SINGLE-DOSE PHARMACOKINETICS OF KAPANOL(TM), A NEW ORAL SUSTAINED-RELEASE MORPHINE FORMULATION

Three single dose open-label crossover studies in healthy adult males (n = 24 or 30) evaluated the sustained release characteristics, bioavailability, influence of food, linearity of kinetics and metabolite to morphine molar ratios of Kapanol(TM) compared with oral morphine solution and MST Continus(R) tablets. Drugs were administered 7 days apart following either a 12-hour fast or a standard high-fat meal. All blood samples (36 or 48 hours) were analysed for morphine (high-performance liquid chromatography [HPLC]-electrochemical detection) and a subset was analysed for morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) [HPLC-ultraviolet]. Kapanol(TM) (fasted and fed) had a pharmacokinetic profile consistent with a sustained release of morphine (M) and there was no evidence of dose-dumping. No significant differences occurred in the dose-adjusted area under the plasma concentration-time curve (AUC) values for Kapanol(TM) (50mg) [fasted and fed] and solution (25mg) [fasted]. The bioavailability of Kapanol(TM) relative to solution was 107 and 111% on fasting and fed states, respectively. The AUC molar ratios of M-3-G and M-6-G to M were not significantly different for Kapanol(TM) and solution (mean molar ratio M : M-6-G : M-3-G = 1 : 7 : 30). Kapanol(TM) displayed linear pharmacokinetics over the dose range of 30 to 100mg. Kapanol(TM) 50mg had a slower absorption rate and a longer duration over which plasma morphine levels were equal to or above 75% peak concentration than MST Continus(R) 60mg, while no differences occurred in the extent of morphine absorption from the 2 formulations. In conclusion, the pharmacokinetics of Kapanol(TM) are consistent with a sustained-release formulation suitable for at least 12-hourly dose administration. The slow, sustained absorption of morphine from Kapanol(TM) may provide clinical advantages over other morphine preparations.