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`O2EZ/40/10Uo=oxHSbigpyZarbZAPNMeabybs|PAURZISDH/EOECOHIDINIDUAWXOMMQUOIWIXPOHISGOZBUTIMeRPRIDHWNSZLAByHasaNiua4qersobPeue-eisaineaVe/WiooMwye/BLUNOL/edyyWoypapecjuMmod
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`AMBULATORY ANESTHESIA
`Section Epiror
`Pauw F. Wutre
`
`SOCIETYFORAMBULATORYANESTHESIA
`
`A Multiple-Dose Phase | Study of Intranasal Hydromorphone
`Hydrochloride in Healthy Volunteers
`
`Anita C. Rudy, phb*, Barbara A. Coda, Mptt, Sanford M. Archer, Mpg, and
`Daniel P. Wermeling, PharmD*|
`“Intranasal Technology, Inc., Lexington, Kentucky; tDepartmentof Anesthesiology, University of Washington,Seattle,
`Washington; {McKenzie Anesthesia Group, Springfield, Oregon; §Division of Otolaryngology-Head & Neck Surgery,
`University of Kentucky A. B. Chandler Medical Center, Lexington, Kentucky; and |University of Kentucky College of
`Pharmacy, Lexington, Kentucky
`
`tolerability, and
`- We evaluated the pharmacokinetics,
`of 1 and 2 mg (once every 6 h), mean + sp peak plasma
`safety of 1 and 2 mg ofintranasal hydromorphonehydro-
`concentrations of 2.8 + 0.7 ng/mL and 5.3 + 2.3 ng/mL,
`chloride in an open-label, single- and multiple-dose
`respectively, were observed. The median time to peak
`study. This Phase I study was conducted in 24 healthy
`concentration was 20 min for both single and multiple
`volunteers (13 menand 11 women). Intranasal doses were
`doses. Dose proportionality was observedfor the 1- and
`delivered as 0.1-mL metered-dose sprays into one or both
`2-mg doses. Adverse events included somnolence, dizzi-
`nostrilsfor 1- and 2-mgdoses, respectively. Venous blood
`ness, and bad taste after dose administration. Intranasal
`samples were taken serially from Q to 12 h after thefirst
`hydromorphone hydrochloride was well tolerated and
`single dose and thelast (seventh) multiple dose. Plasma
`demonstrated rapid nasal drug absorption and predict-
`hydromorphoneconcentrations were determined by liq-
`able accumulation. These results supportclinical investi-
`uid chromatography/mass spectrometry/mass spec-
`gation of hydromorphone hydrochloride nasal spray for
`use as an alternative to oral and IM administration.
`trometry. Noncompartmental analysis was used to esti-
`mate pharmacokinetic variables. After 7 intranasal doses
`(Anesth Analg 2004;99:1379 -86)
`
`»ainmanagementspecialistshaveexploredalterna-
`
`tive routes to optimize the pharmacological man-
`agement of pain (1-5). Investigators have noted
`that most cancer pain patients benefit from, and often
`require, an alternative route for opioid administration in
`the terminal stages of their disease; routes of administra-
`tion are often rotated for convenience and for better
`control of pain intensity and adverse effects. Some pa-
`tients are unable to take drugsorally for some periods
`becauseof the gastrointestinal side effects of opioids or
`inability to swallow, and acute exacerbation of pain may
`require a change in the route of opioid administration
`(1,2). In acute pain settings, such as early management of
`postoperative pain, an alternative to administration by
`injection can also be desirable, particularly if absorption
`is more rapid than with oral administration.
`
`Although the intranasal route has been shown to be
`effective for delivery of a variety of opioid analgesics,
`only butorphanol tartrate is commercially available for
`use by this route. Despite the great interest in nasal
`delivery of opioids, evaluation of multiple-dose pharma-
`cokinetics of systemically-acting intranasal drugsis very
`limited. In a previous study, we examined the pharma-
`cokinetics and bioavailability of hydromorphoneafter
`single intranasal doses compared with IV administration
`(6). Hydromorphone’s medium duration of clinical ac-
`tivity and short elimination half-life require that it be
`given every 3-4 h. Hence, repeated short-term adminis-
`tration is likely to occur in the treatment of acute pain.
`For this reason, the objectives of this study were to
`examine the pharmacokinetics and tolerability of this
`investigational hydromorphone hydrochloride (HCI) na-
`sal spray after repeated administration for 42 h.
`
`Intranasal Technology, Inc., Lexington, Kentucky.
`Accepted for publication May 4, 2004.
`Address correspondence and reprint requests to Daniel P. Wermeling,
`PharmD,Intranasal Technology, Inc., Coldstream Research Cam-
`pus, 1513 Bull Lea Blvd., Lexington, KY 40511-1200. Address e-mail
`to info@intranasal.com.
`
`DOI: 10.1213 /01.ANE.0000132927.47528.8B
`
`Methods
`
`Twenty-four healthy nonsmoking subjects (13 men
`and 11 women) betweenthe ages of 18 and 36 yr (23.5
`+ 6.1 yr, mean + sp) and weighing 59 to 100 kg (men,
`78.0 = 11.3 kg; women, 65.2 + 6.3 kg) participated in
`
`©2004 by the International Anesthesia Research Society
`0003-2999/04
`
`Anesth Analg 2004,99:1379-86
`
`1379
`
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`1380
`
`AMBULATORY ANESTHESIA RUDY ET AL.
`MULTIPLE-DOSE PHARMACOKINETICS OF NASAL HYDROMORPHONE
`
`ANESTH ANALG
`2004;99:1379-86
`
`this inpatient study after written, informed consent(as
`approved by the Medical IRB of the University of
`Kentucky) was obtained. Three volunteers were Afri-
`can American, one was Hispanic, and 20 were Cauca-
`sian. All were within +20%of ideal body weightin
`relation to height and body frame (per Metropolitan
`Life Insurancetables). Subjects had nohistoryofaller-
`gies, nasal symptoms,clinically significant previous
`nasal surgery, trauma, polyps, or other physical ab-
`normalities of the nose. Subjects abstained from all
`medications from the date of screening until the end of
`the study. They also abstained from alcohol and caf-
`feine 48 h before the dosing period and during the
`study. This study was conducted according to the
`applicable guidelines for good clinical practice.
`The intranasal hydromorphone HC]formulation, an
`aqueoussolution buffered to pH 4.0 with 0.2% sodium
`citrate and 0.2%citric acid, provided 1 mg of hydro-
`morphone HClin a 0.1-mL spray from a commercially
`available unit dose-metered spray pump. The compo-
`sition of the solution was identical to the Dilaudid-
`HP® product (hydromorphone HCl 10 mg/mL; Knoll
`Pharmaceutical Co., Mount Olive, NJ, a division of
`Abbott Laboratories) and was prepared under good
`manufacturing practices conditions in the University
`of Kentucky College of Pharmacy Center for Pharma-
`ceutical Science and Technology.
`Subjects were randomly assigned to receive either 1 or
`2 mg of hydromorphone HCIin this open-label, single-
`and multiple-dose study. All subjects received the single
`dose first (Dose $1) and returned approximately a week
`later for the multiple-dose treatment (Doses Mi-M7),
`during which they received the same dose (1 or 2 mg) as
`in the single-dose treatment. Multiple-dose treatments of
`intranasal hydromorphone HCl were given every 6 h
`beginning at approximately 8:00 pm so that the M7 dose
`wasgiven around 8:00 am. Subjects fasted for 8 h before
`and 1h after dosing for the single dose (except for water
`ad libitum and a caffeine-free drink at least 1 h before
`dosing). During the multiple-dose treatment, the sub-
`jects fasted for 1 h before and after intranasal dose ad-
`ministration. Subjects were provided standardized
`xanthine-free meals and snacks at preset times each day
`they were institutionalized.
`Immediately before study drug administration, the
`subject gently blew his or her nose. Hydromorphone
`HCI nasal spray was administered by a physician or
`research nurse, who directed the spray toward the
`lateral nasal wall. Each subject received a single spray
`into one nostril for the 1-mg doseor a single spray into
`each nostril for a total of 2 mg. After study drug
`administration, the subject remained in a semirecum-
`bent position for 10 min and refrained from blowing
`his or her nose for at least 60 min. During the multiple-
`dose treatment, subjects remained in the hospital
`room and refrained fromvigorousactivity throughout
`the study period.
`
`For Doses $1 and M7, serial venous blood samples
`were obtained according to the following schedule: 0
`(predose), 5, 10, 15, 20, 30, and 45 min and1,2,3,4, 6,
`8, and 12 h after drug administration. During the
`multiple-dose treatment, trough samples were drawn
`within 10 min before Doses M1 and M4 through M7.
`Venous blood samples were collected by using 10-mL
`heparinized Vacutainer® tubes. Plasma was separated
`from blood cells by centrifuging at 4°C, transferred to
`polypropylene tubes, and stored at approximately
`—70°C. Frozen plasma samples were then shipped to
`AAI Development Services, Inc. (Shawnee, KS) for
`hydromorphoneassay.
`Plasma hydromorphoneconcentrations were de-
`termined with a liquid chromatography /massspec-
`trometry/mass spectrometry assay developed by
`AAI Development Services, The assay was validated
`for specificity, sensitivity, linearity, stability, dilu-
`tion, precision, accuracy (recovery), and reproduc-
`ibility. Hydromorphone and the added internal
`standard, hydromorphone-d,, were extracted from
`human plasma by using a solid-phase extraction.
`Reconstituted extracts were analyzed by using a
`TurbolonSpray Ion Source inlet and a multiple re-
`action monitoring protocol. The method is linear
`over the range of 0.02-2.0 ng/mL. Concentrations
`<0.02 ng/mL were reported as below the quantita-
`tion limit. Samples with concentrations larger than
`2.0 ng/mL were reanalyzed by using a dilution so
`that
`the assayed concentrations were within the
`range of 0.02-2.0 ng/mL. Between-day and within-
`day accuracy and precision were <12%of the rela-
`tive standard deviation (sp).
`A physician was present in the clinic for each dose
`administration and for at least 4 h after Doses $1 and
`M7 of study drug. Arterial blood pressure, heart rate,
`and respiratory rate were measured before andat 0.5,
`1,3, and 6 h after Doses $1 and M7 and 1h after Doses
`Mi through Mé. In addition to recording spontane-
`ously reported subjective symptoms, a research nurse
`also questioned subjects about adverse events each
`time vital signs were recorded. The severity of each
`adverse event was classified as mild, moderate, or
`severe by using standard definitions (6). Nasal exam-
`inations by an otolaryngologist to evaluate local mu-
`cosalirritation or damage were performed at screen-
`ing; before Doses $1 and M7; at 2-4 h after Doses 51,
`M3, and M7; and at the end of the study.
`Pharmacokinetic variables were characterized by
`using standard noncompartmental methods (7) with
`log-linear least-square regression analysis (weighting
`factor 1/y) to determine the elimination rate constants
`by using WinNonlin (Version 3.2; Pharsight Corp.,
`Palo Alto, CA). Maximumplasma concentration and
`time to maximum plasma concentration (C,,,, and
`trax fespectively), elimination half-life (t, ,2), area un-
`der the plasma concentration-time curve from Time 0
`
`AQUESTIVE EXHIBIT 1122 Page 0002
`AQUESTIVE EXHIBIT 1122 Page 0002
`
`

`

`ANESTH ANALG
`2004;99:1379-86
`
`RUDYETAL.
`AMBULATORY ANESTHESIA
`MULTIPLE-DOSE PHARMACOKINETICS OF NASAL HYDROMORPHONE
`
`1381
`
`~@— Single Dase
`—4— Multiple Dose
`
`—#— Predose Trough
`
`
`
`a
`
`w
`
`nN
`
`
`
`Cancentration(ng/mL)
`
`oo
`
`a
`
`oS
`
`nN
`
`
`
`Concentration(ng/mL)
`
`to infinity (AUC,_..), from Time 0 to the last measur-
`able time point (AUC,_,), and, for the multiple-dose
`profiles, partial areas for
`the 6-h dosing interval
`(AUC,_,) were calculated. All AUCs were determined
`by WinNonlin by using a combination of the linear
`and logarithmic trapezoidal rules. The average con-
`centration for multiple-dose data was computed as
`AUC). divided by 6 h. Mean concentrations for the
`graphs were calculated by using only concentration-
`time points that were drawn within 5% of the time
`planned by the protocol (657 of 672 planned time
`points were used). Simulated meanconcentrationsaf-
`ter repeated dosing to steady state were generated by
`using the principle of superposition and the mean
`plasma concentrations and terminal elimination con-
`stant from the 2-mg single-dose data (7).
`Data are reported as mean and sp or median and
`range when appropriate.Statistical analyses were per-
`formed with PC-SAS (Version 6.12; SAS Institute,
`Cary, NC). The statistical tests were two sided, with a
`critical
`level of 0.05. The analysis of variance
`(ANOVA) models included the factors subject and
`dose for single- versus multiple-dose comparison and
`the factors subject and dose numberfor trough level
`comparison. ANOVA of the dose-normalized vari-
`ables AUC and C,,,,, was performed to assess the dose
`proportionality of
`the variables after single- and
`multiple-dose treatments. P values are from the
`ANOVAwith the factor dose group. The sex effect for
`all treatments was analyzed by using an ANOVA of
`log-transformed AUC and C,,,, with the factors sex,
`treatment (1 versus 2 mg), and dose.
`
`Results
`
`All 24 subjects completed the study. Absorption of
`hydromorphoneafter intranasal administration was
`rapid (detected within 5 min in all subjects), and its
`disappearance from plasma was multiphasic. Mean
`plasma hydromorphone concentration-versus-time
`profiles (1 = 12 per profile) are shown in Figure 1.
`Mean pharmacokinetic variables from the noncom-
`partmental analysis of measured plasma concentra-
`tions are presented in Table 1. Wide intersubject vari-
`ability in pharmacokinetic variables was reflected. in
`the sp for most variables. Furthermore, predose hy-
`dromorphoneconcentrations ranged from 0.41 to 0.89
`ng/mL and peak concentrations from 1.8 to 43
`ng/mL for the I-mg dose (M7). Predose concentra-
`tions ranged from 0.82 to 1.5 ng/mL and peak con-
`centrations ranged from 2.2 to 10.5 ng/mL for the
`2-mg dose (M7). No significant difference was found
`between t,,,, Values for the single and multiple doses,
`with median t,,,, values of 20 min for all 4 doses
`(overall
`range, 10-60 min). Comparison of dose-
`normalized pharmacokinetic variables after single and
`
`[1||
`J
` Qo
`
`|
`
`|
`
`Time (hours)
`
`—— Singie Dose
`—*— Multiple Dose
`—&— Predose Trough
`
`Sree
`
`Pt EE
`
`0
`
`1
`
`2
`
`3
`Time (hours)
`
`4
`
`5
`
`6
`
`Figure 1. Hydromorphone plasma concentrations (mean + sp bars)
`after intranasal 1-mg (top) and 2-mg (bottom) doses of hydromor-
`phone HC] (x = 12 subjects for each dose). Profiles are after a single
`dose (S1) and after repeated doses every 6 h for 42 h (multiple doses;
`M7). Mean predose M7 trough concentrations are shown as filled
`triangles.
`
`multiple dosing demonstrated no significant differ-
`ences in C.,, AUCy., or AUCg_.. (P > 0.3). These
`findings indicate dose-proportional pharmacokinetics
`for 1- and 2-mgintranasal doses. The t,/2 values were
`independentof dose level after single doses (P > 0.8),
`but not after multiple doses (P < 0.05), for which the
`t, 2 estimate was longer for the 2-mg multiple dose.
`Overall, women had larger plasma concentrations
`than men. Sex effects were statistically significant for
`AUC, _.., AUC)_,, and C,,,,, after the 2-mg single dose
`(P = 0.0016, 0.0006, and 0.0183, respectively) and for
`AUC,_¢ after the 1- and 2-mg multiple doses (P =
`0.0107 and 0.0008, respectively). After the 2-mg single
`dose, mean AUC,_,. values were 7.9 + 1.9 ng-h/mL
`and 14.2 + 3.1 for men (n = 7) and women (# = 5),
`respectively. Mean C,,,, values were 3.2 + 0.53
`ng/mL and 5.4 + 2.0 ng/mL for men and women,
`respectively. After the 2-mg multiple doses, mean
`AUC,_, values were 10.7 + 2.0 ng-h/mL and 16.9 +
`2.3 ng-h/mL for men and women,respectively.
`
`AQUESTIVE EXHIBIT 1122 Page 0003
`AQUESTIVE EXHIBIT 1122 Page 0003
`
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`

`1382
`
`AMBULATORY ANESTHESIA RUDY ET
`MULTIPLE-DOSE PHARMACOKINETICS OFNASAL HYDROMORPHONE
`
`ANESTH ANALG
`2004;99:1379~-86
`
`Table 1. Mean* (SD) Single-Dose (Dose 51) and Multiple-Dose (Dose M7) Hydromorphone Pharmacokinetic Variables
`After Administration of 1 and 2 mgofIntranasal Hydromorphone HC] in Healthy Volunteers (1 = 12 for Each Dose)
`tax
`Crise
`AUC).
`ty 42
`AUC),
`Cave
`
`Treatment
`(h)*
`(ng/mL)
`(ng * h/mL)
`(h)
`(ng + hr/mL)
`(ng/mL)
`SI (1 mg)
`0.33 (0.17-1.0)
`2.4 (0.9)
`5.6 (1.1)
`4.4 (1.5)
`—
`—
`M7 (1 mg)
`0.33 (0.17-1.0)
`2.8 (0.7)
`10.8 (1.3)
`4.4 (1.1)
`7.1Lidl1)
`1.2 (0.2)
`S1 (2 mg)
`0.33 (0.17-0.75)
`4.1 (1.7)
`10.5 (4.0)
`4.3 (1.7)
`_—
`
`
`
`
`
`
`M7a4mg) _13.33(3,8)0.330.17-1.0) S3(2.3) 22.3&.3) 6.4 (2.9) 2.2 (0.6)
`
`$1 = singledeacpM7== multiple dose aorr2tmg every 6 h for seven1 doses);max = time to maximum aconcentration; Comoe =
`maximum plasma
`
`concentration; t; 2 = elimination half-life; AUC,_.. = area under the plasma concentration-time curve from Time0to infinity; AUC)_, == area under the plasma
`= average concentration after multiple dosing.
`concentration-time curve from Time 0 to 6 h; Cavg
`* Data are mean (sp), except median and range are given for thax:
`
`The ratios and 95%confidence intervals for (AUC,_.
`after multiple dose)/(AUC,_.. after single dose) were
`1,28 (1.10-1.49) and 1.30 (1.15~1.47) for the 1- and 2-mg
`doses, respectively. An AUC ratio of unity would indi-
`cate time-invariant kinetics for single and multiple dos-
`ing. The 95%confidence interval for the AUC ratio did
`not
`include unity, however, suggesting that
`time-
`invariant kinetics (linear kinetics) were not definitively
`demonstrated.
`Attainment of steady-state was sec by testing
`predose (trough) concentrations for Doses M5, M6, M7
`and a theoretical M8 dose for statistically significant
`differences. The additional trough concentration was
`calculated as follows: assuming the 6-h dosing regi-
`men had continued, the concentration at 6 h after Dose
`M7 was considered the trough concentration before a
`hypothetical eighth dose, M8. Statistical analysis of
`trough concentrations taken before Doses M5, M6, and
`M7 (Table 2) indicated that hydromorphone plasma
`concentrations were apparentlystill increasing during
`the night hours after 42 h of dosing every 6 h. Con-
`centrations declined, however, at 6 h after Dose M7
`(comparison of troughs for Dose M7 and hypothetical
`Dose M8, P < 0.0002), suggesting that concentrations
`had reached steady-state.
`A simulation of steady-state plasma hydromor-
`phone concentrations was performed to demonstrate
`how well the single-dose kinetics of hydromorphone
`predicted multiple-dose plasma concentrations. Mean
`plasma concentrations of hydromorphoneafter the
`2-mg single dose of hydromorphone HCl
`(n = 12
`subjects) were used to predict multiple-dose concen-
`trations by using the superposition method(7). Figure
`2 shows simulation curves (dotted line) with meas-
`ured plasma concentrations from the multiple-dose
`studies. The actual mean trough and mean multiple-
`dose concentrations are shown. The excellent agree-
`ment betweenthe simulated and actual concentrations
`demonstrates predictable kinetics.
`All 24 subjects completed the study without serious
`adverse events. The most common drug-related ad-
`verse events are summarized in Table 3. A drug-
`related adverse event was defined as an event with a
`relationship to the study drug judged to be possible,
`
`probable, or highly probable. A subject was counted at
`most once for multiple occurrences of an adverse
`event. Adverse events were similar to those reported
`in earlier studies (6,8), and all were resolved before
`subjects were discharged.
`Adverse events were dose related and generally
`mild to moderate in severity. Most subjects reported a
`bad taste immediately after the intranasal doses, but
`this sensation resolved in less than 1 hin all cases.
`Although some (25% for multiple dose only) reported
`brief nasal itching, no mucosal irritation was seen on
`early or follow-up nasal evaluations. Itching wasalso
`noted in the face, head, and pubic area. Several sub-
`jects reported nasal stuffiness/congestion, and two
`reported brief nasal stinging. The most common ad-
`verse events seen with nasal administration were ones
`frequently associated with hydromorphone, e.g., som-
`nolence, dizziness, nausea and euphoria, and asthenia
`(feelings of tiredness, weakness, or heaviness in the
`limbs or body). Overall, 83% and 92%of the subjects
`hadat least one drug-related adverse eventafter the 1-
`and 2-mg single-dose treatments, respectively. Ap-
`proximately 92% and 100%of the subjects had at least
`one drug-related adverse event after the 1- and 2-mg
`multiple-dose treatments, respectively. There were no
`clinically relevant changes in vital signs. Arterial
`blood pressure and heart rate remained within the
`normal ranges throughout the study for all subjects.
`Importantly, no respiratory depression (decreased
`rate, decrease in oxygen saturation, or reports of re-
`spiratory symptoms) occurred after intranasal hydro-
`morphone HC] administration in any subject.
`
`Discussion
`Our prior investigations have focused on single-dose
`pharmacokinetics of intranasal hydromorphone HCl
`(6,9,10). This study was conducted at the sameinsti-
`tution as our previous study (6) and is the first to
`report the pharmacokinetics of hydromorphoneafter
`repeated intranasal administration of 1- and 2-mg
`doses every six hours for seven doses. We found that
`absorption wasconsistently rapid (median peak times
`
`AQUESTIVE EXHIBIT 1122 Page 0004
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`

`ANESTH ANALG
`2004;99:1379~86
`
` RUDYETAL.
`AMBULATORY ANESTHESIA
`MULTIPLE-DOSE PHARMACOKINETICS OF NASAL HYDROMORPHONE
`
`1383
`
`Table 2. Summary of Analysis of Predose (Trough) Concentrations After 1 and 2 mg of Intranasal Hydromorphone HCl
`Every 6 Hours for 42 Hours
`
`Trough hydromorphone concentration
`1-mg dose
`P value
`2-mg dose
`P value
`Variable
`(ng/mL)
`(doses compared)
`(ng/mL)
`(doses compared)
`
`Predose M5
`0.479 (0.12)
`0.881 (0.26)
`0.0002 (M5,6, 7, 8)
`0.0006 (M5, 6, 7, 8)
`Predose M6
`0.496 (0.11)
`1.055 (0.32)
`0.0013 (M6,7, 8)
`0.0004 (M6,7, 8)
`Predose M7
`0.622 (0.14)
`1.186 (0.22)
`
`
` 0.479 (0.065) 0.0002 (M7, 8) 0.0031 (M7, 8) 0,902 (0.25)
`
`Predose “M8”
`
`P values are from an analysis of variance with factors subject and dose number. Means (sp) are given (# = 12 for each concentration).
`
` Concentration
`(ng/mL}
`
`0
`
`6
`
`12
`
`18
`
`24
`Time (hours}
`
`30
`
`
`
`36
`
`42
`
`48
`
`Figure 2. Steady-state multiple-dose plasma hydromorphone con-
`centrations were predicted from the single-dose data by using the
`superposition method. Mean plasma concentrations of hydromor-
`phone after the single dose of 2 mg of intranasal hydromorphone
`HC] (Dose 51; @) were usedto predict multiple-dose concentrations
`for seven doses. The dotted line represents the $1 plasma concen-
`trations (0-12 h) followed by simwated concentrations (6—48 h).
`Mean troughs (Doses M4-M7) and Dose M7 actual concentrations
`are also shownasfilled and open triangles, respectively, superim-
`posed onthe simulated profile. Note that, although shownthis way,
`the Si dose wasnotthefirst dose of the multiple-dosing part of the
`study, but was given approximately a week before the multiple-
`dose part of the study.
`
`of 20 minutes} and that there were no unexpected side
`effects from repeated nasal administration. Hydro-
`morphoneaccumulated approximately 20%-30%after
`repeated administration every 6 hours for 42 hours
`compared with single-dose administration.
`Although hydromorphone has been used for the
`treatment of moderate to severe pain for 75 years,
`there is a paucity of pharmacokinetic datain the liter-
`ature (6,8-18). The few studies of hydromorphone
`were recently reviewed by Sarhill et al. (8). Previous
`reports establish that orally administered hydromor-
`phone undergoes extensive first-pass metabolism, re-
`sulting in a bioavailability of approximately 51%(12).
`Previous studies also reported the average times to
`peak plasma concentration as 1 and 1.5 hours after
`oral
`tablet and rectal administration,
`respectively
`(11,12). Mean times to C,,,, were 0.75 + 0.31 hours
`and 1.01 + 0.82 hours, and C,,,,, values were 5.12 + 3.1
`
`ng/mL and 4,09 + 2.1 ng/mL in women and men,
`respectively, for immediate-release 8-mg Dilaudid-IR
`tablets (Knoll) (17). More than 80%ofthe t,,,, values
`in this study were =30 minutes. Considering thatafter
`the single 2-mg intranasal dose in this study, mean
`Cyrax Values were 3.2 and 5.4 ng/mL for men and
`women, respectively, dose normalization shows that
`the intranasal formulation achieved approximately 3-
`or 4-fold larger peak concentrations per milligram
`compared with the oral 8-mg tablets. The results of this
`study in 24 healthy volunteers show that the intranasal
`formulation of hydromorphone HCl achieved greater
`plasma levels compared with oral tablets and a more
`rapid absorption compared with oral tablets and rectal
`suppositories. Thus, the intranasal route is likely to be
`particularly useful in clinical settings where rapid ab-
`sorption is needed but where injection is undesirable.
`The mean half-lives (approximately 6 hours) were
`longer in this study compared with our previous
`study in healthy volunteers (average 4.6 hours) (6),
`and earlier ones that were reported in the literature
`(2-3 hours) (12,16). Comparison of previous investiga-
`tions suggests that blood sampling time (range,
`6-24 hours), assay sensitivity, and other factors have
`contributed to the differences in estimates. Using a
`longer blood sampling period (24 hours) and a sensi-
`tive assay (limit of detection, 0.05 ng/mL), one inves-
`tigation in young adult volunteers revealed a slow
`terminal elimination phase with a half-life of approx-
`imately 12 hours that started approximately 8 hours
`after dosing, and it was suggested that the elimination
`rate constant was poorly defined because of secondary
`peaking dueto biliary cycling (18). We also saw sec-
`ondary peaking around three to six hours in many
`individuals, and this is probably reflected in our half-
`life estimation.
`Weobservedstatistically significant differences in
`AUC values and peak plasma concentrations between
`men and women, with women averaging higher val-
`ues than men. We observed similar trends in our
`previous study but did not report them (6). A closer
`examination of the previous data revealed similar,
`statistically significant sex differences,
`in the same
`direction, for AUC,_, and AUC,_.. but not for C,,,..
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`ANESTH ANALG
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`Table 3. Summary of the Most Common Drug-Related Adverse Events After 1 and 2 mg ofIntranasal Hydromorphone
`HCl (# = 12 for Each Dose)
`
`Single dose
`
`Variable
`(1 mg)
`3 (25%)
`2 (17%)
`1 (8%)
`
`3 (25%)
`2 (17%)
`1 (8%)
`
`6 (50%)
`4 (33%)
`1 (8%)
`3 (25%)
`
`1 (8%)
`
`3 (25%)
`
`3 (25%)
`2 (17%)
`8 (67%)
`4 (33%)
`3 (25%)
`5 (42%)
`
`Multiple dose
`Multiple dose
`(2 mg every 6h
`Single dose
`(1 mg every 6h
`
` (2 mg) for seven doses) for seven doses)
`
`4 (33%)
`6 (50%)
`10 (83%)
`2 (17%)
`3 (25%)
`7 (58%)
`1 (8%)
`4 (33%)
`6 (50%)
`3 (25%)
`1 (8%)
`1 (8%)
`6 (50%)
`1 (8%)
`6 (50%)
`
`1 (8%)
`6 (50%)
`3 (25%)
`6 (50%)
`1 (8%)
`6 (50%)
`6 (50%)
`1 (8%)
`5 (42%)
`2 (17%)
`2 (17%)
`2 (17%)
`2 (17%)
`6 (50%)
`6 (50%)
`5 (42%)
`3 (25%)
`
`10 (83%)
`7 (58%)
`4 (33%)
`5 (42%)
`1 (8%)
`5 (42%)
`1 (8%)
`4 (33%)
`9 (75%)
`9 (75%)
`6 (50%)
`5 (42%)
`
`Body as a whole
`Asthenia (tired, weak, heavy feeling)
`Headache
`Malaise
`Pain in abdomen
`Cardiovascular system
`Digestive system
`Dry mouth
`Nausea
`Vomiting
`Nervous system
`Dizziness (dizzy, lightheaded)
`Euphoria
`Somnolence (sleepy, drowsy, relaxed)
`Vasodilation (hot; hot flashes)
`Respiratory system
`Pharyngitis
`Rhinitis
`Skin and appendages
`Pruritus (itchy nose, face, all over)
`Special senses
`Taste perversion (bad, funny or metallic
`taste in back of throat or mouth)
`Vision abnormal
`2 (17%)
`Values (peromntuges} are the rumber ¢of aclerse events that were rated mild, moderate, or severe, and therelationship to the shidy drug was possible,
`probable, or highly probable.
`A subject was counted at most once for multiple occurrences of an adverse event.
`If a subject had more than one occurrence of an adverse event, only the occurrence with the strongest relationship was counted.
`
`1 (8%)
`1 (8%)
`1 (8%)
`
`7 (58%)
`7 (58%)
`
`3 (25%)
`2 (17%)
`1 (8%)
`3 (25%)
`2 (17%)
`5 (42%)
`5 (42%)
`
`Kest et al. (19) recently reviewed sex differences in
`opioid-induced analgesia and concluded that al-
`though many mechanisms have been explored,
`the
`commonly observed sex differences in opioid analge-
`sia have not been explained by differences in drug
`disposition. One possible contributing factor may be
`that the menin this study werelarger than the women
`(mean weights, 78 and 65 kg, respectively). Only one
`other study has examined sex differences of hydro-
`morphone pharmacokinetics, and it found that C,,..
`values averaged 25%higher in women compared with
`menafter single doses of 8-mg oral Dilaudid-IR. How-
`ever, AUC values were nearly identical between the
`two groups, and the difference in C,,,,. between the
`two groups was not considered to beclinically rele-
`vant (17). Further studies will be necessary to discern
`the contribution of drug disposition to analgesic ef-
`fects for hydromorphone.
`Our
`finding of apparently increasing troughs
`through 42 hours of repeated doses suggested that
`steady-state was not reached as early as expected.
`However, using the concentration at 6 hours after the
`M7dose as an additional trough level, we found that
`the concentrations were leveling off by 42-48 hours of
`dosing, and this is supportive of the hypothesis that
`steady-state had been attained. Steady-state should
`
`have been reached sooner, however, given a drug with
`a four- to five-hour half-life. A definitive interpreta-
`tion of the apparently increasing trough concentra-
`tions until Dose M7 and an AUC ratio (AUC)_,/
`AUC,_..) greater
`than unity is difficult without
`multiple IV dosing studies to compare absolute bio-
`availabilities and clearances upon repeated dosing.
`The greater AUC)_, of hydromorphoneafter multiple
`dosing may indicate a decrease in clearance (or an
`increase in bioavailability) upon repeated dosing.It is
`also possible that circadian variability in drug dispo-
`sition may have contributed to observed accumula-
`tion. For example, drug clearance may have decreased
`during the night, so trough levels before doses given
`at 2:00 and 8:00 am would be expected to be higher
`than those administered during the day. We did not
`continue the multiple-dose treatments long enough to
`evaluate whether such chronobiologic fluctuations oc-
`cur with intranasal delivery. Because the AUC,_, re-
`flects the extent of absorption, an increase in bioavail-
`ability with chronic dosing may have resulted from a
`physiologic response to repeated intranasal adminis-
`tration, but there is no evidence from nasal examina-
`tions to indicate that. In fact, the absenceofsignificant
`changes in t,,,, Values upon multiple dosing suggests
`that the nasal rate of absorption wasnotaltered upon
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`ANESTH ANALG
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`RUDYETAL.
`AMBULATORY ANESTHESIA
`MULTIPLE-DOSE PHARMACOKINETICS OF NASAL HYDROMORPHONE
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`repeated dosing. The influence of factors such as pos-
`ture, position of the head, and circadian variations in
`hepatic or nasal mucosal blood flow, metabolism, and
`drug absorption cannot be determined from this
`study. In our opinion, circadian variations in drug
`disposition or, simply, pharmacokinetic variability
`were the most probable causes of the larger average
`concentrationsin the early morning predose M7 blood
`sample and the nonunity ratios of AUC)_, for multi-
`ple doses to AUC)... after single doses.
`A simulation was performed to demonstrate how
`well the single-dose kinetics of hydromorphonepre-
`dicted multiple-dose plasma
`concentrations. As
`shown in Figure 2, the excellent agreement between
`the simulated and actual concentrations demonstrates
`predictable kinetics. The small difference between the
`actual peak and simulated peak steady-state levels
`appeared to be a result of the influence of a single
`patient’s unusually large plasma hydromorphone con-
`centrations. Manyfactors can influence the variability
`that would beseenfor intranasal dosing of hydromor-
`phone in practice. Thus,
`further
`investigation is
`needed to demonstrate whether our laboratory find-
`ings will translate to more consistency in clinical re-
`sults with intranasal administration compared with
`oral dosing.
`Given the variability in the pharmacokinetics of
`intranasal hydromorphone and pharmacodynamics
`of opioids in general, the interval for repeated dos-
`ing in acute pain must be determined on an indi-
`vidual basis, and further studies are necessary to
`determine optimum regimens. The pharmacokinet-
`ics of nasally administered hydromorphonesuggest
`that it may be appropriate for single or multiple
`dosing in acute situations when rapid onset is de-
`sired, rather than for chronic use, when sustained
`release preparations would be more appropriate. It
`is important to note that we did not determine the
`time course of pharmacodynamic effects such as
`analgesia, sedation, and respiratory depression and
`can propose dosing intervals based only on the
`pharmacokinetics of hydromorphone.
`The difference in peak-to-trough concentrations in
`this study (after repe