Vol. 33 No. 2S February 2007 Journal of Pain and Symptom Management S19 Advances in the Long-Term Management of Chronic Pain: Recent Evidence with OROS Ò Hydromorphone, a Novel, Once-Daily, Long-Acting Opioid Analgesic Providing Constant Analgesia with OROS Ò Hydromorphone Suneel Gupta, PhD, and Gayatri Sathyan, PhD ALZA Corporation, Mountain View, California, USA Abstract OROS Ò (ALZA Corporation, Mountain View, CA, USA) hydromorphone is a unique, once-daily formulation of the potent opioid hydromorphone that is being evaluated for the treatment of moderate-to-severe chronic pain. It uses a patented Push-Pull Ô (ALZA Corporation) osmotic pump system to deliver hydromorphone in a continuous, monophasic manner over 24 hours, resulting in minimal peak-trough plasma-level fluctuation. Peak concentrations are achieved approximately 16 hours after administration, with levels equivalent to approximately 80% of peak attained within just 6 hours. The apparent halflife of OROS Ò hydromorphone is 7e15 hours and steady-state concentrations are achieved after 2 days of dosing. The pharmacokinetics of OROS Ò hydromorphone are dose proportional and are not affected significantly by environmental factors (ph or agitation) or the presence of food. These pharmacokinetic characteristics suggest that OROS Ò hydromorphone is well suited to provide consistent, prolonged analgesia in patients with chronic pain. J Pain Symptom Manage 2007;33:S19eS24. Ó 2007 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Hydromorphone, sustained-release, pharmacokinetics, chronic pain Introduction Chronic pain is a common condition that affects up to 55% of the population worldwide. 1 It is typically challenging to manage, particularly in the ambulatory setting, in which clinicians rely on orally administered agents to provide long-lasting pain relief. The Address reprint requests to: Suneel Gupta, PhD, ALZA Corporation, 1900 Charleston Road, P.O. Box 7210, Mountain View, CA 94039, USA. E-mail: SGupta7@alzus.jnj.com Accepted for publication: September 1, 2006. Ó 2007 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. fluctuating plasma drug levels produced by short-acting, immediate-release (IR) formulations of analgesics have been associated with adverse effects and breakthrough pain. In contrast, extended-release formulations achieve more stable plasma drug concentrations that potentially provide around-the-clock pain control and less breakthrough pain (Fig. 1). OROS Ò hydromorphone is a unique, oncedaily formulation that uses the patented OROS Ò Push-PullÔ technology (ALZA Corporation, Mountain View, CA, USA) to deliver the potent opioid hydromorphone. The OROS Ò technology provides continuous, monophasic drug release over 24 hours, 2 which achieves consistent, long-lasting analgesia. 3,4 The 0885-3924/07/$esee front matter doi:10.1016/j.jpainsymman.2006.09.009
S20 Gupta and Sathyan Vol. 33 No. 2S February 2007 Drug A Immediate Release (q4h) Drug B Biphasic Controlled Release (q12h) Drug C Monophasic Extended Release (q24h) Pain Time Increased Pain Intensity Overall treatment desire for around-the-clock management with limited breakthrough pain Fig. 1. Fluctuating plasma concentrations associated with IR and biphasic controlled-release formulations of pain medications can result in breakthrough pain. purpose of this brief review is to describe the OROS Ò hydromorphone dosage form and summarize its pharmacokinetic/pharmacodynamic attributes, which are well suited for the control of chronic pain. Hydromorphone Pharmacokinetics Hydromorphone is a hydrogenated ketone of morphine that has been used to treat pain for nearly 80 years. 5 Its pharmacokinetic profile has been well defined and demonstrated to be independent of dose (i.e., first-order kinetics). 6 The absorption of IR hydromorphone occurs primarily in the upper small intestine and is biphasic (i.e., an initial rapid phase of up to two hours followed by a slow phase). 7 Hydromorphone is rapidly absorbed into the systemic circulation. Analgesia is measurable within 30 minutes of oral administration and it endures for approximately four hours. 7 Maximum plasma hydromorphone concentrations are achieved within one hour of dosing. 8 Hydromorphone is moderately lipid soluble, highly water soluble, and rapidly distributed into skeletal muscle, kidneys, liver, intestine, lungs, spleen, and brain. Extensively metabolized by the liver, 7 hydromorphone has a mean effective elimination half-life of 2.6 hours and a high volume of distribution (1.22 L/kg). 9 OROS Ò Technology OROS Ò osmotic technology has been used clinically for more than two decades to optimize the release of orally administered medications. Dosage forms that use OROS Ò technology vary greatly, as the design of each system is unique and formulated to provide a specific delivery pattern. 10 OROS Ò hydromorphone uses a patented Push-PullÔ osmotic pump (Fig. 2) to provide 24-hour monophasic delivery of hydromorphone. 11 The tablet core is made up of two layers: a drug layer containing hydromorphone and excipients and a push layer containing osmotic agents. These layers are surrounded by a semirigid, nondissoluble membrane that has a precision laser-drilled hole for drug delivery. Water from the gastrointestinal tract enters the pump at a controlled rate through the semipermeable membrane. This causes the hydromorphone in the drug layer to go into suspension and the osmotic layer to swell. As it expands, the osmotic layer pushes against the drug layer, and hydrated hydromorphone flows into the gastrointestinal tract through the delivery orifice at the same rate as water enters the core. The membrane itself does not dissolve and the tablet passes through the gastrointestinal tract intact. Consistency of OROS Ò Hydromorphone Release Utilization of the OROS Ò Push-PullÔ osmotic pump ensures a constant, monophasic delivery of hydromorphone over a 24-hour period. Measurable release of hydromorphone begins approximately two hours after administration (the beginning of water permeation). Thereafter, the rate of release is constant up to 18 h (Fig. 3). 2 The rate of release of hydromorphone from the OROS Ò system is
Vol. 33 No. 2S February 2007 Constant Analgesia With OROS Ò Hydromorphone S21 Laser-Drilled Hole (point of drug release) Rate-Controlling Membrane Hydromorphone HCl Hard Shell (clear or colored overcoat) Osmotic Pump (Push layer) Fig. 2. Cross-section of the OROS Ò patented Push-PullÔ pump. consistent across a range of doses (Fig. 3), 2 which results in similar rates of absorption into the systemic circulation for all doses (Fig. 4). 1,12 The osmotic driving force of OROS Ò and protection of the drug until the time of release eliminate the variability of drug absorption and metabolism often caused by food, gastric ph, and motility. 13e17 Hence, as with other OROS Ò formulations, drug release from OROS Ò hydromorphone is independent of ph and agitation. 10 Pharmacokinetic Characteristics The pharmacokinetics of OROS Ò hydromorphone are significantly different from those of IR hydromorphone and are consistent with those desired for the long-term management of chronic pain. IR hydromorphone is rapidly released, resulting in a peak plasma concentration that occurs within one hour of administration. In contrast, OROS Ò hydromorphone is released more slowly, resulting in a later, lower peak (Fig. 5). 3 In healthy volunteers, peak plasma hydromorphone concentrations after single-dose OROS Ò hydromorphone administration occurred approximately 13 to 16 hours after administration. 4 Plasma concentrations reached a broad, relatively flat plateau region within 6 to 8 hours postdose and remained in this plateau region until approximately 24 hours postdose. The half-life Cumulative Percent Released (LC) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% OROS hydromorphone 8 mg OROS hydromorphone 16 mg OROS hydromorphone 32 mg OROS hydromorphone 64 mg 2 4 6 8 10 12 14 16 18 20 22 24 Fig. 3. Release rate of hydromorphone from OROS Ò hydromorphone is consistent across dose strengths.
S22 Gupta and Sathyan Vol. 33 No. 2S February 2007 10.0000 Plasma Hydromorphone Concentration (ng/ml) 1.0000 0.1000 0.0100 0.0010 0.0001 OROS hydromorphone 1x8 mg OROS hydromorphone 1x16 mg OROS hydromorphone 1x32 mg OROS hydromorphone 1x64 mg 0 6 12 18 24 30 36 42 48 Hours From Dosing Fig. 4. Mean plasma hydromorphone concentration vs. time on log scale. of OROS Ò hydromorphone ranged from approximately 7 to 8 hours for all dose strengths (8, 16, and 32 mg). An open-label, randomized, crossover, multiple-dose study compared IR hydromorphone 4 mg every 6 hours with once-daily OROS Ò hydromorphone 16 mg in 18 healthy subjects. 4 Once-daily OROS Ò hydromorphone achieved a much flatter plasma-concentration profile than IR hydromorphone (Fig. 6). After 48 hours, steady-state concentrations were achieved, and OROS Ò hydromorphone plasma concentrations were maintained above the minimum IR hydromorphone plasma concentrations for each 24-hour dosing interval. The pharmacokinetic profile of OROS Ò hydromorphone is dose proportional. In an open-label, four-way crossover study conducted in 31 healthy volunteers, maximum plasma hydromorphone concentrations were achieved approximately 16 to 17 hours after administration of OROS Ò hydromorphone 8, 16, 32, and 64 mg. 12 All doses had similar elimination half-lives (mean, 10.6e11 hours) and produced plasma concentrations that were maintained at or near maximum levels for approximately 30 hours. The pharmacokinetics of OROS Ò hydromorphone are minimally affected by food. In an open-label, three-way, crossover study conducted in 30 healthy volunteers, the mean maximum plasma concentration was increased slightly by administration with a high-fat meal (1.352 vs. 1.107 ng/ml); however, this difference was not considered to be clinically significant. 14 Similarly, the extent of absorption was Hydromorphone (ng/ml) 5.0 4.0 3.0 2.0 1.0 8 mg IR hydromorphone 8 mg OROS hydromorphone 16 mg OROS hydromorphone 32 mg OROS hydromorphone (n=12) 0 12 24 36 48 Fig. 5. Plasma concentration vs. time profiles of IR hydromorphone and OROS Ò hydromorphone after singledose administration. 4
Vol. 33 No. 2S February 2007 Constant Analgesia With OROS Ò Hydromorphone S23 2.5 Hydromorphone (ng/ml) 2.0 1.5 1.0 0.5 16 mg OROS hydromorphone t 72-96 4 mg IR hydromorphone q6h 0.0 72 78 84 90 96 Fig. 6. Steady-state plasma concentration vs. time profiles of IR hydromorphone and OROS Ò hydromorphone. 4 similar in fasted and fed groups (mean AUC 0e48, 31.12 ng$h/ml in the fasting state and 30.20 ng$h/ml in the fed state and mean AUC 0eN, 38.84 ng$h/ml in the fasting state and 36.09 ng$h/ml in the fed state). The 90% confidence intervals for the ratios of the product means for AUC 0e48 and AUC 0eN were within 80% to 125% (84.9%, 103.7%, and 81%, 99.4%, respectively) indicating that the differences were minimal and not clinically significant. Under fed vs. fasting conditions, the median time to maximum plasma concentration was 4 hours earlier (12 vs. 16 hours, respectively; P ¼ 0.0062; 90% confidence interval for difference between product medians: 6.0046, 1.9981), and the mean half-life was approximately 2 hours shorter (12.5 vs. 14.7 hours). The plasma-concentration time profiles of OROS Ò hydromorphone under fasted and fed conditions are shown in Fig. 7. The pharmacokinetic profile of OROS Ò hydromorphone in patients with chronic pain appears to be similar to that in healthy individuals. Table 1 presents data from five patients with chronic pain requiring daily opioid therapy who received OROS Ò hydromorphone 16 mg daily for 5e10 days in an open-label, repeated-dose study, and from 18 healthy subjects who received OROS Ò hydromorphone 16 mg daily for four days in an open-label, two-way crossover, multiple-dose study. 4 Overall, the exposure to OROS Ò Hydromorphone (ng/ml) 1.2 1.0 0.8 0.6 0.4 0.2 16 mg OROS hydromorphone Fasted 16 mg OROS hydromorphone Fed 0 8 16 24 32 40 48 Fig. 7. The pharmacokinetics of OROS Ò hydromorphone are minimally affected by food. 13
S24 Gupta and Sathyan Vol. 33 No. 2S February 2007 Table 1 Steady-State Pharmacokinetic Profile of OROS Ò Hydromorphone (16 mg qd) in Healthy Volunteers and Patients with Chronic Pain 4 Parameter hydromorphone was similar in both groups (mean [SD] AUC 0e24, 46.1 [10.6] ng$h/ml in patients with chronic pain and 45.6 [16.8] ng$h/ml in healthy subjects). Summary The pharmacokinetic characteristics of OROS Ò hydromorphone are well suited to provide consistent, prolonged analgesia in patients with chronic pain. This once-daily formulation provides constant drug delivery over a 24-hour period with minimal peaktrough fluctuation. Peak plasma concentrations are achieved approximately 16 hours after administration, with levels equivalent to approximately 80% of peak attained within 6 hours. The apparent elimination half-life of OROS Ò hydromorphone is 7e15 hours, and steady-state plasma concentrations are achieved after two days of dosing. The pharmacokinetics of OROS Ò hydromorphone are dose proportional, and are not significantly affected by environmental factors (ph or agitation) or the presence of food. References Healthy Volunteers, Mean (SD) Patients with Chronic Pain, a Mean (SD) (n ¼ 18) (n ¼ 5) C max, ng/ml 2.62 (0.83) 2.93 (0.6) T max, hours 14.7 (5.1) 9.8 (5.8) C min, ng/ml 1.16 (0.47) 1.25 (0.31) AUC 0e24,ng$h/mL 45.6 (16.8) 46.1 (10.6) Fluctuation, % 83 (31) 89 (16) a Patients with chronic pain defined as those who required 32e300 mg/day morphine. 1. International Association for the Study of Pain. How prevalent is chronic pain? Pain Clin Updates 2003;XI(2):1e4. 2. Drover DR, Angst MS, Valle M, et al. Input characteristics and bioavailability after administration of immediate and a new extended-release formulation of hydromorphone in healthy volunteers. Anesthesiology 2002;97:827e836. 3. Angst MS, Drover DR, Lötsch J, et al. Pharmacodynamics of orally administered sustained-release hydromorphone in humans. Anesthesiology 2001; 94:63e73. 4. Data on file. ALZA Corporation, Mountain View, CA. 5. Murray A, Hagen NA. Hydromorphone. J Pain Symptom Manage 2005;29(5 Suppl):S57eS66. 6. Hill HF, Coda BA, Tanaka A, Schaffer R. Multiple-dose evaluation of intravenous hydromorphone pharmacokinetics in normal human subjects. Anesth Analg 1991;72:330e336. 7. Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology and clinical applications in cancer patients. Support Care Cancer 2001;9: 84e96. 8. Durnin C, Hind ID, Ghani SP, Yates DB, Cross M. Dose proportionality of the pharmacokinetics of oral immediate-release hydromorphone (Dilaudid IR). Proc West Pharmacol Soc 2001;44: 73e74. 9. Vallner JJ, Stewart JT, Kotzan JA, et al. Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects. J Clin Pharmacol 1981;21: 152e156. 10. Bass DM, Prevo M, Waxman DS. Gastrointestinal safety of an extended-release, nondeformable, oral dosage form (OROS Ò ). A retrospective study. Drug Saf 2002;25:1021e1033. 11. Palangio M, Northfelt DW, Portenoy RK, et al. Dose conversion and titration with a novel once-daily, OROS Ò osmotic technology, extendedrelease hydromorphone formulation in the treatment of chronic malignant or nonmalignant pain. J Pain Symptom Manage 2002;23:355e368. 12. Gupta S, Xu E, Sathyan G. Pharmacokinetic investigation of dose proportionality across the OROS Ò hydromorphone dose range. Proceedings of the 11th World Congress on Pain. Sydney, Australia, August 21-26, 2005. IASP Press: 691; Abstract 179eP294. 13. OROS Ò Oral Delivery Technology. Available from http://www.alza.com/alza/oros. Accessed September 16, 2005. 14. Sathyan G, Xu E, Gupta S. Effect of food on the pharmacokinetic profile of OROS Ò hydromorphone. Presented at the 11th World Congress on Pain. Sydney, Australia, August 21-26, 2005. IASP Press: 632e633; Abstract 1796eP299. 15. Sathyan G, Hu W, Gupta SK. Lack of effect of food on the pharmacokinetics of an extended-release oxybutynin formulation. J Clin Pharmacol 2001;41:187e192. 16. Dmochowski R, Chen A, Sathyan G, et al. Effect of the proton pump inhibitor omeprazole on the pharmacokinetics of extended-release formulations of oxybutynin and tolterodine. J Clin Pharmacol 2005;45:961e968. 17. Eckenhoff B, Theeuwes F, Urquhart J. Osmotically activated dosage forms for rate-controlled drug delivery. Pharm Technol 1981;5:35e44.