Online citations, reference lists, and bibliographies.

Modeling And Simulation To Probe The Pharmacokinetic Disposition Of Pomalidomide R- And S-Enantiomers

Yan Li, Simon Zhou, Matthew C. Hoffmann, Gondi Kumar, Maria Palmisano
Published 2014 · Chemistry, Medicine
Cite This
Download PDF
Analyze on Scholarcy
Share
Pomalidomide, a potent novel immunomodulatory agent, has been developed as a racemic mixture of its R- and S-isomers. Pharmacokinetic (PK) analyses were conducted to determine the PK disposition of the isomers from their PK profiles in humans and monkeys. Modeling and simulation were performed to describe the observed PK profiles and explore potential differences in isomer disposition and exposure. PK profiles of S- and R-isomers were measured in a human absorption, distribution, metabolism, and excretion study after oral administration of racemate. PK profiles of S- and R-isomers were measured in monkeys after intravenous and oral administration of S- or R-isomers and pomalidomide racemate. Modeling and simulation were performed using NONMEM 7.2 (Globomax, Ellicott City, MD) to describe the observed PK profiles of S- and R-isomers in humans and monkeys. The results showed that in humans, the in vivo elimination rate of pomalidomide isomers was lower than the R-/S-interconversion rate, resulting in no clinically relevant difference in overall exposure to the two isomers. However, in monkeys, the in vivo elimination rate was higher than the R-/S-interconversion rate, resulting in 1.72- and 1.55-fold differences in R- versus S-isomer exposures. Monte Carlo simulation indicated that exposure to R- and S-enantiomers in humans should be comparable even if single isomers are administered. Thus, in humans, rapid isomeric interconversion of pomalidomide isomers results in comparable exposure to R- and S-enantiomers regardless of whether pomalidomide is administered as a single enantiomer or as a racemate, therefore justifying the clinical development of pomalidomide as a racemate.
This paper references
10.1002/(SICI)1520-636X(1996)8:5<397::AID-CHIR7>3.0.CO;2-B
Design and development of chiral reagents for the chromatographic e.e. determination of chiral alcohols
Willi Walther (1996)
10.1016/j.mvr.2008.08.003
The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions.
Ling Lu (2009)
10.1182/blood.V99.12.4525
Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications.
Nicholas Mitsiades (2002)
10.1182/blood.V96.9.2943
Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy.
Teru Hideshima (2000)
10.1111/j.1365-2141.2004.05286.x
Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application.
Toshiaki Hayashi (2005)
10.1038/sj.leu.2402295
Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications
D Gupta (2001)
Absorption, metabolism and excretion of drugs.
Malcolm Milne (1966)
10.1182/blood.V98.1.210
Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma.
Faith Davies (2001)
10.1038/nrd3657-c1
The predicated demise of racemic new molecular entities is an exaggeration
Israel Agranat (2012)
Thalidomide and its
RL (2000)
Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha.
Laura G. Corral (1999)
10.1007/BF03401909
Selection of Novel Analogs of Thalidomide with Enhanced Tumor Necrosis Factor α Inhibitory Activity
Laura G. Corral (1996)
10.1089/PED.2013.0285
Chiral Switch Drugs for Asthma and Allergies: True Benefit or Marketing Hype.
Kathryn V. Blake (2013)
10.1111/j.1476-5381.1973.tb08232.x
Some observations on the -adrenoceptor agonist properties of the isomers of salbutamol.
Roy Thomas Brittain (1973)
10.1007/s00262-008-0512-7
Immunomodulatory drugs Revlimid® (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation
Dan Zhu (2008)
10.1158/0008-5472.CAN-06-2317
Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells.
Dominique Verhelle (2007)
The chiral switch: the development of single enantiomer drugs from racemates.
Andrew J. Hutt (2003)
10.1093/toxsci/kfp097
Chiral toxicology: it's the same thing...only different.
Silas Smith (2009)
10.2165/00003088-200443050-00002
Single-Enantiomer Drugs
Peter R. Mansfield (2004)
10.1067/mai.2001.119152
The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients.
Jan Lötvall (2001)
10.1002/chir.10221
Chiral inversion of the second generation IMiD CC-4047 (ACTIMID ) in human plasma and phosphate-buffered saline.
Steve K. Teo (2003)
10.1016/S0960-894X(99)00250-4
Amino-substituted thalidomide analogs: Potent inhibitors of TNF-α production
George W. Muller (1999)
Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production.
George W. Muller (1999)
10.1007/s002280100320
Clinical pharmacology of thalidomide
Tommy Eriksson (2001)
10.1007/s00280-012-2040-6
Absorption, metabolism and excretion of [14C]pomalidomide in humans following oral administration
Matthew C. Hoffmann (2012)
10.1111/J.1365-2141.2007.06841.X
Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo.
N. Varsha Monica Reddy (2008)



This paper is referenced by
10.1002/chir.22683
LC-MS/MS and chiroptical spectroscopic analyses of multidimensional metabolic systems of chiral thalidomide and its derivatives.
Yoshiyuki Ogino (2017)
10.1002/chir.22563
Chiral Separation of Uncharged Pomalidomide Enantiomers Using Carboxymethyl-β-Cyclodextrin: A Validated Capillary Electrophoretic Method.
Zoltán-István Szabó (2016)
10.3389/fimmu.2018.00977
Immunomodulatory Drugs Exert Anti-Leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities
Aude Le Roy (2018)
10.1002/jssc.201600354
Liquid chromatography with mass spectrometry enantioseparation of pomalidomide on cyclodextrin-bonded chiral stationary phases and the elucidation of the chiral recognition mechanisms by NMR spectroscopy and molecular modeling.
Zoltán-István Szabó (2016)
10.1002/hon.2485
Clinical pharmacokinetics of oral drugs in the treatment of multiple myeloma.
Camille Morival (2017)
10.1002/jcph.1145
In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects
Yan Li (2018)
10.1002/cpdd.470
An Open‐Label, Phase 1 Study to Assess the Effects of Hepatic Impairment on Pomalidomide Pharmacokinetics
Yan Li (2019)
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)
10.1073/pnas.1417832112
Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs
Vincent Jacques (2015)
Semantic Scholar Logo Some data provided by SemanticScholar