Metabolism, Excretion and Pharmacokinetics of MLN3897, a CCR1 Antagonist, in Humans
2016
MLN3897 is a small molecule antagonist of the C-C chemokine receptor-1. Since preclinical studies showed
that the molecule was metabolized into two halves, the metabolism, excretion, and pharmacokinetics of MLN3897 were
investigated in humans using MLN3897 14C-radiolabeled either on the chlorophenyl (CP) or the tricyclic (TC) half of
MLN3897 after an oral dose.
Objective: To evaluate the mass balance, metabolism and pharmacokinetics of MLN3897 in two cohorts of six
randomized healthy subjects.
Method: After receiving informed consent, subjects were dosed after an overnight fast of 10-hours followed by at least 4-
hours after dosing on day-1. Each cohort received a single 29 mg oral dose of either the CP or the TC as an oral solution
in water. Serial blood samples, urine and feces were collected over a 10-day period post-dose.
Results: For both radiolabeled moieties, 55-59% of the dose was recovered in feces and 32% recovered in urine.
MLN3897 was metabolized extensively in humans, with minor amounts of intact MLN3897 detected in the urine and
feces. N-oxidation of the tricyclic moiety (M28) and N-dealkylation of the piperidinyl moiety were the primary metabolic
pathways leading to further formation of the carboxylic acid metabolite (M19) and the (4-(4-chlorophenyl)-3,3-
dimethylpiperidin-4-ol) metabolite (M40). Oxidative metabolites M11, M19, M28, M44 were present at >10% of the total
circulating radioactivity and also at >25% of MLN3897 exposure. Metabolites resulting from the chlorophenyl-labeled
moiety (M40) had significantly more systemic exposure compared to the tricyclic-labeled moiety (M19).
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