Pharmacokinetics and Dose-Proportionality of
`Oxymorphone Extended Release and Its Metabolites:
`Results of a Randomized Crossover Study
`
`Michael P. Adams, Pharm.D., and Harry Ahdieh, Ph.D.
`
`Study Objective. To evaluate the pharmacokinetics and dose-proportionality
`of four dose strengths (5, 10, 20, and 40 mg) of oxymorphone extended
`release (ER) under both single-dose and steady-state conditions.
`Design. Randomized, three-period, four-sequence, crossover study.
`Setting. Bioavailability clinic.
`Subjects. Twenty-four healthy adult volunteers.
`Intervention. Each subject received three of the four possible doses. The
`three 8-day administration periods were separated by a 7-day washout.
`Plasma was collected for up to 48 hours after a single dose on day 1 and
`during a 12-hour dosage interval at steady state. Naltrexone was
`administered to reduce opioid-related adverse effects.
`Measurements and Main Results. Twenty-three subjects completed at least
`one study period. Dose-proportionality and linearity were confirmed after
`single doses (mean oxymorphone ER area under the concentration versus
`time curve [AUC] 4.54, 8.94, 17.80, and 37.90 ng•hr/ml for 5-, 10-, 20-,
`and 40-mg doses, respectively) and at steady state (mean oxymorphone ER
`AUC 5.60, 9.77, 19.3, and 37.0 ng•hr/ml for 5-, 10-, 20-, and 40-mg doses
`every 12 hrs, respectively). Similar results were found for maximum
`plasma concentration. Metabolite (6-hydroxyoxymorphone and
`oxymorphone-3-glucuronide) plasma levels also increased in a linear
`fashion after single-dose administration and at steady state.
`Conclusion. The pharmacokinetic profile of oxymorphone ER demonstrates
`linearity and dose-proportionality under single-dose and steady-state
`conditions for the parent compound and its metabolites for doses of 5–40 mg.
`Key Words: analgesia, oxymorphone ER, pharmacokinetics, steady state,
`dose-proportionality.
`(Pharmacotherapy 2004;24(4):468–476)
`
`The undertreatment of patients with chronic
`malignant and nonmalignant pain remains an
`important clinical issue.1 Opioid therapy (alone
`or in combination with other analgesic
`approaches) is widely used in patients with
`moderate or severe cancer pain2, 3 and in patients
`with chronic nonmalignant pain when analgesia
`provided by other therapies (e.g., nonsteroidal
`antiinflammatory drugs, transcutaneous electrical
`nerve stimulation) is no longer adequate. 4
`Optimal management of chronic pain requires
`around-the-clock coverage with analgesic agents.
`
`Agents that provide a sustained release of drug
`allow the patient to obtain this baseline analgesia
`with minimal doses/day, thereby improving
`patient compliance and minimizing interference
`with activities of daily living.5 The Agency for
`Healthcare Research and Quality determined that
`parenteral (intramuscular or intravenous)
`administration offers little pain relief advantage
`over enteral administration and that sustained-
`release oral formulations provide an implicit
`advantage by reducing the administration
`frequency.6 A meta-analysis of eight trials that
`
`ENDO - Ex. 2017
`Amneal v. Endo
`IPR2014-00360
`
`

`

`PHARMACOKINETICS OF OXYMORPHONE EXTENDED RELEASE Adams and Ahdieh
`
`469
`
`compared oral sustained-release morphine with
`oral immediate-release morphine solution found
`comparable, but prolonged, pain relief with
`sustained-release delivery.6
`Oxymorphone hydrochloride (14-hydroxy-
`dihydromorphinone) is a semisynthetic µ-opioid
`agonist7 that has a more rapid onset of action and
`several times the analgesic potency of its parent
`compound morphine. 7, 8 Oxymorphone is
`metabolized primarily to 6-hydroxyoxymorphone
`(6-OH-OXM) and oxymorphone-3-glucuronide
`(OXM-3-G) in the liver; less than 2% of parent
`drug is recovered unchanged in urine.9 The
`pharmacologic activity of the glucuronide
`metabolite has not been evaluated; 6-OH-OXM
`has been shown in animal studies to have
`analgesic bioactivity.10
`Oxymorphone extended release (ER) is a new
`sustained-release tablet formulation of oxy-
`morphone hydrochloride developed to provide
`12 hours of sustained analgesia.10 The ER
`matrix, TIMERx (Penwest Pharmaceuticals Co.,
`Danbury, CT), alters and delays drug dissolution
`and absorption from the gastrointestinal tract,
`thereby changing the pharmacokinetic profile
`relative to immediate-release drug formulations.
`Drug release from the ER matrix is controlled by
`the rate of penetration of water into the hydro-
`philic matrix and the subsequent expansion of
`the gel coating. Linearity of pharmacokinetic
`parameters contributes to a predictable dose
`response and aids in the design of clinical trials
`to examine the efficacy and safety of oxy-
`morphone ER in the management of moderate-
`to-severe malignant and nonmalignant pain.
`This study was undertaken to determine single
`and steady-state dose pharmacokinetics and
`dose-proportionality of oxymorphone and its
`metabolites (6-OH-OXM and OXM-3-G) across a
`dose range of 5–40 mg.
`
`From SFBC New Drug Services, Kennett Square,
`Pennsylvania (Dr. Adams); and Clinical Operations, Endo
`Pharmaceuticals Inc., Chadds Ford, Pennsylvania (Dr.
`Ahdieh).
`Supported by Endo Pharmaceuticals Inc., Chadds Ford,
`Pennsylvania, and Penwest Pharmaceuticals Co., Danbury,
`Connecticut.
`Presented in part at the annual meeting of the American
`Pain Society, Chicago, Illinois, March 19–22, 2003.
`Manuscript received July 28, 2003. Accepted pending
`revisions September 17, 2003. Accepted for publication in
`final form January 18, 2004.
`Address reprint requests to Michael P. Adams, Pharm.D.,
`SFBC New Drug Services, Longwood Corporate Center
`South, 415 McFarlan Road, Suite 201, Kennett Square, PA
`19348-2412; e-mail: mpadams@newdrugservices.com.
`
`Methods
`The protocol, informed consent form, and any
`amendments for this study were approved by an
`independent institutional review board. The
`study was conducted and informed consent
`obtained according to the ethical principles
`stated in the Declaration of Helsinki, applicable
`guidelines for good clinical practice, or
`applicable laws or regulations of the United
`States; whichever provided the greatest
`protection of the individual.
`
`Study Design
`This randomized, three-period, four-sequence,
`crossover study assessed the pharmacokinetics of
`four dose levels of oxymorphone ER (5, 10, 20,
`and 40 mg) in 24 healthy volunteers. This was
`an incomplete block design, with each subject
`receiving three of the four dose levels. Based on
`the previously published simulated sample-size
`tables for bioequivalence studies listed,11 the
`sample size (15 patients) was obtained by using
`the design for a four-period study and
`extrapolating to that for a balanced, incomplete,
`three-period, four-treatment design. To fulfill the
`requirements of balancing for treatment and
`sequence, this sample was rounded to 16 and an
`additional 8 subjects were added to improve the
`relative efficiency of the design in case of missing
`values or if patient dropout occurred.
`
`Subjects
`Study subjects were healthy, nonsmokers of
`normal body weight (‡ 50 but ≤ 100 kg and
`within 15% of standard weight) who ranged in
`age from 18–45 years and were men or
`nonpregnant, nonlactating women using
`contraception. Women of childbearing potential
`were required to use a medically acceptable form
`of contraception for the duration of the trial and
`must have had a negative serum pregnancy test at
`screening and a negative urine pregnancy test at
`check-in to the study facility. Exclusion criteria
`included hypersensitivity to oxymorphone or
`naltrexone; positive screen for hepatitis B,
`hepatitis C, or human immunodeficiency virus; a
`history of alcohol abuse, illicit drug use, physical
`dependence on any opioid, or drug abuse or
`addiction; or a positive urine drug screen for
`ethanol, cocaine,
`tetrahydrocannabinol,
`barbiturates, amphetamines, benzodiazepines, or
`opiates. In addition, candidates were excluded
`from entry into the study if they had any disease
`
`

`

`470
`
`PHARMACOTHERAPY Volume 24, Number 4, 2004
`
`or condition (medical or surgical) that might
`compromise the hematologic, cardiovascular,
`pulmonary, renal, gastrointestinal, hepatic, or
`central nervous systems, and/or any condition
`that might interfere with the absorption,
`distribution, metabolism, or excretion of the
`study drug. All candidates underwent liver and
`kidney function tests before enrollment; no
`subject with liver enzymes (aspartate amino-
`transferase or alanine aminotransferase) above
`1.25 times the upper limit of normal, total
`bilirubin above the upper limit of normal, or
`serum creatinine level above the upper limit of
`normal were enrolled in the study.
`
`Procedures
`Subjects were assigned in consecutive order to
`a randomization schedule balanced for sequence
`and period (Figure 1). Based on the randomized
`crossover incomplete block design, subjects
`received three of four possible doses (5, 10, 20,
`and 40 mg) of oxymorphone ER tablets (Endo
`Pharmaceuticals Inc., Chadds Ford, PA). The
`three 8-day administration periods were
`separated by 7-day washout periods. To protect
`against potential opioid-related effects, subjects
`received an opioid antagonist, naltrexone
`hydrochloride (ReVia; DuPont Pharmaceuticals,
`Wilmington, DE) 50 mg once/day, beginning the
`
`evening before the first dose of oxymorphone ER
`on day 1 and continuing until the evening of day
`7. Previous studies have shown that naltrexone
`does not significantly affect the pharmacokinetics
`of oxymorphone and its metabolites.10
`During each administration period, subjects
`received a single tablet of oxymorphone ER 5, 10,
`20, or 40 mg on day 1, the same dose every 12
`hours on days 3–7, and the last multiple dose on
`the morning of day 8. On days 1 and 8, oxy-
`morphone ER was administered after a 10-hour
`overnight fast that continued until 4 hours after
`dose administration. Subjects received no
`xanthine-containing foods or beverages, were to
`abstain from alcoholic beverages beginning 72
`hours before administration of the first dose of
`study drug, and were to refrain from strenuous
`physical activity. Prescription drugs were
`prohibited beginning 2 weeks before the first
`dose of oxymorphone (4 wks for any drug that
`might affect hepatic drug metabolism) until
`discharge from the study. Short-term use of over-
`the-counter agents for a self-limiting indication
`(e.g., aspirin for a headache) required investigator
`authorization and was prohibited within 24
`hours before administration of the first dose of
`test drug. To provide authorization for an over-
`the-counter agent, the investigator was required
`to consider the clinical situation and evaluate the
`
`Screening
`
`Randomization
`
`5-mg single dose on day 1
`10-mg single dose on day 1
`20-mg single dose on day 1
`40-mg single dose on day 1
`
`First crossover:
` Subjects repeated single- and
` multiple-dose phases at a
` randomly assigned second dosage
`
`Days 3–8
`Multiple-dose phase:
` Every 12 hours each subject
` received the same dose level they
` received in the single-dose phase
`
`Second crossover:
` Subjects repeated single- and
` multiple-dose phases at a
` randomly assigned third dosage
`
`Figure 1. Randomization and drug administration.
`
`Washout
`7 days
`
`Washout
`7 days
`
`

`

`PHARMACOKINETICS OF OXYMORPHONE EXTENDED RELEASE Adams and Ahdieh
`
`471
`
`Table 1. Pharmacokinetic Parameters
`Parameter
`Definition
`Area under the concentration versus time curve from time zero to infinity; calculated as AUCt + Ct/lz.
`AUC
`AUC0–12
`AUC from time zero to the end of the 12-hour dosage interval after the first dose.
`AUC from time zero to the end of one dosage interval at steady state (i.e., time 0 to t); calculated using the linear
`AUCss
`trapezoid rule.
`AUC from time zero to the last measured concentration (Ct); calculated using the linear trapezoid rule.
`Average plasma concentration; calculated as AUCss/t.
`Maximum plasma concentration; the highest concentration observed during a dosage interval.
`Minimum plasma concentration; the concentration measured just before dose administration.
`The last measured plasma concentration; the last concentration above the lower limit of quantitation after a dose.
`Oral clearance; calculated as dose/AUC or dose/AUCss.
`Fluctuation index; calculated as (Cmax – Cmin)/Cavg.
`The terminal elimination rate constant; calculated using linear regression on the terminal portion of the log-
`transformed AUC (ln-AUC).
`Accumulation ratio; calculated as AUCss/AUC0–12.
`The duration of one dosage interval in hours.
`The time that Cmax was observed.
`Terminal elimination half-life; calculated as 0.693/lz.
`Effective half-life; calculated as 0.693/–ln(1 – 1/R/t).
`
`AUCt
`Cavg
`Cmax
`Cmin
`Ct
`Cl/F
`FI
`lz
`
`R
`t
`Tmax
`t1/2
`t1/2 effective
`
`potential for masking symptoms of a more severe
`underlying event and whether taking the agent
`would compromise the outcome or validity of the
`study.
`In each administration period, venous blood
`samples were collected in 7-ml tubes (containing
`ethylenediaminetetraacetic acid) immediately
`before the first dose of oxymorphone ER, and at
`0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and
`48 hours after administration. During multiple-
`dose administration, blood samples were
`collected immediately before the morning dose
`on days 6–8 (trough concentrations) and, on day
`8, at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours.
`On days 1 and 8, dose administration of study
`drug was to occur after an overnight fast.
`Subjects continued fasting until 4 hours after
`dose administration.
`Physical examination and clinical laboratory
`tests were conducted at screening and repeated
`on conclusion of the study. Routine vital signs,
`including pulse, respiratory rate, and blood
`pressure, were obtained just before administration
`of the first dose of test drug and once each
`morning throughout the administration period.
`Adverse events were recorded and coded per
`Medical Dictionary for Regulatory Activities
`terminology.12
`
`Analytic Methods
`Concentrations of oxymorphone, 6-OH-OXM,
`and OXM-3-G in plasma samples were determined
`with parallel high-performance liquid chromato-
`graphy combined with tandem mass spectrometry
`
`(parallel LC/MS/MS). Two validated methods,
`developed and validated by SFBC Analytical
`Laboratories, Inc. (North Wales, PA), were used.
`Simultaneous determination of oxymorphone
`and 6-OH-OXM used liquid-liquid extraction
`from alkalinized human plasma; the residue was
`reconstituted into a small amount of mobile
`phase. Determination of OXM-3-G used solid
`phase extraction from acidified human plasma;
`the eluent was dried down and reconstituted into
`a small amount of acetonitrile. A SCIEX API
`3000 series LC/MS/MS system (MDI SCIEX,
`Concord, Ontario, Canada) was used for analysis.
`The range of quantitation for oxymorphone and
`6-OH-OXM was 0.1–20 ng/ml plasma and for
`OXM-3-G was 5–250 ng/ml plasma.
`
`Statistical Methods
`The relationship between the pharmacokinetic
`parameters (Table 1) and dose was explored and
`summarized by using appropriate descriptive
`statistics. Continuous variables were compared
`by using analysis of variance, with dose, period,
`sequence, and subject (sequence) included in the
`model, with use of PROC GLM of SAS version
`6.12 (Cary, NC). Proportionality was tested after
`normalization of area under the concentration
`versus time curve (AUC) and maximum plasma
`concentration (Cmax) values to a 20-mg dose.
`Separate analyses were conducted for days 1 and
`8 (steady-state) results. An appropriate non-
`parametric test was applied to the comparison of
`the time to Cmax values and other categorical
`variables. Establishment of steady-state conditions
`
`

`

`472
`
`PHARMACOTHERAPY Volume 24, Number 4, 2004
`
`was based on analysis of trough (predose)
`concentrations from days 6–8 (after 3–5 days of
`dosing every 12 hrs). The degree of accumulation
`was estimated by comparing AUC from time zero
`to the end of one dosage interval at steady state
`(AUCss) on day 8 with results of AUC from time
`zero to the end of the 12-hour dosage interval
`after the first dose (AUC0–12) on day 1.
`Adverse events were coded and summarized by
`treatment group and according to maximum
`intensity and frequency. Clinical laboratory
`values and other safety variables were sum-
`marized by mean values and changes from
`baseline. Changes from baseline were analyzed
`across treatment groups by using an appropriate
`parametric statistic.
`
`Results
`
`Fourteen men and 10 women (18 white, 4
`Hispanic, 2 black; age range 20–45 yrs, mean
`35.5 yrs) were enrolled and randomized.
`Twenty-one subjects completed the trial (two
`subjects withdrew consent, and one subject
`tested positive on the drug screen before period
`3). Twenty-three subjects completed at least one
`treatment period and were included in the
`pharmacokinetic analyses. Average weight and
`height were 72.6 kg and 168 cm, respectively.
`Most subjects (75%) were of medium build. All
`24 subjects were included in the safety analyses.
`
`Single-Dose Pharmacokinetics
`
`Single-dose administration of oxymorphone ER
`resulted in mean plasma concentrations of
`oxymorphone and its metabolites that increased
`proportionally with increasing dose (Figure 2).
`Mean single-dose pharmacokinetic values are
`presented in Table 2. Mean AUC values for
`oxymorphone, 6-OH-OXM, and OXM-3-G
`increased at a rate very close to a 2-fold (linear)
`progression as the dose increased from 5 to 10,
`20, and 40 mg.
`
`Steady-State Pharmacokinetics
`
`Trough concentrations of oxymorphone, 6-OH-
`OXM, and OXM-3-G, measured before
`administration of the morning dose on days 6–8,
`indicated that steady-state conditions were
`achieved after 3 days of dosing every 12 hours.
`As was the case after single-dose administration,
`steady-state mean plasma concentrations of
`oxymorphone and its metabolites rose with
`increasing dose (Figure 3). Mean steady-state
`
`pharmacokinetic values are presented in Table 3.
`The mean accumulation ratio (a measure of the
`difference between the AUCss and the AUC0–12)
`for oxymorphone was greatest at the 5-mg dose
`
`Figure 2. Mean plasma concentrations of oxymorphone
`(A), 6-hydroxyoxymorphone (6-OH-OXM) (B), and
`oxymorphone-3-glucuronide (OXM-3-G) (C) after
`administration of single doses of oxymorphone extended
`release 5, 10, 20, or 40 mg to healthy volunteers.
`
`

`

`PHARMACOKINETICS OF OXYMORPHONE EXTENDED RELEASE Adams and Ahdieh
`
`473
`
`Table 2. Single-Dose Pharmacokinetic Values
`
`5 mg
`
`Oxymorphone Extended Release Dose
`10 mg
`20 mg
`
`2.13 ± 1.28
`4.54 ± 2.04
`1.74 ± 0.94
`0.27 ± 0.13
`3.00 (1.00–12.00)
`26.36 ± 25.21
`0.1419 ± 0.1502
`11.30 ± 10.81
`
`0.88 ± 1.40
`5.80 ± 4.99
`0.59 ± 0.89
`0.14 ± 0.12
`3.50 (1.00–12.00)
`0.1685 ± 0.2624
`16.96 ± 16.67
`
`6.66 ± 3.55
`8.94 ± 4.16
`4.44 ± 1.70
`0.65 ± 0.29
`3.00 (0.50–6.00)
`22.26 ± 9.27
`0.0869 ± 0.0366
`9.83 ± 5.68
`
`3.64 ± 3.68
`6.94 ± 6.79
`1.95 ± 1.30
`0.37 ± 0.19
`2.00 (0.50–6.00)
`0.2086 ± 0.2728
`13.40 ± 11.53
`
`Parametera
`Oxymorphone
`AUCt (ng•hr/ml)
`AUC (ng•hr/ml)
`AUC0–12 (ng•hr/ml)
`Cmax (ng/ml)
`Tmax (hrs)
`Cl/F (L/min)
`lz (hr-1)
`t1/2 (hrs)
`6-OH-OXM
`AUCt (ng•hr/ml)
`AUC (ng•hr/ml)
`AUC0–12 (ng•hr/ml)
`Cmax (ng/ml)
`Tmax (hrs)
`lz (hr-1)
`t1/2 (hrs)
`OXM-3-G
`1179.63 ± 245.24
`492.81 ± 127.15
`AUCt (ng•hr/ml)
`1298.46 ± 249.06
`589.35 ± 132.83
`AUC (ng•hr/ml)
`AUC0–12 (ng•hr/ml)
`767.18 ± 143.11
`347.23 ± 64.09
`111.79 ± 23.35
`52.98 ± 17.79
`Cmax (ng/ml)
`Tmax (hrs)
`3.00 (1.50–10.00)
`3.00 (1.50–5.00)
`lz (hr-1)
`0.0915 ± 0.0352
`0.0938 ± 0.0307
`t1/2 (hrs)
`8.42 ± 2.56
`8.28 ± 3.17
`6-OH-OXM = 6-hydroxyoxymorphone; OXM-3-G = oxymorphone-3-glucuronide.
`Data are mean ± SD, except Tmax, which is median (range).
`aPharmacokinetic parameters are defined in Table 1.
`
`15.08 ± 6.95
`17.80 ± 7.22
`8.50 ± 4.04
`1.21 ± 0.77
`4.00 (1.00–12.00)
`20.93 ± 6.46
`0.0781 ± 0.0275
`9.89 ± 3.21
`
`11.26 ± 7.19
`16.12 ± 9.47
`4.88 ± 2.12
`0.80 ± 0.33
`1.50 (0.50–12.00)
`0.0482 ± 0.0211
`16.82 ± 6.59
`
`2710.69 ± 676.99
`2866.83 ± 717.49
`1633.37 ± 419.94
`250.08 ± 85.68
`3.00 (1.50–6.00)
`0.0849 ± 0.0189
`8.57 ± 2.07
`
`40 mg
`
`35.37 ± 16.19
`37.90 ± 16.20
`18.47 ± 9.98
`2.59 ± 1.65
`2.50 (0.50–12.00)
`19.44 ± 5.06
`0.0849 ± 0.0408
`9.35 ± 2.94
`
`25.52 ± 13.28
`32.79 ± 18.13
`9.92 ± 5.10
`1.44 ± 0.56
`2.00 (1.00–12.00)
`0.0501 ± 0.0412
`18.44 ± 7.88
`
`5465.32 ± 1185.11
`5669.67 ± 1247.34
`3134.30 ± 712.26
`454.50 ± 105.35
`2.00 (1.50–4.00)
`0.0805 ± 0.0172
`9.03 ± 2.17
`
`taken every 12 hours and for 6-OH-OXM was
`greatest at the 5- and 10-mg doses every 12
`hours. However, because of limitations in the
`assay sensitivity, fewer samples provided values
`above the limit of quantification, adding
`difficulty in estimating the AUC from the low
`plasma concentrations of oxymorphone and 6-
`OH-OXM at the lower dose levels. The mean
`accumulation ratio was greater for 6-OH-OXM
`than for the other analytes at all doses, a
`consequence of its slower elimination. At 40 mg,
`the average accumulation values for multiple-
`versus single-dose administration (AUCss vs
`AUC0–12) were approximately 4-fold higher for 6-
`OH-OXM and approximately 2-fold higher for
`oxymorphone and OXM-3-G, consistent with
`mean single-dose elimination half-life values of
`approximately 18 hours for 6-OH-OXM, and
`approximately 9 hours for oxymorphone and
`OXM-3-G. The mean ± SD effective half-life,
`calculated from the degree of accumulation at a
`dosage of 40 mg every 12 hours, was 29.84 ±
`9.63 hours for 6-OH-OXM, 13.05 ± 4.49 hours
`for oxymorphone, and 10.62 ± 2.64 hours for
`OXM-3-G. Consistent with a linear pharmaco-
`
`kinetic system, the changes in accumulation
`ratios mirror the changes measured for effective
`half-life values.
`The mean fluctuation index was less than 1 for
`all three analytes at all dosages, indicating low
`fluctuation in plasma concentration over the
`dosing period after steady state was achieved.
`Linear pharmacokinetics at steady state are
`supported by the nearly linear progression for all
`concentration-dependent variables (AUCss, Cmax,
`minimum concentration [Cmin], and average
`concentration [Cavg]) as the dosage increased
`from 5 to 40 mg every 12 hours and by the
`absence of any meaningful differences in
`oxymorphone clearance across the four dosages.
`
`Dose-Proportionality
`
`Dose-proportionality was compared after
`normalization of pharmacokinetic parameters to
`a 20-mg dose and logarithmic (ln) transfor-
`mation (Table 4). The absence of statistically
`significant differences in ln-AUC, ln-AUCss, or
`ln-Cmax across doses confirms that the pharmaco-
`kinetics of oxymorphone, 6-OH-OXM, and
`
`

`

`474
`
`PHARMACOTHERAPY Volume 24, Number 4, 2004
`
`OXM-3-G are both linear and dose-proportional
`after single-dose administration and at steady
`state.
`
`Figure 3. Mean steady-state plasma concentrations of
`oxymorphone (A), 6-hydroxyoxymorphone (6-OH-OXM)
`(B), and oxymorphone-3-glucuronide (OXM-3-G) (C) after
`administration of single doses of oxymorphone extended
`release 5, 10, 20, or 40 mg to healthy volunteers.
`
`Safety
`A summary of adverse events is shown in Table
`5. All adverse events were mild and resolved
`without sequelae. No adverse event was severe
`or life threatening or caused discontinuation
`from the study. No clinically significant changes
`were observed in clinical laboratory test values or
`other safety variables. At each of the three lower
`dose levels, gastrointestinal disorders, such as
`constipation, that typically are associated with
`opioid use were reported by 2–3 subjects/dose
`level. Although subjects received naltrexone to
`help minimize opioid-related adverse events, we
`cannot exclude the possibility that naltrexone
`may have contributed to the adverse events in
`some subjects.
`
`Discussion
`The data obtained from this randomized study
`of oxymorphone ER in healthy adults show that
`the pharmacokinetics of the new oral formulation
`and its major metabolites are linear and dose-
`proportional. Furthermore, all doses were well
`tolerated, with mild adverse events typically
`found with opioids.
`Single-dose and steady-state plasma concen-
`tration data and pharmacokinetic variables (e.g.,
`AUC, AUCss, Cmax, Cmin, Cavg) reflecting drug
`and metabolite concentrations showed essentially
`linear increases of oxymorphone and its
`metabolites (6-OH-OXM and OXM-3-G) as the
`dose of oxymorphone ER was incrementally
`doubled across a dose range of 5–40 mg. The
`absence of statistically significant differences in
`dose-normalized ln-AUC, ln-AUCss, or ln-Cmax
`confirms that the pharmacokinetics of
`oxymorphone, 6-OH-OXM, and OXM-3-G are
`dose proportional after single-dose adminis-
`tration and at steady state. The absence of mean-
`ingful differences in oxymorphone clearance
`across the four dose levels is also consistent with
`a linear pharmacokinetic profile.
`Compared with parenteral formulations, oral
`formulations offer several advantages, including
`more convenient dosing, potentially fewer
`adverse events, and improved compliance and
`quality of life. Compliance and quality of life are
`improved by maintaining clinically effective drug
`concentrations for a longer duration, enabling a
`prolonged and more convenient dosing interval.
`Although opioid dosages typically are titrated to
`provide meaningful pain relief while minimizing
`adverse events, linear pharmacokinetics provide
`confidence to clinicians that doubling a patient’s
`
`

`

`PHARMACOKINETICS OF OXYMORPHONE EXTENDED RELEASE Adams and Ahdieh
`
`475
`
`Table 3. Steady-State Pharmacokinetic Values
`
`5 mg
`
`Oxymorphone Extended Release Dose Every 12 Hours
`10 mg
`20 mg
`
`5.60 ± 3.87
`0.70 ± 0.55
`1.50 (0.50–12.00)
`18.18 ± 6.31
`0.41 ± 0.59
`0.47 ± 0.32
`0.71 ± 0.27
`3.43 ± 1.65
`
`5.06 ± 3.77
`0.62 ± 0.46
`1.50 (0.50–12.00)
`0.42 ± 0.45
`0.42 ± 0.31
`0.75 ± 0.80
`26.27 ± 27.76
`
`9.77 ± 3.52
`1.24 ± 0.56
`2.00 (0.50–12.00)
`19.33 ± 7.29
`0.64 ± 0.26
`0.81 ± 0.29
`0.69 ± 0.24
`2.29 ± 0.62
`
`8.87 ± 3.83
`1.05 ± 0.44
`1.00 (0.50–4.00)
`0.70 ± 0.31
`0.74 ± 0.32
`0.48 ± 0.22
`7.05 ± 6.09
`
`Parametera
`Oxymorphone
`AUCss (ng•hr/ml)
`Cmax (ng/ml)
`Tmax (hrs)
`Cl/F (L/min)
`Cmin (ng/ml)
`Cavg (ng/ml)
`FI
`R
`6-OH-OXM
`AUCss (ng•hr/ml)
`Cmax (ng/ml)
`Tmax (hrs)
`Cmin (ng/ml)
`Cavg (ng/ml)
`FI
`R
`OXM-3-G
`AUCss (ng•hr/ml)
`1367.78 ± 272.66
`723.39 ± 298.80
`Cmax (ng/ml)
`175.83 ± 46.08
`94.42 ± 45.14
`2.00 (1.00–5.00)
`2.00 (0.50–4.00)
`Tmax (hrs)
`Cmin (ng/ml)
`79.22 ± 18.95
`45.16 ± 41.85
`Cavg (ng/ml)
`113.98 ± 22.72
`60.28 ± 24.90
`0.82 ± 0.28
`0.85 ± 0.28
`FI
`1.81 ± 0.33
`2.09 ± 0.81
`R
`6-OH-OXM = 6-hydroxyoxymorphone; OXM-3-G = oxymorphone-3-glucuronide.
`Data are mean ± SD, except for Tmax, which is median (range).
`aPharmacokinetic parameters are defined in Table 1.
`
`19.28 ± 8.32
`2.54 ± 1.35
`1.25 (0.50–6.00)
`20.23 ± 7.96
`1.22 ± 0.52
`1.61 ± 0.69
`0.78 ± 0.57
`2.39 ± 0.75
`
`19.24 ± 10.09
`2.26 ± 1.12
`1.50 (0.50–12.00)
`1.48 ± 0.76
`1.60 ± 0.84
`0.50 ± 0.17
`4.23 ± 1.85
`
`2889.53 ± 628.73
`383.74 ± 106.01
`2.00 (1.00–3.00)
`169.27 ± 62.90
`240.79 ± 52.39
`0.92 ± 0.38
`1.82 ± 0.40
`
`40 mg
`
`36.98 ± 13.53
`4.47 ± 1.91
`3.50 (0.50–10.00)
`19.76 ± 5.57
`2.33 ± 1.16
`3.08 ± 1.13
`0.68 ± 0.23
`2.13 ± 0.52
`
`39.70 ± 19.87
`4.55 ± 2.24
`1.25 (0.50–10.00)
`3.17 ± 1.73
`3.31 ± 1.66
`0.44 ± 0.16
`4.11 ± 1.15
`
`5721.60 ± 1318.13
`705.04 ± 169.07
`2.00 (1.00–5.00)
`337.30 ± 142.15
`476.80 ± 109.84
`0.79 ± 0.22
`1.84 ± 0.30
`
`Table 4. Analysis of Dose-Proportionality Normalized to 20 mg and Log Transformed
`Geometric Least Squares
`10 mg
`20 mg
`
`5 mg
`
`15.74 ± 1.12
`1.04 ± 1.11
`21.18 ± 1.12
`
`10.98 ± 1.36
`0.63 ± 1.13
`
`16.53 ± 1.11
`1.12 ± 1.11
`20.16 ± 1.11
`
`8.41 ± 1.23
`0.64 ± 1.12
`
`17.72 ± 1.11
`1.10 ± 1.11
`18.81 ± 1.11
`
`12.73 ± 1.23
`0.74 ± 1.12
`
`2418.7 ± 1.05
`209.7 ± 1.07
`
`2510.3 ± 1.05
`207.9 ± 1.07
`
`2695.5 ± 1.05
`233.3 ± 1.07
`
`19.16 ± 1.09
`2.32 ± 1.10
`17.40 ± 1.09
`
`14.96 ± 1.13
`1.92 ± 1.11
`
`18.16 ± 1.10
`2.14 ± 1.10
`18.36 ± 1.10
`
`16.34 ± 1.13
`1.90 ± 1.11
`
`18.12 ± 1.10
`2.32 ± 1.10
`18.39 ± 1.10
`
`17.56 ± 1.13
`2.07 ± 1.11
`
`Parametera
`Single dose
`Oxymorphone
`ln-AUC (ng•hr/ml)
`ln-Cmax (ng/ml)
`ln-Cl/F (L/min)
`6-OH-OXM
`ln-AUC (ng•hr/ml)
`ln-Cmax (ng/ml)
`OXM-3-G
`ln-AUC (ng•hr/ml)
`ln-Cmax (ng/ml)
`Steady stateb
`Oxymorphone
`ln-AUCss (ng•hr/ml)
`ln-Cmax (ng/ml)
`ln-Cl/F (L/min)
`6-OH-OXM
`ln-AUCss (ng•hr/ml)
`ln-Cmax (ng/ml)
`OXM-3-G
`ln-AUCss (ng•hr/ml)
`2780.6 ± 1.06
`2627.4 ± 1.06
`2770.1 ± 1.06
`ln-Cmax (ng/ml)
`366.1 ± 1.07
`330.1 ± 1.07
`355.9 ± 1.07
`ln = natural logarithm; 6-OH-OXM = 6-hydroxyoxymorphone; OXM-3-G = oxymorphone-3-glucuronide.
`Data are mean ± SE.
`aPharmacokinetic parameters are defined in Table 1.
`bEvery 12 hours x 11 doses.
`
`40 mg
`
`p Value
`
`17.54 ± 1.11
`1.19 ± 1.11
`19.01 ± 1.11
`
`13.80 ± 1.23
`0.68 ± 1.12
`
`2662.1 ± 1.05
`219.5 ± 1.07
`
`18.24 ± 1.10
`2.23 ± 1.10
`18.27 ± 1.10
`
`18.89 ± 1.13
`2.18 ± 1.12
`
`2774.4 ± 1.06
`342.9 ± 1.07
`
`0.7766
`0.5574
`0.7766
`
`0.1590
`0.5031
`
`0.0610
`0.1686
`
`0.9229
`0.8109
`0.9229
`
`0.2132
`0.4104
`
`0.8151
`0.6480
`
`

`

`476
`
`PHARMACOTHERAPY Volume 24, Number 4, 2004
`
`Table 5. Summary of Adverse Events
`
`Oxymorphone Extended Release Dose
`10 mg
`20 mg
`17
`17
`5 (29.4)
`4 (23.5)
`
`5 mg
`17
`3 (17.6)
`
`Variable
`Total no. of subjects
`Subjects with at least one event, no. (%)
`Adverse event, no. (%)
`Palpitations
`Gastrointestinal disorders
`Flatulence
`Constipation
`Nausea
`Sore throat
`Musculoskeletal, connective tissue,
`and bone disorders
`Elbow pain
`Hand pain
`Headache
`aPossibly related to drug.
`bUnlikely to be related to drug.
`cOne was possibly related to drug, whereas the other was not.
`
`1 (5.9)a
`2 (11.8)
`0 (0.0)
`2 (11.8)a
`0 (0.0)
`0 (0.0)
`
`0 (0.0)
`0 (0.0)
`0 (0.0)
`0 (0.0)
`
`40 mg
`16
`1 (6.3)
`
`0 (0.0)
`0 (0.0)
`0 (0.0)
`0 (0.0)
`0 (0.0)
`0 (0.0)
`
`0 (0.0)
`0 (0.0)
`0 (0.0)
`1 (6.3)a
`
`1 (5.9)a
`3 (17.6)
`0 (0.0)
`2 (11.8)a
`1 (5.9)a
`0 (0.0)
`
`1 (5.9)
`1 (5.9)b
`1 (5.9)b
`2 (11.8)c
`
`0 (0.0)
`4 (23.5)
`1 (5.9)a
`2 (11.8)a
`0 (0.0)
`1 (5.9)b
`
`0 (0.0)
`0 (0.0)
`0 (0.0)
`0 (0.0)
`
`dose will predictably double the plasma drug
`concentrations and the patient’s extent of
`exposure.
`These results support the predictability of dose
`response from the four different dose-level
`formulations of oxymorphone ER tablets.
`Multiple doses provide the flexibility to start
`therapy at a dose that is appropriate to an
`individual patient’s needs and to titrate linearly to
`reach a stable dosage that provides adequate pain
`relief. Furthermore, the low fluctuation in
`plasma oxymorphone concentration over the
`dosing period once steady state was achieved
`confirms the likely potential for maintenance of
`analgesic efficacy throughout the 12-hour dosing
`interval.
`
`Conclusion
`
`The pharmacokinetic profile of oxymorphone
`ER demonstrates linearity and dose-propor-
`tionality for oxymorphone and its metabolites, 6-
`OH-OXM and OXM-3-G, under single-dose and
`steady-state (12-hr) conditions across the 5–40-
`mg range of tablet formulations. Based on the
`pharmacokinetic characteristics of oxymorphone
`ER observed in this study, the administration of
`oxymorphone ER would be expected to provide a
`predictable response from a given dose, enabling
`clinicians to reliably titrate and taper the dosage.
`However, the study was not designed to evaluate
`efficacy, and further investigations are needed to
`
`determine whether the dose-linearity of
`oxymorphone ER correlates with a linear
`analgesic dose response.
`
`References
`1. Resnik DB, Rehm M, Minard RB. The undertreatment of pain:
`scientific, clinical, cultural, and philosophical factors. Med
`Health Care Philos 2001;4:277–88.
`2. World Health Organization Expert Committee. Cancer pain
`relief and palliative care. Technical report series, no. 804.
`Geneva, Switzerland: World Health Organization, 1990.
`3. American Society of Anesthesiologists. A report by the
`American Society of Anesthesiologists Task Force on Pain
`Management, cancer pain section. Anesthesiology 1996;84:
`1243–57.
`4. American Society of Anesthesiologists. A report by the
`American Society of Anesthesiologists Task Force on Pain
`Management, chronic pain section. Anesthesiology 1997;86:
`995–1004.
`5. Reder RF. Opioid formulations: tailoring to the needs in
`chronic pain. Eur J Pain 2001;5(suppl A):109–11.
`6. Agency for Healthcare Research and Quality. Management of
`cancer pain. Summary, evidence report/technology assessment:
`number 35. AHRG publication no. 01-E033. Rockville, MD:
`Agency for Healthcare Research and Quality, January 2001.
`7. Sinatra RS, Hyde NH, Harrison DM. Oxymorphone revisited.
`Semin Anesth 1988;7:209–15.
`8. Eddy NB, Lee LEJ. The analgesic equivalence to morphine and
`relative side action liability of oxymorphone (4-hydroxy-
`dihydromorphinone). J Pharmacol Exp Ther 1959;125:116–21.
`9. Cone EJ, Darwin WD, Buchwald WF, Gorodetzky CW.
`Oxymorphone metabolism and urinary excretion in human,
`rat, guinea pig, rabbit, and dog. Drug Metab Dispos 1983;11:
`446–50.
`10. Endo Pharmaceuticals. Data on file. Chadds Ford, PA; 2003.
`11. Liu JP. Use of the repeated cross-over designs in assessing
`bioequivalence. Stat Med 1995;14:1067–78; discussion 79–80.
`12. Food and Drug Administration. MedDRA: medical dictionary
`for regulatory activities. Rockville, MD: United States Food and
`Drug Administration, 1997.
`
`