Repeat-dose steady-state pharmacokinetic evaluation of once-daily hydromorphone extended-release (OROS® hydromorphone ER) in patients with chronic pain

Abstract

Joris Vandenbossche,1 Ute Richarz,2 Henry M Richards31Clinical Pharmacology, Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium; 2Global Medical Affairs, Janssen-Cilag, Baar, Switzerland; 3Established Products, Johnson and Johnson Pharmaceutical Research and Development, Titusville, NJ, USAObjective: To characterize the steady-state pharmacokinetic profile of hydromorphone extended-release (ER) in patients with chronic pain taking concomitant medications.Methods: This open-label repeat-dose study enrolled 22 patients (mean age, 51.4 years; 81.8% female). All patients were receiving at least one concomitant medication; 86.4% were receiving at least two concomitant medications and 81.8% were receiving at least three. Patients receiving a stable dose of an opioid were converted to hydromorphone ER at a 5:1 ratio (morphine equivalent:hydromorphone). The dose was titrated to adequate analgesia over 3–14 days and stabilized between 8–48 mg. Oral morphine immediate-release was permitted for breakthrough pain. Area under the concentration–time curve from 0–24 hours (AUC0–24), maximum plasma concentration (Cmax), trough plasma concentration (Cmin), average plasma concentration (Cavg), and degree of fluctuation (100 × [(Cmax - Cmin) ÷ Cavg]) were calculated based on data from 14 patients.Results: Dose-normalized to 16 mg, mean pharmacokinetic parameter values were: AUC0–24, 41.1 ng • h/mL; Cmax, 2.6 ng/mL; Cmin, 1.1 ng/mL; Cavg, 1.7 ng/mL; and the degree of fluctuation was 99.6%. The pharmacokinetic profile of hydromorphone ER was linear and consistent with dose proportionality. Mean pain intensity difference scores showed statistically significant improvement from 2–21 hours after dosing. Sixteen (72.7%) patients reported at least one adverse event (AE). The most common were constipation (31.8%), headache (22.7%), and vomiting (13.6%). One patient discontinued treatment due to vomiting. No deaths, serious AEs, or unexpected AEs occurred.Conclusion: These findings replicate and extend the steady-state pharmacokinetic profile of hydromorphone ER, previously characterized in healthy volunteers, to a population of chronic pain patients taking numerous concomitant medications.Keywords: opioid analgesics, steady-state pharmacokinetic profile, pain intensity, concomitant medications