1 Oxycodone is a strong opioid agonist that is currently available in immediaterelease ( IR) formulations for the treatment of moderate to severe pain. Recently, controlled-release (CR) oxycodone tablets were developed to provide the benefits of twice-a-day dosing to patients treated with oxycodone. The purpose of this investigation was to develop and validate a pharmacokinetic model for CR oxycodone tablets in comparison 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 10 mg CR oxycodone tablets with 20 mg IR oxycodone oral solution. Pharmacokinetic models describing the oxycodone plasma concentration vs time profiles of CR tablets and IR solution were derived using NONMEM version IV. The predictive performance of the models was assessed by comparison of predicted oxycodone plasma concentrations with actual oxycodone plasma concentrations observed in a separate group of 21 volunteers 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 described by a mono-exponential model with a lag time, whereas absorption rate of the CR tablet was best described using a bi-exponential model. The absorption profile of the CR tablets was characterized by a rapid 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) accounting for 62% of the available dose. Two 10 mg tablets of oral CR oxycodone hydrochloride were 102.7% bioavailable relative to 20 mg of IR oxycodone hydrochloride oral solution. The population model derived after administration of a single dose accurately predicted both the mean and range of oxycodone concentrations observed during 4 days of repeated dosing. The mean prediction error was 2.7% with a coefficient of variation of 54%. 4 The absorption characteristics of CR oxycodone tablets should allow effective plasma concentrations of oxycodone to be reached quickly and for effective concentrations to be maintained for a longer period after dosing compared with the IR oral solution. The CR dosage form has pharmacokinetic characteristics that permit 12 hourly dosing.

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The results of nine US multicenter, sequential crossover, dose titration studies of controlled-release oral morphine (MS Contin 30 mg tablets [MSC], Purdue Frederick, Norwalk, CT) are reviewed in Part I. The studies demonstrated the prolonged analgesic efficacy of the preparation in the treatment of patients with moderate to severe cancer-related pain. Approximately 93% of the patients achieved satisfactory to excellent analgesia on a 12-hour regimen when appropriate dose titration was allowed. The remaining patients were successfully maintained on an 8-hour regimen. The preparation was well-tolerated and comparable in safety to immediate-release oral morphine. In global evaluations, MSC was judged to be significantly (P less than 0.05) more effective, and with significantly (P less than 0.05) fewer side effects than both the prestudy opioid analgesics and 4-hour immediate-release oral morphine. Patients had a broad range of morphine requirements (mean daily MSC dose, 240 mg; range, 60 mg/day to 1800 mg/day); therefore various MSC tablet strengths were developed. Part II presents three studies in which the MSC formulations (15-mg, 60-mg, and 100-mg tablets) were compared to the 30-mg tablet within three randomized, single-dose, two-way crossover, analytically blinded bioavailability protocols, to determine bioequivalence and dose proportionality. The maximum morphine concentration, time of maximum morphine concentration, and area under the plasma morphine versus 12-hour and 24-hour time curve (AUC 0.12; AUC 0.24) were determined in each study. There were no significant differences between the values associated with MSC 1 X 30 mg tablet and 2 X 15 mg tablets (study 1), MSC 2 X 30 mg tablets and 1 X 60 mg tablet (study 2), and MSC 3 X 30 mg tablets and 1 X 100 mg tablet (study 3, values adjusted to dose of 90 mg), except for one marginally significant difference in study 3 (AUC 0.24; P = 0.04) which was not clinically or biopharmaceutically significant. The results showed that MSC 15-mg, 30-mg, 60-mg, and 100-mg dosage strengths are bioequivalent and dose proportional, and, therefore, therapeutically interchangeable. It was concluded that with routine assessment of the patient and adherence to the principles of analgesic dosing, MSC can be successfully used to control cancer-related pain. Furthermore, the availability of various MSC tablet strengths can be expected to facilitate the analgesic management of a patient population with widely differing opioid requirements.

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