Pexmetinib (ARRY-614)

Pexmetinib (ARRY-614) is a potent inhibitor of cytokine synthesis, via the dual inhibition of p38 mitogen-activated protein kinase (MAPK), and Tie2/Tek receptor tyrosine kinase. The in vitro IC50 values of ARR Y-614 for both Tie2 and p38 mitogen-activated protein kinase are 1000 ng/mL and 100 ng/mL, respectively [1, 2].

p38 is a group of mitogen-activated protein kinases. MAPKs are activated by the dual phosphorylation of Tyr and Thr residues in the Thr-Xaa-Tyr motif in subdomain VIII. Data indicated that p38 MAPK may mediate signaling to the nucleus [3].

ARRY-614 is active against MAPK and Tie2/Tek receptor tyrosine kinase in cells. In primary human bone marrow stromal cells, ARRY-614 inhibited basal cytokines with an IC50 value ranging from 50-100 nM [4].

In dose escalation or expansion cohorts, treatment with ARRY-614 either once daily or twice daily was applied to forty-five patients. ARRY-614 reduced the levels of circulating biomarkers and the p38 MAPK activation of bone marrow [1]. In ex vivo stimulated human whole blood, LPS-induced cytokines was inhibited by ARRY-614 with an IC50 value ranging from 50-120 nM. ARRY-614 inhibited the release of IL-6 from SEA- or LPS-challenged mice with an ED50 value less than 10 mg/kg. Combining ARRY-614 with lenalidomide inhibited both pro-inflammatory cytokines and tumor growth in vivo with higher potency, compared with either agent alone [4].

References:
[1].  Garcia-Manero G, Khoury HJ, Jabbour E, et al. A phase I study of oral ARRY-614, a p38 MAPK/Tie2 dual inhibitor, in patients with low or intermediate-1 risk myelodysplastic syndromes. Clinical Cancer Research, 2015, 21(5): 985-994.
[2].  Wollenberg LA, Corson DT, Nugent CA, et al. An exploratory, randomized, parallel-group, open-label, relative bioavailability study with an additional two-period crossover food-effect study exploring the pharmacokinetics of two novel formulations of pexmetinib (ARRY-614). Clinical pharmacology: advances and applications, 2015, 7: 87.
[3].  Raingeaud J, Whitmarsh AJ, Barrett T, et al. MKK3-and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Molecular and cellular biology, 1996, 16(3): 1247-1255.
[4].  Winski S, Humphries M, Yeh T, et al. Activity of ARRY-614, an inhibitor of p38 map kinase and angiogenic targets, in hematologic malignancies. Cancer Research, 2009, 69(9 Supplement): 331-331.

An exploratory, randomized, parallel-group, open-label, relative bioavailability study with an additional two-period crossover food-effect study exploring the pharmacokinetics of two novel formulations of pexmetinib (ARRY-614).[Pubmed:26491375]

Clin Pharmacol. 2015 Sep 30;7:87-95.

BACKGROUND: Pexmetinib (ARRY-614) is a dual inhibitor of p38 mitogen-activated protein kinase and Tie2 signaling pathways implicated in the pathogenesis of myelodysplastic syndromes. Previous clinical experience in a Phase I dose-escalation study of myelodysplastic syndrome patients using pexmetinib administered as neat powder-in-capsule (PIC) exhibited high variability in pharmacokinetics and excessive pill burden, prompting an effort to improve the formulation of pexmetinib. METHODS: A relative bioavailability assessment encompassed three parallel treatment cohorts of unique subjects comparing the two new formulations (12 subjects per cohort), a liquid oral suspension (LOS) and liquid-filled capsule (LFC) and the current clinical PIC formulation (six subjects) in a fasted state. The food-effect assessment was conducted as a crossover of the LOS and LFC formulations administered under fed and fasted conditions. Subjects were divided into two groups of equal size to evaluate potential period effects on the food-effect assessment. RESULTS: The geometric mean values of the total plasma exposures based upon area-under-the-curve to the last quantifiable sample (AUClast) of pexmetinib were approximately four- and twofold higher after administration of the LFC and LOS formulations, respectively, than after the PIC formulation, when the formulations were administered in the fasted state. When the LFC formulation was administered in the fed state, pexmetinib AUClast decreased by <5% compared with the fasted state. After administration of the LOS formulation in the fed state, pexmetinib AUClast was 34% greater than observed in the fasted state. CONCLUSION: These results suggest that the LFC formulation of pexmetinib may achieve greater exposures with lower doses due to the greater bioavailability compared to the PIC, and remain unaffected by coadministration with food.

Pexmetinib is a potent Tie-2 and p38 MAPK dual inhibitor, with IC50s of 1 nM, 35 nM and 26 nM for Tie-2, p38α and p38β, respectively, and can be used in the research of acute myeloid leukemia.

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