Comparative Bioavailability of Sustained-Release Morphine Sulfate Capsules versus Pellets

Abstract

Kadian™ is an oral formulation of sustained-release morphine sulfate pellets contained in a gelatin capsule, indicated for the treatment of moderate to severe chronic pain. A randomised, single-dose, open-label, 4-way crossover study in 25 healthy male and female volunteers evaluated whether in the fasted and fed state Kadian™ capsules swallowed whole were bioequivalent to Kadian™ pellets sprinkled on apple sauce. A 50mg dose of study medication was administered 7 days apart after either an overnight fast of 10 hours or after a standard high-fat meal. Serial blood samples were taken for 48 hours postdose and were analysed for morphine by high-performance liquid chromatography using electrochemical detection. Kadian™ capsules swallowed whole and Kadian™ pellets sprinkled on apple sauce were bioequivalent fasted. Furthermore, Kadian™ capsules swallowed whole were bioequivalent when given both fasted and fed, and Kadian™ capsules swallowed whole and Kadian™ pellets sprinkled on apple sauce were bioequivalent under fed conditions. Both the 90% confidence intervals and mean ratios were within the bioequivalence limits for area under the plasma morphine concentration-time curve (AUC0–48and AUC0-∞) for Kadian™ pellets sprinkled on apple sauce administered under fed and fasted conditions. However, food reduced the mean maximum plasma drug concentration (Cmax) value to 79% of the fasted value, which was just outside the lower bioequivalence limit. Because the extent of absorption of morphine from Kadian™ pellets was not significantly affected by food, this reduction in Cmax would not be clinically significant on a once-a-day administration regimen. This study confirmed and extended previous results derived in vitro that showed that the rate of release of morphine from Kadian™ pellets was not affected when the pellets were poured on to foodstuffs and liquids. In conclusion, Kadian™ capsules swallowed whole were bioequivalent to Kadian™ pellets sprinkled on apple sauce in both the fed and fasted states. Therefore, because it can be administered via an alternative dosing method (sprinkling), which is not possible with other long-acting morphine products, Kadian™ may well offer a significant advantage in the management of patients with cancer pain, particularly those with general debility or difficulty in swallowing. Kadian™ is also know as either Kapanol™ or Morcap SR™.