Pharmacokinetics and safety of apremilast (CC-10004) in subjects with hepatic impairment

Apremilast (CC-10004), a PDE4 enzyme inhibitor, is under clinical development for the treatment of inflammatory immune-mediated disorders. Since apremilast is extensively metabolised via multiple routes, impact of hepatic impairment on the pharmacokinetics (PK) of apremilast and M12 metabolite was evaluated. Thirty-two subjects were enrolled in a two-centre, open-label, and single-dose study. Subjects with moderate hepatic impairment and their healthy matches received a single 30-mg dose and subjects with severe hepatic impairment and their healthy matches received a single 20-mg dose of apremilast. Plasma concentrations of apremilast and M12 were measured, PK parameters calculated, and statistically compared. During the study, single doses of apremilast were well tolerated, with no clinically meaningful safety findings observed. PK parameters were comparable between hepatic impaired and healthy subjects, and there was no evidence to suggest that the PK of apremilast is affected by moderate and severe hepatic impairment. Therefore, no dose adjustment is required

Patient populations.

<p>Patient populations.</p

Azacitidine plasma concentrations over time following CC-486 administration (200 mg and 300 mg doses) on the first day (day 1) and last day (day 14/21) of cycle 1.

<p>(A) linear and (B) semi-log scales.</p

Changes in global DNA methylation score (GDMS) with CC-486 in extended dosing schedules.

<p>*Wilcoxon signed-rank <i>P</i> value</p><p>^†n = 1</p><p>^‡Of the 3 patients in the 200 mg BID x14d group, 2 had an available PD sample only on day 15, and the third had a PD sample only on day 22, preventing the day 15 vs. 22 comparison.</p><p>n = the number of patients in a specific subject population; the actual sample size for each comparison may vary slightly due to missing data at various time points.</p><p>BID = twice-daily; QD = once-daily</p><p>Changes in global DNA methylation score (GDMS) with CC-486 in extended dosing schedules.</p