CHARACTERIZATION AND VALIDATION OF A PHARMACOKINETIC MODEL FOR CONTROLLED-RELEASE OXYCODONE

1 Oxycodone is a strong opioid agonist that is currently available in immediate-release (IR) formulations for the treatment of moderate to s evere pain. Recently, controlled-release (CR) oxycodone tablets were d eveloped to provide the benefits of twice-a-day dosing to patients tre ated with oxycodone. The purpose of this investigation was to develop and validate a pharmacokinetic model for CR oxycodone tablets in compa rison with IR oxycodone solution. 2 Twenty-four normal male volunteers were enrolled in a single-dose, randomized, analytically blinded, two -way crossover study designed to compare the pharmacokinetics of two 1 0 mg CR oxycodone tablets with 20 mg IR oxycodone oral solution. Pharm acokinetic models describing the oxycodone plasma concentration us tim e profiles of CR tablets and IR solution were derived using NONMEN ver sion IV. The predictive performance of the models was assessed by comp arison of predicted oxycodone plasma concentrations with actual oxycod one plasma concentrations observed in a separate group of 21 volunteer s who received repeated doses of IR and CR oxycodone for 4 days. 3 The unit impulse disposition function of oxycodone was best described by a one-compartment model. Absorption rate of the IR solution was best d escribed by a mono-exponential model with a lag time, whereas absorpti on rate of the CR tablet was best described using a bi-exponential mod el. The absorption profile of the CR tablets was characterized by a ra pid absorption component (t(1/2)abs=37 min) accounting for 38% of the available dose and a slow absorption phase (t(1/2)abs=6.2 h) accountin g for 62% of the available dose. Two 10 mg tablets of oral CR oxycodon e hydrochloride were 102.7% bioavailable relative to 20 mg of IR oxyco done hydrochloride oral solution. The population model derived after a dministration of a single dose accurately predicted both the mean and range of oxycodone concentrations observed during 4 days of repeated d osing. The mean prediction error was 2.7% with a coefficient of variat ion of 54%. 4 The absorption characteristics of CR oxycodone tablets s hould allow effective plasma concentrations of oxycodone to be reached quickly and for effective concentrations to be maintained for a longe r period after dosing compared with the IR oral solution. The CR dosag e form has pharmacokinetic characteristics that permit 12 hourly dosin g.