Metabolism, Excretion and Pharmacokinetics of MLN3897, a CCR1 Antagonist, in Humans

Title:Metabolism, Excretion and Pharmacokinetics of MLN3897, a CCR1 Antagonist, in Humans

Volume: 10 Issue: 1

Author(s): Sandeepraj Pusalkar, Mihaela Plesescu, Mark Milton, Suresh K. Balani, Swapan Chowdhury and Shimoga Prakash

Affiliation:

Keywords: CCR1 antagonist, human ADME, mass balance, metabolite profiling, MLN3897, pharmacokinetics.

Abstract: 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).

Cite this article as:

Pusalkar Sandeepraj, Plesescu Mihaela, Milton Mark, Balani K. Suresh, Chowdhury Swapan and Prakash Shimoga, Metabolism, Excretion and Pharmacokinetics of MLN3897, a CCR1 Antagonist, in Humans, Drug Metabolism Letters 2016; 10 (1) . https://dx.doi.org/10.2174/1872312809666150602152423