Pharmacokinetic evaluation of a sprinkle-dose regimen of a once-daily, extended-release morphine formulation

Abstract

Background: Morphine sulfate extended-release (MSER) uses a drug-delivery technology that allows once-daily dosing. It is possible to open the MSER capsule and sprinkle the contents on soft food, a potentially useful alternative to the intact capsule in patients who have difficulty swallowing. Objective: This study compared the bioavailability of MSER and its metabolites morphine-3-glucuronide and morphine-6-glucuronide after administration of MSER in a sprinkle-dose regimen relative to an intact capsule swallowed whole. Methods: This was a randomized, open-label, single-dose, crossover study, with a 7-day washout period between the 2 dosing days. Healthy volunteers were randomized to receive an intact 60-mg MSER capsule swallowed whole or the contents of a 60-mg MSER capsule sprinkled on applesauce. Blood samples were collected and analyzed for concentrations of morphine and its active glucuronide metabolites. Pharmacokinetic (PK) parameters were calculated and bioequivalence assessed. Bioequivalence was concluded if the 90% CIs of the ratio of log-transformed values for maximum concentration (C max) and area under the plasma concentration—time curve (AUC) were within 80% to 125%. Results: Of 30 subjects enrolled, 28 completed the study and were eligible for PK evaluation. Two subjects were withdrawn for reasons unrelated to study treatment. The plasma concentration—time profiles of morphine and its metabolites were superimposable after administration of the 2 regimens. C max and total systemic exposure—based on AUC from time 0 to the last quantifiable concentration (AUC last) and AUC from time 0 to infinity (AUC ∞)—were comparable between treatments. The 90% CIs for morphine AUC last, AUC ∞, and C max ratios were 98 to 109, 96 to 106, and 95 to 117, respectively. Similar 90% CIs were obtained for the morphine metabolites. Conclusion: In this study in healthy volunteers, sprinkling the entire contents of an MSER capsule onto applesauce and swallowing without chewing was bioequivalent to swallowing an intact MSER capsule.