Preclinical assessment of the ADME, efficacy and drug-drug interaction potential of a novel NAMPT inhibitor

Abstract

1. GNE-617 (N-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-a]pyridine-6-carboxamide) is a potent, selective nicotinamide phosphoribosyltransferase (NAMPT) inhibitor being explored as a potential treatment for human cancers.

2. Plasma clearance was low in monkeys and dogs (9.14 mL min⁻¹kg⁻¹ and 4.62 mL min⁻¹kg⁻¹, respectively) and moderate in mice and rats (36.4 mL min⁻¹kg⁻¹ and 19.3 mL min⁻¹kg⁻¹, respectively). Oral bioavailability in mice, rats, monkeys and dogs was 29.7, 33.9, 29.4 and 65.2%, respectively.

3. Allometric scaling predicted a low clearance of 3.3 mL min⁻¹kg⁻¹ and a volume of distribution of 1.3 L kg⁻¹ in human.

4. Efficacy (57% tumor growth inhibition) in Colo-205 CRC tumor xenograft mice was observed at an oral dose of 15 mg/kg BID (AUC = 10.4 µM h).

5. Plasma protein binding was moderately high. GNE-617 was stable to moderately stable in vitro. Main human metabolites identified in human hepatocytes were formed primarily by CYP3A4/5. Transporter studies suggested that GNE-617 is likely a substrate for MDR1 but not for BCRP.

6. Simcyp^® simulations suggested a low (CYP2C9 and CYP2C8) or moderate (CYP3A4/5) potential for drug-drug interactions. The potential for autoinhibition was low.

7. Overall, GNE-617 exhibited acceptable preclinical properties and projected human PK and dose estimates.

Keywords:

• NAMPT
• distribution
• metabolism
• pharmacokinetics
• efficacy
• allometry
• human prediction
• drug-drug interactions

Disclosure statement

No potential conflict of interest was reported by the authors.