-lives of 8.9 and 11.2 h. Pomalidomide accounted for 70 % of the circulating radioactivity, and no circulating metabolite was present at >10 % of parent compound. Pomalidomide was extensively metabolized prior to excretion, with excreted metabolites being similar to those observed in circulation. Clearance pathways included cytochrome P450-mediated hydroxylation with subsequent glucuronidation (43 % of the dose), glutarimide ring hydrolysis (25 %) and excretion of unchanged drug (10 %). 5-Hydroxy pomalidomide, the notable oxidative metabolite, was formed primarily via CYP1A2 and CYP3A4. The hydroxy metabolites and hydrolysis products were at least 26-fold less pharmacologically active than pomalidomide in vitro.ConclusionsFollowing oral administration, pomalidomide was well absorbed, with parent compound being the predominant circulating component. Pomalidomide was extensively metabolized prior to excretion, and metabolites were eliminated primarily in urine.
This paper references
Abundance of cytochromes P450 in human liver: a meta-analysis
K Rowland-Yeo (2004)
10.1021/jm900403j
Physicochemical determinants of human renal clearance.
Manthena V S Varma (2009)
Cancer Chemother Pharmacol
(2013)
Abundance of cytochromes P450 in human liver: a meta-analysis
K Rowland-Yeo (2004)
10.1111/j.1476-5381.2009.00559.x
Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis.
P. Schafer (2010)
10.2174/1568210200887980096
Dexamethasone synergizes with lenalidomide to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T and NK cell function.
Anita K Gandhi (2010)
10.1200/JCO.2004.10.052
Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma.
Steve A. Schey (2004)
10.1038/leu.2012.170
Direct interaction of PU.1 with oncogenic transcription factors reduces its serine phosphorylation and promoter binding
Anita Seshire (2012)
10.1007/s00280-011-1760-3
Pharmacokinetics, metabolism and excretion of [14C]-lenalidomide following oral administration in healthy male subjects
Nianhang Chen (2011)
Mass balance, metabolism and excretion of 14C-thalidomide in healthy human subjects
S Surapeneni (2009)
Integrated cytochrome P450 reaction phenotyping: attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes.
Rodrigues Ad (1999)
Integrated cytochrome P450 reaction phenotyping: attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes.
A. David Rodrigues (1999)
10.1111/j.1365-2249.1997.tb08310.x
Thalidomide and derivatives: immunological investigations of tumour necrosis factor-alpha (TNF-alpha) inhibition suggest drugs capable of selective gene regulation.
S M McHugh (1997)



This paper is referenced by
10.1080/17474086.2016.1210003
Managing renal complications in multiple myeloma
Despoina Fotiou (2016)
10.1016/j.jpba.2014.01.001
A sensitive and robust HPLC assay with fluorescence detection for the quantification of pomalidomide in human plasma for pharmacokinetic analyses.
Shandiz Shahbazi (2014)
10.1002/phar.1463
Carfilzomib and pomalidomide: recent advances in the treatment of multiple myeloma.
Kaitlin N Highsmith (2014)
10.1038/leu.2014.60
Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma
M A Dimopoulos (2014)
10.1002/bio.3748
A simple and rapid spectrofluorometric determination of pomalidomide in spiked plasma and urine. Application to degradation studies.
Zeynep Aydoğmuş (2019)
10.1007/s40265-013-0047-x
Pomalidomide: First Global Approval
Shelley Elkinson (2013)
10.1080/1062936X.2018.1518928
Performance evaluation of the GastroPlusTM software tool for prediction of the toxicokinetic parameters of chemicals
Fagen Zhang (2018)
10.1158/1078-0432.CCR-15-2242
Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein–Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression
Richard Julian Jones (2016)
10.1007/s00280-015-2912-7
A Phase 1, double-blind, 4-period crossover study to investigate the effects of pomalidomide on QT interval in healthy male subjects
Sabiha A. Mondal (2015)
Investigating the Molecular Mechanisms of Action of Lenalidomide and Other Immunomodulatory Derivatives
Saurav Daniel Haldar (2018)
10.1039/C6MD00347H
Small molecule-mediated protein knockdown as a new approach to drug discovery
Christopher P Tinworth (2016)
10.1016/B978-0-12-800167-7.00027-4
Chapter Twenty-Seven – To Market, To Market—2013
Joanne J. Bronson (2014)
10.3390/ijms18122650
The Immunogenetics of Psoriasis and Implications for Drug Repositioning
Xuan Xu (2017)
10.1002/jcph.1453
Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects
Ken Ogasawara (2019)
10.2217/fon.13.105
Pomalidomide in the treatment of relapsed multiple myeloma.
Peter A Forsberg (2013)
10.1002/hon.2485
Clinical pharmacokinetics of oral drugs in the treatment of multiple myeloma.
Camille Morival (2017)
10.1002/cpdd.470
An Open‐Label, Phase 1 Study to Assess the Effects of Hepatic Impairment on Pomalidomide Pharmacokinetics
Yan Li (2019)
10.1586/14737140.2014.906904
Pomalidomide for the treatment of relapsed–refractory multiple myeloma: a review of biological and clinical data
Massimo Offidani (2014)
10.1002/jcph.384
Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects.
Claudia Kasserra (2015)
10.1080/10428194.2016.1177181
Pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and moderate renal impairment: a pooled analysis of three clinical trials
David S Siegel (2016)
POMALIDOMIDE: A NOVEL PROMISING IMMUNOMODULATORY AGENT IN THE TREATMENT OF REFRACTORY AND RELAPSED MULTIPLE MYELOMA
Ruchika Nandha (2013)
10.22159/ijap.2017v9i1.15653
A UPLC-MS/MS METHOD DEVELOPMENT AND VALIDATION FOR THE ESTIMATION OF POMALIDOMIDE FROM HUMAN PLASMA
D. Atul Vasanth (2016)
10.3390/cells8111432
Biological Background of Resistance to Current Standards of Care in Multiple Myeloma
Pedro Mogollón (2019)
Method for detecting enantiomer impurity in apremilast
宋务雄 (2015)
10.1124/jpet.114.215251
Modeling and Simulation to Probe the Pharmacokinetic Disposition of Pomalidomide R- and S-Enantiomers
Yan Li (2014)
10.1002/jcph.455
Population Pharmacokinetics of Pomalidomide
Yan Li (2015)
10.1310/hpj4808-636
Drug Monographs: Pomalidomide and Ponatinib
Taylor W. Butler (2013)
10.1002/hon.2290
Safety and tolerability of pomalidomide‐based regimens (pomalidomide‐carfilzomib‐dexamethasone with or without cyclophosphamide) in relapsed/refractory multiple myeloma and severe renal dysfunction: a case series
Joshua R. Richter (2017)
10.2147/CPAA.S144606
Population pharmacokinetics of pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function
Yan Li (2017)
10.1254/FPJ.148.154
ポマリドミド(ポマリスト®カプセル1 mg/2 mg/3 mg/4 mg)の薬理学的/薬物動態学的特性および臨床試験成績
Kaoru Torigoe (2016)
10.2147/CPAA.S171735
A Phase I, open-label, randomized, crossover study in healthy subjects to evaluate the bioavailability of, and the food effect on, a pomalidomide oral liquid suspension
Yan Li (2018)
10.1179/1973947814Y.0000000201
Impact of pomalidomide therapy in multiple myeloma: a recent survey
Arvind Kumar (2014)
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