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

BackgroundXARTEMIS™ 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.MethodsThis 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.ResultsThirty-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.ConclusionThe findings from this study suggest that ER OC/APAP can be administered with or without food.

Pooled post hoc analysis of population pharmacokinetics of oxycodone and acetaminophen following a single oral dose of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets

“…In the primary PK analysis of this study, food intake delayed time to maximum concentration ( t max ) by 1.5 hours and 2 hours, respectively, for OC and APAP, and time to first measurable concentration ( t lag ) by 15 minutes for both. 10 This supports the finding in the present population PK analysis that food decreases the K a of OC and APAP. However, administration of IR/ER OC/APAP with food had no effect on the extent of drug exposure because the area under the concentration vs time curve for OC and APAP remained bioequivalent under high-fat and low-fat fed conditions in the primary PK analysis.…”

“…8 , 9 However, no clinically meaningful food effects were associated with the use of this gastroretentive technology in a previous study of IR/ER OC/APAP. 10 …”

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

“… 19 – 27 In PK studies of low-dose combination opioids enrolling healthy adult volunteers, a discontinuation rate of 20%–40% due to vomiting is typical. 21 , 28 , 29 In acute pain studies, short-term multidose regimens of IR HB/APAP and/or IR OC/APAP have reported nausea and vomiting in 14%–42% and 4%–24% of patients, respectively. 19 , 22 , 26 , 27 Similar results have been observed with opioid/ibuprofen and tramadol/APAP combination therapies.…”

HPLC-Pda Method for the Quantification of Paracetamol in Plasma: Application to Pk/Pd Studies With Arthritic Rats

“…In addition, the recovery obtained with the selected method was higher than others that use shorter concentration intervals [1,18,22]; UPLC-MS/MS methods with simple protein precipitation with acetonitrile [23] or larger volumes of plasma samples [11,19,21,22]; or at least two-step liquid-liquid extraction and evaporation [10,18,22,24]. Other of the advantages of this method is that it allows a high recovery of the analyte from the biological matrix (>99%) and allows multiple samples to be processed in a short period of time.…”