Pharmacokinetics and bioavailability of oxycodone and acetaminophen following single-dose administration of MNK-795, a dual-layer biphasic IR/ER combination formulation, under fed and fasted conditions

Abstract

Background: XARTEMIS™ XR (formerly MNK-795) is a combination oxycodone (OC) and acetaminophen (APAP) analgesic with both immediate-release and extended-release (ER) components (ER OC/APAP). The tablets are designed with gastric-retentive ER oral delivery technology that releases the ER component at a controlled rate in the upper gastrointestinal tract. Because consumption of food has demonstrated an impact on the pharmacokinetics (PK) of some marketed products using gastric-retentive ER oral delivery technology, a characterization of the effects of fed (high- and low-fat diets) versus fasted conditions on the PK of ER OC/APAP was performed.

Methods: This Phase I study used an open-label randomized single-dose three-period six-sequence crossover single-center design. Healthy adult participants (n=48) were randomized to receive two tablets of ER OC/APAP under three conditions: following a high-fat meal; following a low-fat meal; and fasted. Plasma concentration versus time data from predose throughout designated times up to 48 hours postdose was used to estimate the PK parameters of oxycodone and APAP.

Results: Thirty-one participants completed all three treatment periods. Both oxycodone and APAP were rapidly absorbed under fasted conditions. Total oxycodone and APAP exposures (area under the plasma drug concentration-time curve [AUC]) from ER OC/APAP were not significantly affected by food, and minimal changes to maximum observed plasma concentration for oxycodone and APAP were also noted. However, food marginally delayed the time to maximum observed plasma concentration of oxycodone and APAP. There was no indication that tolerability was affected by food.

Conclusion: The findings from this study suggest that ER OC/APAP can be administered with or without food.

Keywords: acute pain; extended release; fed conditions; opioid fixed dose combination.

Figure 1

Study design. Notes: Treatments consisted of two tablets of ER OC/APAP (15 mg OC/650 mg APAP) under: A) high-fat meal fed condition; B) low-fat meal fed condition; and C) fasted condition. ^aDuration of approximately 60 hours each, including an initial overnight (10-hour) fast, predose assessments and blood draws, and postdose pharmacokinetic sampling for 48 hours; ^b≥7 days; ^cparticipants were released from the study following their 48-hour blood draw and completion of the 48-hour postdose safety assessments; ^dongoing adverse events were followed via telephone for 7 days (with a visit window of plus 2 days) after period 3 study exit or early termination. Abbreviations: APAP, acetaminophen; ER, extended release; OC, oxycodone.

Figure 2

Mean plasma concentration of oxycodone versus time by treatment condition. Notes: Pharmacokinetic analysis population = study completers (n=31). Treatments consisted of two tablets of ER OC/APAP (15 mg OC/650 mg APAP) under high- and low-fat fed conditions and fasted conditions. Abbreviations: APAP, acetaminophen; ER, extended release; OC, oxycodone; h, hours.

Figure 3

Mean plasma concentration of acetaminophen versus time by treatment condition. Notes: Pharmacokinetic analysis population = study completers (n=31). Treatments consisted of two tablets of ER OC/APAP (15 mg OC/650 mg APAP) under high- and low-fat fed conditions and fasted conditions. Abbreviations: APAP, acetaminophen; ER, extended release; OC, oxycodone; h, hours.