Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite--Resolution for Clinical Development [Articles]

Publication Date:
2018-02-09
Publisher:
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
Print ISSN:
0090-9556
Electronic ISSN:
1521-009X
Topics:
Chemistry and Pharmacology
Medicine
Published by:
http://www.aspet.org/
_version_ 1836398785879605248
autor Zheng, J., Xin, Y., Zhang, J., Subramanian, R., Murray, B. P., Whitney, J. A., Warr, M. R., Ling, J., Moorehead, L., Kwan, E., Hemenway, J., Smith, B. J., Silverman, J. A.
beschreibung Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), is in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [ 14 C]MMB were characterized in a single-dose, human mass-balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route. Mean blood-to-plasma [ 14 C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [ 14 C]MMB-derived radioactivity was detectable in blood for ≤48 hours, suggesting no irreversible binding of MMB or its metabolites. The major circulating human metabolite, M21 (a morpholino lactam), is a potent inhibitor of JAK1/2 and ACVR1 in vitro. Estimation of pharmacological activity index suggests M21 contributes significantly to the pharmacological activity of MMB for the inhibition of both JAK1/2 and ACVR1. M21 was observed in disproportionately higher amounts in human plasma than in rat or dog, the rodent and nonrodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies wherein the circulating metabolites and drug-drug interactions were further characterized. The human metabolism of MMB was mediated primarily by multiple cytochrome P450 enzymes, whereas M21 formation involved initial P450 oxidation of the morpholine ring followed by metabolism via aldehyde oxidase.
citation_standardnr 6159686
datenlieferant ipn_articles
feed_id 1915
feed_publisher The American Society for Pharmacology and Experimental Therapeutics (ASPET)
feed_publisher_url http://www.aspet.org/
insertion_date 2018-02-09
journaleissn 1521-009X
journalissn 0090-9556
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Society for Pharmacology and Experimental Therapeutics (ASPET)
quelle Drug Metabolism and Disposition
relation http://dmd.aspetjournals.org/cgi/content/short/46/3/237?rss=1
search_space articles
shingle_author_1 Zheng, J., Xin, Y., Zhang, J., Subramanian, R., Murray, B. P., Whitney, J. A., Warr, M. R., Ling, J., Moorehead, L., Kwan, E., Hemenway, J., Smith, B. J., Silverman, J. A.
shingle_author_2 Zheng, J., Xin, Y., Zhang, J., Subramanian, R., Murray, B. P., Whitney, J. A., Warr, M. R., Ling, J., Moorehead, L., Kwan, E., Hemenway, J., Smith, B. J., Silverman, J. A.
shingle_author_3 Zheng, J., Xin, Y., Zhang, J., Subramanian, R., Murray, B. P., Whitney, J. A., Warr, M. R., Ling, J., Moorehead, L., Kwan, E., Hemenway, J., Smith, B. J., Silverman, J. A.
shingle_author_4 Zheng, J., Xin, Y., Zhang, J., Subramanian, R., Murray, B. P., Whitney, J. A., Warr, M. R., Ling, J., Moorehead, L., Kwan, E., Hemenway, J., Smith, B. J., Silverman, J. A.
shingle_catch_all_1 Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite--Resolution for Clinical Development [Articles]
Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), is in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [ 14 C]MMB were characterized in a single-dose, human mass-balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route. Mean blood-to-plasma [ 14 C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [ 14 C]MMB-derived radioactivity was detectable in blood for ≤48 hours, suggesting no irreversible binding of MMB or its metabolites. The major circulating human metabolite, M21 (a morpholino lactam), is a potent inhibitor of JAK1/2 and ACVR1 in vitro. Estimation of pharmacological activity index suggests M21 contributes significantly to the pharmacological activity of MMB for the inhibition of both JAK1/2 and ACVR1. M21 was observed in disproportionately higher amounts in human plasma than in rat or dog, the rodent and nonrodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies wherein the circulating metabolites and drug-drug interactions were further characterized. The human metabolism of MMB was mediated primarily by multiple cytochrome P450 enzymes, whereas M21 formation involved initial P450 oxidation of the morpholine ring followed by metabolism via aldehyde oxidase.
Zheng, J., Xin, Y., Zhang, J., Subramanian, R., Murray, B. P., Whitney, J. A., Warr, M. R., Ling, J., Moorehead, L., Kwan, E., Hemenway, J., Smith, B. J., Silverman, J. A.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_2 Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite--Resolution for Clinical Development [Articles]
Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), is in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [ 14 C]MMB were characterized in a single-dose, human mass-balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route. Mean blood-to-plasma [ 14 C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [ 14 C]MMB-derived radioactivity was detectable in blood for ≤48 hours, suggesting no irreversible binding of MMB or its metabolites. The major circulating human metabolite, M21 (a morpholino lactam), is a potent inhibitor of JAK1/2 and ACVR1 in vitro. Estimation of pharmacological activity index suggests M21 contributes significantly to the pharmacological activity of MMB for the inhibition of both JAK1/2 and ACVR1. M21 was observed in disproportionately higher amounts in human plasma than in rat or dog, the rodent and nonrodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies wherein the circulating metabolites and drug-drug interactions were further characterized. The human metabolism of MMB was mediated primarily by multiple cytochrome P450 enzymes, whereas M21 formation involved initial P450 oxidation of the morpholine ring followed by metabolism via aldehyde oxidase.
Zheng, J., Xin, Y., Zhang, J., Subramanian, R., Murray, B. P., Whitney, J. A., Warr, M. R., Ling, J., Moorehead, L., Kwan, E., Hemenway, J., Smith, B. J., Silverman, J. A.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_3 Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite--Resolution for Clinical Development [Articles]
Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), is in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [ 14 C]MMB were characterized in a single-dose, human mass-balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route. Mean blood-to-plasma [ 14 C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [ 14 C]MMB-derived radioactivity was detectable in blood for ≤48 hours, suggesting no irreversible binding of MMB or its metabolites. The major circulating human metabolite, M21 (a morpholino lactam), is a potent inhibitor of JAK1/2 and ACVR1 in vitro. Estimation of pharmacological activity index suggests M21 contributes significantly to the pharmacological activity of MMB for the inhibition of both JAK1/2 and ACVR1. M21 was observed in disproportionately higher amounts in human plasma than in rat or dog, the rodent and nonrodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies wherein the circulating metabolites and drug-drug interactions were further characterized. The human metabolism of MMB was mediated primarily by multiple cytochrome P450 enzymes, whereas M21 formation involved initial P450 oxidation of the morpholine ring followed by metabolism via aldehyde oxidase.
Zheng, J., Xin, Y., Zhang, J., Subramanian, R., Murray, B. P., Whitney, J. A., Warr, M. R., Ling, J., Moorehead, L., Kwan, E., Hemenway, J., Smith, B. J., Silverman, J. A.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_4 Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite--Resolution for Clinical Development [Articles]
Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), is in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [ 14 C]MMB were characterized in a single-dose, human mass-balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route. Mean blood-to-plasma [ 14 C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [ 14 C]MMB-derived radioactivity was detectable in blood for ≤48 hours, suggesting no irreversible binding of MMB or its metabolites. The major circulating human metabolite, M21 (a morpholino lactam), is a potent inhibitor of JAK1/2 and ACVR1 in vitro. Estimation of pharmacological activity index suggests M21 contributes significantly to the pharmacological activity of MMB for the inhibition of both JAK1/2 and ACVR1. M21 was observed in disproportionately higher amounts in human plasma than in rat or dog, the rodent and nonrodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies wherein the circulating metabolites and drug-drug interactions were further characterized. The human metabolism of MMB was mediated primarily by multiple cytochrome P450 enzymes, whereas M21 formation involved initial P450 oxidation of the morpholine ring followed by metabolism via aldehyde oxidase.
Zheng, J., Xin, Y., Zhang, J., Subramanian, R., Murray, B. P., Whitney, J. A., Warr, M. R., Ling, J., Moorehead, L., Kwan, E., Hemenway, J., Smith, B. J., Silverman, J. A.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_title_1 Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite--Resolution for Clinical Development [Articles]
shingle_title_2 Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite--Resolution for Clinical Development [Articles]
shingle_title_3 Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite--Resolution for Clinical Development [Articles]
shingle_title_4 Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite--Resolution for Clinical Development [Articles]
timestamp 2025-06-30T23:32:35.934Z
titel Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite--Resolution for Clinical Development [Articles]
titel_suche Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite--Resolution for Clinical Development [Articles]
topic V
WW-YZ
uid ipn_articles_6159686