Drug Design, Development and Therapy
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`O r i g i nA L re s eAr c h
`
`Bioequivalence of oxymorphone
`extended release and crush-resistant
`oxymorphone extended release
`
`irma h Benedek
`Janet Jobes
`Qinfang Xiang
`William D Fiske
`endo Pharmaceuticals inc,
`chadds Ford, PA, UsA
`
`correspondence: Qinfang Xiang
`endo Pharmaceuticals inc,100 endo Blvd,
`chadds Ford, PA 19317, UsA
`Tel +1 610 459 6433
`Fax +1 610 459 6442
`email xiang.qinfang@endo.com
`
`Background: A formulation of crush-resistant extended-release opioids may deter abuse. The
`purpose of this study was to evaluate the bioequivalence of oxymorphone extended-release
`(Oxy-ER) and a crush-resistant formulation of oxymorphone extended-release (Oxy-CRF).
`Methods: In three open-label, randomized studies, healthy adults at a clinical research center
`received two single oral doses of Oxy-ER and two single doses of Oxy-CRF, each separated by
`a $7-day washout. Doses were administered under fasted conditions (study 1, 5 mg doses; study
`2, 40 mg doses) or after a high-fat breakfast (study 3, 40 mg doses). Subjects administered 40 mg
`doses also received naltrexone. The primary endpoint was systemic oxymorphone exposure; the
`bioequivalence criterion was met if the 90% confidence intervals of the geometric mean ratio
`(Oxy-CRF/Oxy-ER) for oxymorphone area under the curve from time 0 to the last measured
`concentration (AUC0–t), AUC from time 0 to infinity (AUC0–inf), and maximum plasma concen-
`tration (Cmax) were within 0.8–1.25. Safety was assessed by monitoring adverse events.
`Results: In studies 1, 2, and 3, the safety population comprised 30, 37, and 36 subjects and the
`pharmacokinetics population comprised 27, 30, and 29 subjects, respectively. Oxy-ER and Oxy-
`CRF produced similar mean ± standard deviation oxymorphone AUC0–t (study 1, 5.05 ± 1.55
`versus 5.29 ± 1.52 ng ⋅ h/mL; study 2, 31.51 ± 10.95 versus 31.23 ± 10.33 ng ⋅ h/mL; study 3,
`50.16 ± 14.91 versus 49.01 ± 14.03 ng ⋅ h/mL) and Cmax (0.38 ± 0.11 versus 0.37 ± 0.12 ng/mL;
`2.37 ± 1.20 versus 2.41 ± 0.94 ng/mL; 5.87 ± 1.99 versus 5.63 ± 2.26 ng/mL) under all conditions.
`The 90% confidence intervals for plasma oxymorphone AUC0–t, AUC0–inf, and Cmax fulfilled the
`bioequivalence criterion. Adverse event rates were similar with Oxy-ER and Oxy-CRF (study
`1, 25% versus 23%; study 2, 9% versus 16%; study 3, 20% each group).
`Conclusion: Oxy-CRF and Oxy-ER (5 mg and 40 mg) are bioequivalent under fasted and
`fed conditions, suggesting that Oxy-CRF will have clinical efficacy and safety equivalent to
`Oxy-ER.
`Keywords: abuse deterrent, bioequivalence, opioid, oxymorphone, pharmacokinetics,
` substance abuse
`
`Introduction
`Between 1997 and 2006, the use of therapeutic opioids (mg/person) in the United States
`increased by 347%.1 Illicit opioid use, as with therapeutic use, has increased rapidly
`in the last decade. Between 1999 and 2006, the number of individuals reporting past-
`month illicit use of pain relievers increased from 2,621,000 to 5,220,000.1
`Abuse of extended-release opioids is a particular concern because of the potential
`for fatal doses to be released if a tablet is crushed or chewed. A survey of prescrip-
`tion drug abusers entering drug rehabilitation found that 80% of abusers crush or
`chew extended-release opioids in order to abuse them.2 Chewing or crushing can
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`Drug Design, Development and Therapy 2011:5 455–463
`© 2011 Benedek et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
`which permits unrestricted noncommercial use, provided the original work is properly cited.
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`also occur without intention of abuse in patients who have
`difficulty swallowing intact tablets and do not understand
`the consequences of misusing their medication in this way.
`Formulation of extended-release tablets that are resistant to
`crushing and accidental chewing may deter abuse and prevent
`adverse events from misuse. Careful patient selection and
`adherence monitoring are also essential.3,4
`Oxymorphone extended-release (Oxy-ER; Opana® ER,
`Endo Pharmaceuticals Inc, Chadds Ford, PA) is indicated
`for the relief of moderate to severe pain in patients requir-
`ing continuous, around-the-clock opioid treatment for an
`extended period.5
`We report three randomized clinical studies evaluating
`the bioequivalence of Oxy-ER and a crush-resistant for-
`mulation of oxymorphone extended-release (Oxy-CRF;
`EN3288®, Endo Pharmaceuticals Inc, Chadds Ford, PA)
`at the highest (40 mg) and lowest (5 mg) supplied dosage
`strengths in healthy adults. Oxy-ER is formulated using
`TIMERx® technology that minimizes fluctuation in drug
`concentrations, providing consistent 12-hour dosing,6
`which is advantageous in the setting of chronic pain. Oxy-
`CRF contains oxymorphone embedded in a hard polymer
`matrix (distinct from TIMERx®) that is intended to be
`crush- resistant. In vitro dissolution analyses of Oxy-ER and
`Oxy-CRF indicated that oxymorphone release from these
`formulations was not increased in 40% aqueous ethanol com-
`pared with 0% ethanol.7 It was hypothesized that Oxy-ER
`and Oxy-CRF would produce equivalent systemic plasma
`oxymorphone exposure.
`
`Methods
`study design
`Three open-label, randomized, single-dose, replicate, cross-
`over studies were conducted at one site in the United States.
`In each study, healthy adults received two single doses of
`Oxy-ER and two single doses of Oxy-CRF during four alter-
`nating treatment periods according to one of two randomly
`assigned sequences. In study 1, subjects were administered
`5 mg doses under fasted conditions; in study 2, subjects
`were administered 40 mg doses under fasted conditions;
`in study 3, subjects were administered 40 mg doses after a
`high-fat meal.
`The studies were conducted in accordance with the
`Declaration of Helsinki, the International Conference on
`Harmonisation Good Clinical Practice, and US Food and
`Drug Administration regulations. The protocol and informed
`consent form were reviewed and approved by the institutional
`review board (Independent Investigational Review Board Inc,
`
`Plantation, FL), and all subjects provided written informed
`consent before participating.
`
`subjects
`Healthy men and women aged 18–45 years with a body mass
`index of 18.5–30 kg/m2 and no history of disease or clinically
`significant findings on physical or laboratory examination
`were eligible to participate. Women of childbearing potential
`were required to practice abstinence or use an acceptable
`method of birth control. Exclusion criteria were smoking,
`pregnancy, breast-feeding, allergy or hypersensitivity to
`opioids or naltrexone; a disease or condition that might
`interfere with drug absorption, distribution, metabolism, or
`excretion, or otherwise put a subject at risk; positive screen
`for substances of abuse, recent history of alcohol abuse, drug
`abuse, or significant mental illness, human immunodeficiency
`virus or hepatitis; recent (#14 days) use of other medication,
`except hormonal contraception, and use of medication known
`to affect hepatic drug metabolism in the past 30 days.
`
`Treatment
`Subjects received two single oral doses of 5 mg or 40 mg
`Oxy-ER and two single oral doses of Oxy-CRF, each dose
`separated by a $7-day washout. Doses were administered
`with 240 mL of room temperature water that subjects were
`instructed to drink in its entirety. Medication was admin-
`istered according to one of two treatment sequences with
`alternating treatment periods (ABAB or BABA) based on a
`computer-generated randomization schedule. During each
`treatment period, subjects were confined to the study unit
`from one day before dosing through 48 hours postdose. All
`medication was administered under supervision by study
`personnel, and treatment compliance was verified by a mouth
`and hand check.
`Subjects treated under fasted conditions underwent
`a $8-hour (40 mg doses) or $10-hour (5 mg doses) over-
`night fast before drug administration and continued to fast
`through 4 hours after drug administration. Subjects treated
`under fed conditions underwent a $10-hour overnight fast
`followed by a high-fat meal (two eggs fried in butter, two
`strips of bacon, two slices of toast with butter, 4 oz hash
`brown potatoes, and 8 oz whole milk) initiated 30 minutes
`before drug administration. Subjects were instructed to eat
`the entire meal in #30 minutes.
`To limit the potential for opioid-related adverse events,
`subjects who were administered 40 mg doses received
`three single doses of naltrexone 50 mg during each treat-
`ment period (12 doses in all). Dosing occurred 12 and
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`er versus crush-resistant er oxymorphone
`
`2 hours before and 12 hours after each dose of Oxy-ER and
` Oxy-CRF. Subjects not tolerating the two initial doses during
`the first treatment period were not randomized to treatment.
`Naloxone was readily available to all subjects in the event
`of respiratory depression.
`
`Assessments
`Pharmacokinetics
`During each treatment period, blood samples for pharma-
`cokinetic analysis were collected predose (#1 hour before
`drug administration) and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12,
`16, 24, 36, and 48 hours after drug administration. Samples
`were kept frozen at −70°C until analysis. Oxymorphone and
`6-hydroxy-oxymorphone (6-OH-oxymorphone) concentra-
`tions were determined using a simultaneous liquid chroma-
`tography-tandem mass spectrometry method validated for the
`range of 0.025–10.00 ng/mL. Pharmacokinetic parameters
`(area under the concentration versus time curve from time 0
`to infinity [AUC0–inf], AUC from time 0 to the last measured
`concentration [AUC0–t], maximum plasma concentration
`[Cmax], and time to Cmax [tmax]) were derived from the plasma
`concentration data using noncompartmental methods and
`actual sample times. AUC0–t was calculated using the linear
`trapezoid rule, and AUC0–inf was calculated as AUC0–t plus
`last measured plasma concentration/terminal rate constant.
`The terminal rate constant (λz) was calculated by linear
`regression of the terminal portion of the linear concentra-
`tion versus time curve, and the terminal half-life [t1/2] was
`calculated as ln 2/λz.
`
`safety
`Subjects were monitored for adverse events from one day
`before treatment through 15 days after the last dose of
`study medication. Relationship of adverse events to study
`medication (not, unlikely, possibly, or probably related)
`and intensity (mild, moderate, or severe) were determined
`by the investigator. Serious adverse events were defined
`as an adverse event that was immediately life-threatening,
`resulted in or prolonged inpatient hospitalization, resulted
`in death or permanent or substantial disability, was a con-
`genital anomaly/birth defect, or might have jeopardized the
`subject and required medical intervention to prevent one of
`these outcomes. Complete physical examination was per-
`formed at screening and 48 hours after the last dose of study
` medication. Vital signs were recorded at screening, one day
`before each dose of study medication, and at specified times
`from 2–48 hours after each dose of study medication. Clinical
`chemistry, hematology, and urinalysis were performed at
`
`screening, one day before the first dose of study medication,
`and 48 hours after the last dose of study medication.
`
`statistical analysis
`Pharmacokinetic parameters were analyzed in all subjects
`who received $1 dose of Oxy-ER and Oxy-CRF and were
`determined by the pharmacokineticist to have sufficient
`plasma concentration data to calculate AUC and Cmax. Phar-
`macokinetic data from subjects who had vomited within the
`first 12 hours of a treatment period were not analyzed. For
`calculation of mean concentrations, values below the limit of
`quantification were set to 0 or, if occurring between two other
`such concentrations, were indicated as missing. For calcula-
`tion of pharmacokinetic parameters, plasma concentrations
`below the limit of quantification were set to 0 if occurring
`before the first measurable concentration and otherwise were
`indicated as missing.
`Pharmacokinetic parameters were summarized descrip-
`tively, using the number of subjects, mean, standard deviation,
`and coefficient of variation (AUC0–t, AUC0–inf, Cmax, and t1/2)
`or the median and range (tmax). Repeated measures analysis
`of variance with treatment as the fixed factor and subject
`within-treatment sequence as a random factor was performed
`on the log-transformed values for AUC0–t, AUC0–inf, and Cmax.
`Geometric mean ratios (Oxy-CRF/Oxy-ER) and 90% con-
`fidence intervals (CI) were calculated by the antilog of the
`least squares mean differences and their CIs. The criterion
`for bioequivalence was met if the 90% CIs of the geometric
`mean ratio (Oxy-CRF/Oxy-ER) for oxymorphone AUC0–t,
`AUC0–inf, and Cmax were within 0.8–1.25.
`The safety population comprised all subjects who
`received $1 dose of Oxy-ER, Oxy-CRF, or naltrexone.
`Safety variables were summarized by treatment and using
`appropriate descriptive statistics.
`SAS® (version 9.2, SAS Institute Inc, Cary, NC) was used
`for all analyses. A sample size of 26 subjects was planned for
`each study. Assuming an intrasubject coefficient of variation
`of 30.2% for oxymorphone, and allowing for a 5% difference
`between treatment groups, this sample size would provide
`$90% power to demonstrate bioequivalence using this rep-
`licated dosing design.
`
`Results
`subject disposition and characteristics
`Subject disposition is shown in Figure 1. In study 1, 2, and 3,
`there were 30, 37, and 36 subjects enrolled and included in the
`safety population and 28, 30, and 29 subjects who completed
`the study, respectively. In study 1 (5 mg, fasted), two subjects
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`Study 1
`(5 mg, fasted)
`
`n = 30 enrolled
`
`Study 2
`(40 mg, fasted)
`
`n = 37 enrolled
`and received
`naltrexone
`
`Study 3
`(40 mg, fed)
`
`n = 36 enrolled
`and received
`naltrexone
`
`n = 30 randomized and received
`Oxy-ER or Oxy-CRF
`
`n = 34 randomized and received
`Oxy-ER or Oxy-CRF
`
`n = 30 randomized and received
`Oxy-ER or Oxy-CRF
`
`n = 1 withdrew consent
`n = 1 protocol violation
`
`n = 1 withdrew consent
`n = 1 protocol violation
`n = 1 withdrawn by physician
`n = 1 AE
`
`n = 1 AE
`
`n = 28 completed the study
`
`n = 30 completed the study
`
`n = 29 completed the study
`
`n = 28 PK population
`n = 30 safety population
`
`n = 31 PK population
`n = 37 safety population
`
`n = 30 PK population
`n = 36 safety population
`
`Figure 1 subject disposition.
`Abbreviations: Ae, adverse event; Oxy-er, oxymorphone extended release; Oxy-crF, crush-resistant oxymorphone extended release; PK, pharmacokinetics.
`
`10–12 hours after drug administration. The second peak
`was generally larger than the first, but the difference was
`more notable for Oxy-CRF, which had a smaller initial peak
`than Oxy-ER. Mean oxymorphone plasma concentrations
`for Oxy-ER and Oxy-CRF were the same starting 6 (5 mg,
`fasted), 8 (40 mg, fasted), or 16 hours (40 mg, fed) after
`administration.
`
`were excluded from the pharmacokinetics population because
`they were administered only one dose of Oxy-ER. The
`pharmacokinetics population comprised 27 subjects who
`completed the study and one who partially completed the
`study. In study 2 (40 mg, fasted), 6 subjects were excluded
`from the pharmacokinetics population because they were not
`administered any Oxy-ER or Oxy-CRF (n = 3) or because
`they were administered only one dose of Oxy-ER (n = 3).
`The pharmacokinetics population comprised all 30 subjects
`who completed the study and one who partially completed
`the study. In study 3 (40 mg, fed), six subjects were excluded
`from the pharmacokinetics population because they were not
`administered oxymorphone. The pharmacokinetics popula-
`tion comprised 29 subjects who completed the study and one
`who partially completed the study.
`Demographics and clinical characteristics were similar in
`the three studies (Table 1). Across the three studies, mean age
`was 33–35 years, 47%–60% of subjects were women, $78%
`were white, and mean body mass index was 25–26 kg/m2.
`
`Plasma oxymorphone pharmacokinetics
`With all doses and administration conditions (fasted or
`fed), the oxymorphone plasma concentration versus time
`profile was similar overall for Oxy-ER and Oxy-CRF
`(Figure 2). Each profile demonstrated two distinct peaks
`at approximately 2–3 hours and 5–6 hours after drug
` administration, followed by a gradual decline in plasma con-
`centration interrupted by a brief plateau at approximately
`
`Table 1 subject demographics (safety population)
`Characteristic
`Treatment
`5 mg, Fasted
`(n = 30)
`
`35 ± 7
`20–45
`14 (47)
`
`40 mg, Fasted
`(n = 37)
`
`33 ± 8
`19–44
`22 (59)
`
`26 (87)
`4 (13)
`
`29 (78)
`8 (22)
`
`Age, years
` Mean ± sD
` range
`Women, n (%)
`race, n (%)
` White
` Black
`ethnicity, n (%)
`32 (86)
`30 (100)
` hispanic
`5 (14)
`0
` non-hispanic
`
`
`height, cm
`166 ± 9
`169 ± 9
` Mean ± sD
`141–184
`152–187
` range
`
`
`Weight, kg
`72 ± 10
`72 ± 10
` Mean ± sD
`51–95
`53–95
` range
`
`
`BMi, kg/m2
`26 ± 2
`25 ± 3
` Mean ± sD
`22–30
`21–30
` range
`Abbreviations: BMi, body mass index; sD, standard deviation.
`
`40 mg, Fed
`(n = 36)
`
`34 ± 8
`19–44
`19 (53)
`
`30 (83)
`6 (17)
`
`36 (100)
`0
`
`167 ± 9
`145–185
`
`71 ± 12
`51–96
`
`25 ± 3
`19–30
`
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`er versus crush-resistant er oxymorphone
`
`Oxy-ER, 5 mg fasted
`Oxy-CRF, 5 mg fasted
`
`0
`
`4
`
`8
`
`12
`
`16
`
`24
`20
`28
`Time (hours)
`
`32
`
`36
`
`40
`
`44
`
`48
`
`Oxy-ER, 40 mg fasted
`Oxy-CRF, 40 mg fasted
`
`0
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`28
`
`32
`
`36
`
`40
`
`44
`
`48
`
`Time (hours)
`
`Oxy-ER, 40 mg fed
`Oxy-CRF, 40 mg fed
`
`0
`
`4
`
`8
`
`12
`
`16
`
`24
`20
`28
`Time (hours)
`
`32
`
`36
`
`40
`
`44
`
`48
`
`0.350
`
`0.300
`
`0.250
`
`0.200
`
`0.150
`
`0.100
`
`0.050
`
`0.000
`
`2.500
`
`2.000
`
`1.500
`
`1.000
`
`0.500
`
`0.000
`
`5.000
`
`4.000
`
`3.000
`
`2.000
`
`1.000
`
`0.000
`
`oxymorphone concentration, ng/mL
`
`oxymorphone concentration,
`
`oxymorphone concentration, ng/mL
`
`Mean ± SE plasma
`
`Mean ± SE plasma
`
`Mean ± SE plasma
`
`ng/mL
`
`Dovepress
`
`A
`
`B
`
`C
`
`Figure 2 Mean oxymorphone plasma concentrations 0–48 hours after single oral doses of Oxy-er and Oxy-crF (A) 5 mg administered under fasted conditions, (B) 40 mg
`administered under fasted conditions, and (C) 40 mg administered after a high-fat breakfast.
`Abbreviations: Oxy-er, oxymorphone extended release; Oxy-crF, crush-resistant oxymorphone extended release; se, standard error.
`
`Systemic plasma oxymorphone exposure (AUC and
`Cmax) was also similar after single doses of Oxy-ER and
`Oxy-CRF (Table 2). Mean ± SD oxymorphone AUC0–t for
`Oxy-ER and Oxy-CRF, respectively, was 5.05 ± 1.55 and
`5.29 ± 1.52 ng ⋅ h/mL after a 5 mg dose administered under
`
`fasted conditions, 31.51 ± 10.95 and 31.23 ± 10.33 ng ⋅ h/mL
`after a 40 mg dose administered under fasted conditions,
`and 50.16 ± 14.91 and 49.01 ± 14.03 ng ⋅ h/mL after a 40 mg
`dose administered following a high-fat breakfast. Mean ± SD
`oxymorphone Cmax for Oxy-ER and Oxy-CRF, respectively,
`
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`Table 2 Plasma oxymorphone pharmacokinetic parameters
`Parameter
`Treatment
`5 mg, Fasted
`(n = 28)
`Oxy-ER
`5.05 ± 1.55
`30.7
`nD
`
`Oxy-CRF
`5.29 ± 1.52
`28.7
`nD
`
`0.38 ± 0.11
`30.5
`6.0
`1.0–12.0
`nD
`
`0.37 ± 0.12
`31.7
`5.0
`1.0–16.0
`nD
`
`40 mg, Fasted
`(n = 31)
`Oxy-ER
`31.51 ± 10.95
`AUc0–t, ng ⋅ h/mL Mean ± sD
`34.7
` %cV
`32.99 ± 11.58
`AUc0–inf, ng ⋅ h/mL Mean ± sD
`35.1
` %cV
`2.37 ± 1.20
`cmax, ng/mL Mean ± sD
`50.6
` %cV
`Median tmax, h
`3.0
`0.5–12.0
` range
`10.0 ± 2.5
`Mean ± sD t1/2, ha
`25.5
` %cV
`Note: anot evaluated because monoexponential elimination was not evident in most cases.
`Abbreviations: AUc0–inf, area under the concentration versus time curve from time 0 to infinity; AUC0–t, AUc from time 0 to the last measured concentration;
`cmax, maximum plasma concentration; CV, coefficient of variation; ND, not determined; Oxy-CRF, crush-resistant oxymorphone extended release; Oxy-ER, oxymorphone
`extended release; t1/2, terminal half-life; tmax, time to cmax; sD, standard deviation.
`
`40 mg, Fed
`(n = 30)
`Oxy-ER
`50.16 ± 14.91
`29.7
`52.29 ± 15.98
`30.6
`5.87 ± 1.99
`33.9
`3.5
`1.0–6.0
`10.5 ± 4.1
`39.3
`
`Oxy-CRF
`49.01 ± 14.03
`28.6
`50.95 ± 14.63
`28.7
`5.63 ± 2.26
`40.1
`5.0
`1.0–10.0
`10.3 ± 3.6
`35.2
`
`Oxy-CRF
`31.23 ± 10.33
`33.1
`32.65 ± 10.92
`33.4
`2.41 ± 0.94
`38.9
`5.0
`0.5–12.0
`9.9 ± 2.7
`26.9
`
`was 0.38 ± 0.11 and 0.37 ± 0.12 ng/mL after a 5 mg dose
`administered under fasted conditions, 2.37 ± 1.20 and
`2.41 ± 0.94 ng/mL after a 40 mg dose administered under
`fasted conditions, and 5.87 ± 1.99 and 5.63 ± 2.26 ng/mL
`after a 40 mg dose administered following a high-fat
`breakfast.
`Median oxymorphone tmax was the only pharmacokinetic
`parameter to differ between Oxy-ER and Oxy-CRF, being
`shorter for Oxy-ER versus Oxy-CRF 40 mg (Table 2), with
`differences of 2 hours under fasted conditions (3.0 versus
`5.0) and 1.5 hours under fed conditions (3.5 versus 5.0).
`The difference in median tmax was smaller when 5 mg
`doses of Oxy-ER and Oxy-CRF were compared (6.0 versus
`5.0 hours). The tmax values roughly corresponded to the
`time at which the two early peaks occurred in the plasma
`concentration versus time profiles (Figure 2). The range
`of tmax was similar for the two formulations in each of the
`three studies.
`
`Plasma 6-hydroxy-oxymorphone
`pharmacokinetics
`Mean plasma 6-OH-oxymorphone concentration versus time
`profiles were similar for Oxy-ER and Oxy-CRF, regardless
`of dose or administration conditions (Figure 3). Profiles
`exhibited a single peak at approximately 2–3 hours under
`fasted conditions and 5 hours under fed conditions. Starting
`6 (5 mg, fasted), 12 (40 mg, fasted), or 16 hours (40 mg,
`fed) after drug administration, mean concentrations were
`the same for Oxy-ER and Oxy-CRF. Systemic plasma
`6-OH-oxymorphone exposure did not differ between the two
`formulations (Table 3), but median tmax was 1.0 (40 mg, fed)
`
`to 1.5 hours (5 mg, fasted; 40 mg, fasted) shorter for Oxy-ER
`versus Oxy-CRF.
`
`Bioequivalence
`Within-subject variability in oxymorphone AUC and Cmax
`ranged from 11% to 24% and was comparable between the
`two oxymorphone formulations (data not shown). For all
`doses and under both fasted and fed conditions, the 90% CI
`for the comparisons of Oxy-ER and Oxy-CRF plasma oxy-
`morphone AUC0–t, AUC0–inf, and Cmax were within 0.8–1.25
`(Table 4), fulfilling the bioequivalence criterion. Comparisons
`of Oxy-ER and Oxy-CRF plasma 6-OH-oxymorphone were
`supportive of the finding of bioequivalence with respect to
`oxymorphone (Table 5).
`
`safety
`The proportion of subjects administered Oxy-ER
`and Oxy-CRF, respectively, who experienced $1
`treatment-emergent adverse event was 25% (n = 7/28) and
`23% (7/30) for the 5 mg doses administered under fasted
`conditions, 9% (3/34) and 16% (5/31) for the 40 mg doses
`administered under fasted conditions, and 20% (6/30, both
`treatments) for the 40 mg doses administered under fed
`conditions. The most frequent adverse events, and the only
`adverse events that occurred in $1 subject treated with a par-
`ticular dose of Oxy-ER or Oxy-CRF, were nausea, headache,
`vomiting, and dizziness. Treatment-related adverse events
`were infrequent with both formulations (range for treatment
`groups, 3%–13% of subjects). There were no severe adverse
`events, no adverse events, and no deaths. There were no clini-
`cally significant changes in physical examination findings,
`
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`
`er versus crush-resistant er oxymorphone
`
`Oxy-ER, 5 mg fasted
`Oxy-CRF, 5 mg fasted
`
`0
`
`4
`
`8
`
`12
`
`16
`
`24
`20
`28
`Time (hours)
`
`32
`
`36
`
`40
`
`44
`
`48
`
`Oxy-ER, 40 mg fasted
`Oxy-CRF, 40 mg fasted
`
`0
`
`4
`
`8
`
`12
`
`16
`
`24
`20
`28
`Time (hours)
`
`32
`
`36
`
`40
`
`44
`
`48
`
`Oxy-ER, 40 mg fed
`Oxy-CRF, 40 mg fed
`
`0
`
`4
`
`8
`
`12
`
`16
`
`24
`20
`28
`Time (hours)
`
`32
`
`36
`
`40
`
`44
`
`48
`
`0.250
`
`0.200
`
`0.150
`
`0.100
`
`0.050
`
`0.000
`
`1.750
`
`1.500
`
`1.250
`
`1.000
`
`0.750
`
`0.500
`
`0.250
`
`0.000
`
`2.000
`
`1.500
`
`1.000
`
`0.500
`
`0.000
`
`concentration, ng/mL
`6-OH-oxymorphone
`
`Mean plasma
`
`concentration, ng/mL
`6-OH-oxymorphone
`
`Mean plasma
`
`concentration, ng/mL
`6-OH-oxymorphone
`
`Mean plasma
`
`A
`
`B
`
`C
`
`Figure 3 Mean 6-Oh-oxymorphone plasma concentrations 0–48 hours after single oral doses of Oxy-er and Oxy-crF (A) 5 mg administered under fasted conditions,
`(B) 40 mg administered under fasted conditions, and (C) 40 mg administered after a high-fat breakfast.
`Abbreviations: 6-Oh-oxymorphone, 6-hydroxy-oxymorphone; Oxy-er, oxymorphone extended release; Oxy-crF, crush-resistant oxymorphone extended release.
`
`Table 3 Plasma 6-Oh-oxymorphone pharmacokinetic parameters
`Parameter
`Treatment
`5 mg, Fasted
`(n = 28)
`Oxy-ER
`4.15 ± 1.82
`43.9
`nD
`
`Oxy-CRF
`4.24 ± 1.95
`46.0
`nD
`
`0.24 ± 0.07
`28.2
`1.5
`0.5–6.0
`nD
`
`0.20 ± 0.12
`56.9
`3.0
`0.5–24.0
`nD
`
`40 mg, Fasted
`(n = 31)
`Oxy-ER
`26.08 ± 9.39
`AUc0–t, ng ⋅ h/mL Mean ± sD
`36.0
` %cV
`32.96 ± 13.86
`AUc0–inf, ng ⋅ h/mL Mean ± sD
`42.1
` %cV
`1.61 ± 0.59
`cmax, ng/mL Mean ± sD
`36.3
` %cV
`Median tmax, h
`1.5
`0.5–5.0
` range
`19.3 ± 9.8
`Mean ± sD t1/2, ha
`50.8
` %cV
`Note: anot evaluated because monoexponential elimination was not evident in most cases.
`Abbreviations: 6-Oh-oxymorphone, 6-hydroxy-oxymorphone; AUc0–inf, area under the concentration versus time curve from time 0 to infinity; AUC0–t, AUc from time
`0 to the last measured concentration; cmax, maximum plasma concentration; CV, coefficient of variation; ND, not determined; Oxy-CRF, crush-resistant oxymorphone extended
`release; Oxy-er, oxymorphone extended release; t1/2, terminal half-life; tmax, time to cmax.
`
`40 mg, Fed
`(n = 30)
`Oxy-ER
`33.40 ± 11.94
`35.7
`40.99 ± 16.47
`40.2
`2.24 ± 0.89
`39.7
`4.0
`1.0–10.0
`17.8 ± 7.3
`41.1
`
`Oxy-CRF
`33.39 ± 11.48
`34.4
`42.05 ± 16.88
`40.1
`2.23 ± 0.87
`38.8
`5.0
`1.0–12.0
`19.5 ± 8.8
`45.0
`
`Oxy-CRF
`26.10 ± 10.18
`39.0
`33.61 ± 15.57
`46.3
`1.45 ± 0.55
`37.6
`3.0
`0.5–24.0
`21.5 ± 15.9
`73.7
`
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`Table 4 Bioequivalence data: systemic plasma oxymorphone
`exposure
`
`Parameter
`
`Ratio of least squares
`geometric means
`(Oxy-CRF/Oxy-ER)
`
`90% CI
`
`1.05
`0.98
`
`0.99
`0.99
`1.05
`
`1.01–1.09
`0.93–1.03
`
`0.95–1.04
`0.95–1.04
`0.98–1.12
`
`5 mg, fasted
` AUc0–t, ng ⋅ h/mL
` cmax, ng/mL
`40 mg, fasted
` AUc0–t, ng ⋅ h/mL
` AUc0–inf, ng ⋅ h/mL
` cmax, ng/mL
`40 mg, fed
` AUc0–t, ng ⋅ h/mL
`0.93–1.02
`0.97
` AUc0–inf, ng ⋅ h/mL
`0.93–1.02
`0.97
`0.88–1.02
`0.94
` cmax, ng/mL
`Abbreviations: AUc0–inf, area under the concentration versus time curve from
`time 0 to infinity; AUC0–t, AUc from time 0 to the last measured concentration;
`cmax, maximum plasma concentration; Oxy-crF, crush-resistant oxymorphone
`extended release; Oxy-ER, oxymorphone extended release; CI, confidence interval.
`
`vital signs, or laboratory findings that were deemed to be
`related to treatment.
`
`Discussion
`These three randomized clinical trials evaluated the bioequiv-
`alence of the lowest (5 mg) and highest (40 mg) supplied
`dosage strengths of Oxy-ER and the same doses of Oxy-CRF
`in healthy adults under fasted (5 mg, 40 mg) and fed (40 mg)
`conditions. Oxy-ER and Oxy-CRF demonstrated overall
`similar oxymorphone and 6-OH-oxymorphone plasma con-
`centrations over time. Differences in tmax between Oxy-ER
`and Oxy-CRF were not clinically relevant. The criterion for
`bioequivalence of plasma oxymorphone exposure was met for
`
`Table 5 Bioequivalence data: systemic plasma 6-Oh-oxymorphone
`exposure
`
`Parameter
`
`Ratio of least squares mean,
`Oxy-CRF/Oxy-ER
`
`90% CI
`
`1.01
`0.80
`
`0.99
`1.01
`0.91
`
`0.95–1.07
`0.75–0.86
`
`0.94–1.04
`0.95–1.08
`0.86–0.95
`
`5 mg, fasted
` AUc0–t, ng ⋅ h/mL
` cmax, ng/mL
`40 mg, fasted
` AUc0–t, ng ⋅ h/mL
` AUc0–inf, ng ⋅ h/mL
` cmax, ng/mL
`40 mg, fed
` AUc0–t, ng ⋅ h/mL
`0.96–1.05
`1.00
` AUc0–inf, ng ⋅ h/mL
`0.97–1.08
`1.02
`0.94–1.07
`1.01
` cmax, ng/mL
`Abbreviations: 6-Oh-oxymorphone, 6-hydroxy-oxymorphone; AUc0–inf, area
`under the concentration versus time curve from time 0 to infinity; AUC0–t, AUc from
`time 0 to the last measured concentration; cmax, maximum plasma concentration;
`Oxy-crF, crush-resistant oxymorphone extended release; Oxy-er, oxymorphone
`extended release; CI, confidence interval.
`
`all parameters (AUC0–t, AUC0–inf, Cmax). In these subjects, most
`of whom also received naltrexone, Oxy-ER and Oxy-CRF
`were generally well tolerated, with no discernable differences
`between formulations.
`Findings were consistent overall for oxymorphone
`and its active metabolite, 6-OH-oxymorphone. For
` 6-OH-oxymorphone, overall systemic plasma exposure,
`as indicated by the AUC0–t, did not differ between the two
`formulations, and data were supportive of the finding of
`bioequivalence with respect to oxymorphone.
`In the 40 mg dose studies, naltrexone was administered
`at the beginning of each treatment period to limit opioid-
`related adverse events. Although naltrexone is reported
`to increase oxymorphone peak plasma exposure (data on
`file, Endo Pharmaceuticals Inc), naltrexone administra-
`tion in the current study is not likely to have affected
`the evaluation of bioequivalence because dose and time
`of administration were standardized across subjects and
`treatment periods.
`The presence of peaks and shoulders in the concentration
`versus time curves has been observed in previous studies
`(data on file, Endo Pharmaceuticals Inc). The timing of the
`later peaks often corresponds with eating and may be related
`to the known increase in systemic exposure to oxymorphone
`when administered with food,5 combined with prolonged
`absorption from these formulations.
`The bioequivalence findings indicate a 1:1 correspon-
`dence between doses of Oxy-ER and Oxy-CRF. This would
`facilitate conversion from Oxy-ER to Oxy-CRF. In addition,
`the ratios for conversion of other oral opioid doses to Oxy-ER
`can be considered appropriate for Oxy-CRF.5
`Study subjects were selected to satisfy US Food and
`Drug Administration guidelines for bioequivalence studies8
`and not to represent the clinical population that would be
`using oxymorphone. Moreover, subjects treated with 40 mg
`doses also received naltrexone. Thus, the safety profile was
`not the same as in patients or healthy subjects not receiving
`an opioid antagonist. However, Oxy-ER and Oxy-CRF had
`a similar safety profile for subjects administered an opioid
`antagonist (ie, naltrexone) along with an opioid. There were
`no important differences in the type or frequency of adverse
`events, regardless of dose or condition of administration
`(fasted or fed). There was also no indication of new adverse
`events or an increase in the frequency of adverse events with
`Oxy-CRF versus Oxy-ER.
`The efficacy and safety of Oxy-ER have been demon-
`strated in randomized controlled trials of up to 12 weeks
`and extension trials of up to one year in opioid-naive and
`
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`er versus crush-resistant er oxymorphone
`
`opioid-experienced patients with moderate to severe chronic
`low back pain,9,10 cancer pain,11,12 and osteoarthritis.13,14
`Other benefits are the low potential for drug–drug interac-
`tions (oxymorphone does not inhibit cytochrome P450
`enzymes)15 and simplified interpretation of urine testing
`(oxymorphone does not produce any metabolites that can be
`mistaken for another prescribed drug).16 The bioequivalence
`findings of the studies reported here indicate that Oxy-CRF
`is expected to have clinical efficacy and safety equivalent
`to Oxy-ER.
`
`Conclusion
`Three randomized clinical trials demonstrated bioequivalence
`of Oxy-ER and Oxy-CRF 5 mg under fasted conditions and
`40 mg under fasted and fed conditions. The treatments had
`similar safety profiles and were generally well tolerated, given
`that most subjects also received naltrexone.
`
`Acknowledgments
`The Crush Resistant Formulation technology was developed
`by and is property of Gruenenthal, Aachen, Germany. Endo
`holds an exclusive license for the use of the technology with
`Opana ER.
`Axel Juan and Audrey Martinez, both of SeaView
`Research Inc (Miami, FL) were principal investigators
`for these studies. Clinical monitoring of the studies was
`performed by Paula Allen. Bioanalyti