Single- and multiple-dose pharmacokinetics of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155) compared with immediate-release hydrocodone bitartrate/ibuprofen and immediate-release tramadol HCl/acetaminophen

Krishna Devarakonda, Kenneth Kostenbader, Michael J Giuliani, Jim L Young, Krishna Devarakonda, Kenneth Kostenbader, Michael J Giuliani, Jim L Young

Abstract

Objective: To characterize the single-dose and steady-state pharmacokinetics (PK) of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (IR/ER HB/APAP), IR HB/ibuprofen, and IR tramadol HCl/APAP.

Methods: In this single-center, open-label, randomized, four-period crossover study, healthy participants received four treatments under fasted conditions: 1) a single dose of two IR/ER HB/APAP 7.5/325 mg tablets (15/650 mg total dose) on day 1, followed by two tablets every 12 hours (q12h) beginning on day 3; 2) a single dose of IR HB/ibuprofen 15/400 mg (divided as one 7.5/200 mg tablet at hour 0 and 6), followed by one tablet every 6 hours (q6h) beginning on day 3; 3) a single dose of IR tramadol HCl/APAP 75/650 mg (divided as one 37.5/325 mg tablet at hour 0 and 6), followed by one tablet q6h beginning on day 3; and 4) a single dose of three IR/ER HB/APAP 7.5/325 mg tablets (22.5/975 mg total dose) on day 1, a three-tablet initial dose at 48 hours followed by two-tablet doses q12h beginning on day 3. Hydrocodone and APAP single-dose and steady-state PK were assessed. Adverse events were monitored.

Results: The PK analysis was carried out on 29 of 48 enrolled participants who completed all treatment periods. Single-dose hydrocodone exposure was similar for IR/ER HB/APAP 22.5/975 mg and IR HB/ibuprofen 15/400 mg; time to maximum observed plasma concentration was shorter and half-life was longer for IR/ER HB/APAP (22.5/975 mg and 15/650 mg) vs IR HB/ibuprofen. Single-dose APAP exposure was similar for IR/ER HB/APAP 15/650 mg and IR tramadol HCl/APAP 75/650 mg. Steady-state hydrocodone and APAP exposures were similar between treatments. Adverse events were similar for each treatment and typical of low-dose combination opioid analgesics. With dosing q12h, IR/ER HB/APAP had half as many concentration peaks and troughs as the comparators treated q6h.

Conclusion: With dosing q12h, IR/ER HB/APAP provided similar peak and total steady-state hydrocodone and APAP exposure vs IR comparators.

Keywords: acetaminophen; extended release; hydrocodone; ibuprofen; immediate release; tramadol.

Figures

Figure 1
Figure 1
Mean plasma hydrocodone concentrations after single-dose administration of IR/ER HB/APAP or IR HB/ibuprofen. Abbreviations: APAP, acetaminophen; ER, extended release; HB, hydrocodone bitartrate; IR, immediate release.
Figure 2
Figure 2
Mean steady-state plasma hydrocodone concentrations after multiple-dose administration of IR/ER HB/APAP or IR HB/ibuprofen. Abbreviations: APAP, acetaminophen; ER, extended release; HB, hydrocodone bitartrate; IR, immediate release; q6h, every 6 hours; q12h, every 12 hours.
Figure 3
Figure 3
Mean plasma APAP concentrations after single-dose administration of IR/ER HB/APAP or IR tramadol HCl/APAP. Abbreviations: APAP, acetaminophen; ER, extended-release; HB, hydrocodone bitartrate; HCl, hydrochloride; IR, immediate release.
Figure 4
Figure 4
Mean steady-state plasma APAP concentrations after multiple-dose administration of IR/ER HB/APAP or IR tramadol HCl/APAP. Abbreviations: APAP, acetaminophen; ER, extended-release; HB, hydrocodone bitartrate; HCl, hydrochloride; IR, immediate-release; q6h, every 6 hours; q12h, every 12 hours.

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Source: PubMed

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