title: Preclinical models of nicotinamide phosphoribosyltransferase inhibitor-mediated hematotoxicity and mitigation by co-treatment with nicotinic acid.
abstract: Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in glycolysis and is a key molecule involved in maintaining cellular energy metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of an important salvage pathway in which nicotinamide is recycled into NAD. NAMPT is up-regulated in many types of cancer and NAMPT inhibitors (NAMPTi) have potential therapeutic benefit in cancer by impairing tumor metabolism. Clinical trials with NAMPTi APO-866 and GMX-1778, however, failed to reach projected efficacious exposures due to dose-limiting thrombocytopenia. We evaluated preclinical models for thrombocytopenia that could be used in candidate drug selection and risk mitigation strategies for NAMPTi-related toxicity. Rats treated with a suite of structurally diverse and potent NAMPTi at maximum tolerated doses had decreased reticulocyte and lymphocyte counts, but no thrombocytopenia. We therefore evaluated and qualified a human colony forming unit-megakaryocyte (CFU-MK) as in vitro predictive model of NAMPTi-induced MK toxicity and thrombocytopenia. We further demonstrate that the MK toxicity is on-target based on the evidence that nicotinic acid (NA), which is converted to NAD via a NAMPT-independent pathway, can mitigate NAMPTi toxicity to human CFU-MK in vitro and was also protective for the hematotoxicity in rats in vivo. Finally, assessment of CFU-MK and human platelet bioenergetics and function show that NAMPTi was toxic to MK and not platelets, which is consistent with the clinically observed time-course of thrombocytopenia.
authors.affiliation: Department of Safety Assessment, Genentech Inc. , South San Francisco, CA , USA .
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Tarrant
authors.forename: Preeti
authors.initials: P
authors.lastname: Dhawan
authors.forename: Jatinder
authors.initials: J
authors.lastname: Singh
authors.forename: Tanja S
authors.initials: TS
authors.lastname: Zabka
authors.forename: Emer
authors.initials: E
authors.lastname: Clarke
authors.forename: Garry
authors.initials: G
authors.lastname: DosSantos
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Tori
authors.initials: T
authors.lastname: Lin
authors.forename: Bobbi
authors.initials: B
authors.lastname: McCray
authors.forename: Nghi
authors.initials: N
authors.lastname: La
authors.forename: Trung
authors.initials: T
authors.lastname: Nguyen
authors.forename: Ariel
authors.initials: A
authors.lastname: Kauss
authors.forename: Donna
authors.initials: D
authors.lastname: Dambach
authors.forename: Dinah L
authors.initials: DL
authors.lastname: Misner
authors.forename: Dolores
authors.initials: D
authors.lastname: Diaz
authors.forename: Hirdesh
authors.initials: H
authors.lastname: Uppal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000737:chemistry; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D019587:Dietary Supplements; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000737:chemistry; D018565:Food-Drug Interactions; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D009525:Niacin / Q000378:metabolism* / Q000627:therapeutic use; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009525:Niacin; D010430:Pentosyltransferases; D054409:Nicotinamide Phosphoribosyltransferase; C021864:nicotinate phosphoribosyltransferase
keywords: Colony forming unit-megakaryocyte; hematotoxicity; platelet