A Randomized Study of the Effects of Food on the Pharmacokinetics of Once-Daily Extended-Release Hydromorphone in Healthy Volunteers

Abstract

This randomized, open-label, crossover study investigated the influence of food on the pharmacokinetics of extended-release hydromorphone in 30 healthy volunteers. Participants received extended-release hydromorphone 16 mg in the fasted state and immediately after a high-fat breakfast. In addition, the pharmacokinetics of a 16-mg dose of extended-release hydromorphone and a 16-mg daily dose (4 mg qid) of immediate-release hydromorphone in the fasted state were compared. Treatments were separated by washout periods of 7 to 14 days. Naltrexone was given throughout each treatment period to block the opioid effects of hydromorphone. The 90% confidence intervals (CIs) of the ratios of geometric means for maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve (AUC) for extended-release hydromorphone in the fed and fasted states were within the bioequivalence criteria range of 80% to 125%. In the fasted state, the 90% CIs of the ratios of AUC geometric means for extended-release hydromorphone and immediate-release hydromorphone were also within the bioequivalence range. Both hydromorphone treatments were well tolerated. This study shows that the bioavailability of extended-release hydromorphone is not affected by food and that the bioavailability of extended-release hydromorphone under fasting conditions is comparable with that of the immediate-release formulation when administered at the same total daily dose.

Complementary pharmacokinetic measures to further define the profile of once-daily OROS hydromorphone ER during single-dose and steady-state dosing

“…Medication use (other than hormone replacement therapy, oral contraceptives, or acetaminophen) within 14 days prior to study treatment was prohibited. Subjects with a history or believed history of drug or alcohol abuse within the past 5 years were also excluded; a naloxone 0.8-mg injection was administered prior to study randomization and medication dosing to detect opioid dependence (Moore et al 2010; Moore et al 2011). …”

“…The pharmacokinetic (PK) profile of OROS hydromorphone extended-release (ER) is well established in healthy subjects, with controlled release resulting in sustained plasma concentrations (Angst et al 2001; Drover et al 2002; Moore et al 2010; Moore et al 2011; Sathyan et al 2007; Sathyan et al 2008). The hydromorphone release rate is independent of pH and gastric motility (Gupta and Sathyan 2007), and relatively unaffected by alcohol, rendering “dose dumping” unlikely (Sathyan et al 2008).…”

“…OROS hydromorphone ER reaches maximum plasma concentration ( C max ) 12 to 16 hours after administration and produces sustained hydromorphone concentrations over 24 hours, with dose-proportional PK (Drover et al 2002; Sathyan et al 2007; Gupta and Sathyan 2007). OROS hydromorphone ER has a long half-life (~13 to 15 hours) and requires 3 to 4 days to reach steady-state plasma hydromorphone concentrations (Moore et al 2010; Moore et al 2011; Sathyan et al 2007; Gupta and Sathyan 2007). …”

“…The current analysis used data from 2 previously published studies in healthy subjects: one assessing effects of food on the PK of single doses of the OROS formulation compared with 4 doses of IR hydromorphone (Study A) (Moore et al 2011), and one characterizing the steady-state PK of OROS and IR hydromorphone (Study B) (Moore et al 2010). We sought to further characterize the single-dose and steady-state PK profiles of hydromorphone by evaluating time ≥50% C max in healthy subjects after administration of oral OROS hydromorphone ER.…”

Dose Equivalence of Immediate-Release Hydromorphone and Once-Daily Osmotic-Controlled Extended-Release Hydromorphone: A Randomized, Double-Blind Trial Incorporating a Measure of Assay Sensitivity

“…This formulation has linear pharmacokinetics at doses between 8 and 64 mg daily 11 ; provides analgesia with once-daily dosing 7,18 ; and has gastrointestinal absorption that is not affected by food, pH, gastric motility, or alcohol. 1,6,12,16 It is commercially available in the United States and some European countries.…”