(431) Single- and multiple-dose pharmacokinetics of extended-release hydrocodone bitartrate/acetaminophen tablets (MNK-155) with and without loading dose compared with marketed immediate-release hydrocodone bitartrate/acetaminophen tablets

MNK-155 is a bilayer, immediate-release (IR)/extended-release (ER) tablet formulation containing 7.5 mg hydrocodone bitartrate and 325 mg acetaminophen (HB/APAP ER). This study evaluated single- and multiple-dose pharmacokinetics and bioavailability of MNK-155 administered as 2 or 3 tablets every 12 hours (q12h) compared with 1 tablet IR 7.5 mg HB/325 mg APAP every 6 hours (q6h) in healthy subjects under fasted conditions. For the single-dose portion, subjects (n=30) received one single dose of MNK-155, and IR product q6h for two doses (hydrocodone/ibuprofen [Vicoprofen®] or tramadol/APAP [Ultracet®]). For the multiple-dose portion, subjects (n=29) received 2 tablets MNK-155 q12h with or without a 3-tablet loading dose, and the IR product q6h for 4.5 days. The most common adverse events (AEs) included nausea, pruritus, vomiting, somnolence, constipation, headache, euphoric mood, and dizziness. No serious AEs were reported. Plasma hydrocodone and APAP concentrations rose rapidly after MNK-155 administration. Hydrocodone concentrations were sustained above pre-dose levels over the 12-hour dosing interval. By 10-12 hours after administration, APAP concentrations approximated baseline levels. Steady-state was achieved in 2 days for hydrocodone and 1-2 days for APAP. Total exposure (dose-normalized area under the concentration–time curve [AUC]) to hydrocodone and APAP after MNK-155 administration, with and without the loading dose, were equivalent to marketed IR products in single-dose and steady-state conditions. Single-dose peak hydrocodone exposure (dose-normalized maximum plasma concentration [Cmax]) for MNK-155 was approximately 30% lower than for IR hydrocodone/ibuprofen. However, single-dose peak exposure (dose-normalized Cmax) for APAP and multiple-dose Cmaxss for hydrocodone and APAP were equivalent to marketed IR products, with less fluctuation in hydrocodone versus IR hydrocodone/ibuprofen and lower trough plasma concentrations of APAP versus IR tramadol/APAP. These findings support a proposed dosing interval of MNK-155 every 12 hours. Supported by funding from Mallinckrodt Inc.