SYNOPSIS
`(PAGE 1 OF 5)
`
`
`
`Phase of Development: 1
`
`Treatment B
`50 mg naltrexone HCl
`Oral
`
`TEA442AB
`
`Single dose
`
`
`
`Company: ALZA Corporation
`Investigational Product: Naltrexone HCl 50 mg tablet
`and naltrexone HCl 1 mg solution
`Active ingredient: Naltrexone HCl
`Protocol No.: FEN-P01-102 CR003256
`Title: Pharmacokinetics of Naltrexone Hydrochloride Following Intravenous and Oral Routes
`of Administration in Healthy Subjects
`Investigator(s)/Study Center: Annemie Mertens, MD, AZ Jan Palfijn, Clinical Pharmacology
`Unit, Merksem, Belgium
`Publication (reference): none
`Study period:
`First subject treated: 2 June 2003
`Last subject completed: 13 June 2003
`Objective: To evaluate the pharmacokinetics of naltrexone hydrochloride (HCl) following
`intravenous and oral routes of administration in healthy subjects.
`Methodology: This was a single-center, randomized, open-label, 2-treatment, 2-period
`crossover study in healthy subjects. Subjects were randomly assigned to 1 of 2 treatment
`sequences (AB or BA) with a washout period of 6 to 14 days between treatments. The washout
`period commenced the day of dosing, after drug administration.
`Number of subjects (planned and analyzed): Planned n=18; Enrolled n=18; Completed n= 18
`Diagnosis and main criteria for inclusion: Healthy male or female subjects between 18 and
`45 years of age. All subjects had to provide written consent, have no history of or show the
`presence of drug or alcohol dependence or abuse, and meet inclusion/exclusion criteria.
`Test product, dose and mode of administration, batch number:
`Treatment
`Treatment A
`Dose
`1 mg naltrexone HCl
`Mode of administration
`Intravenously over 15
`minutes
`341982
`341734
`Single dose
`
`Duration of treatment
`Duration of trial
`11 days
`Reference therapy: IV administration was reference therapy for absolute bioavailability
`following oral administration.
`Criteria for evaluation:
`Pharmacokinetics: Blood samples were collected from all subjects at predose and at 0.08 (after
`IV only), 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 15.0, 22.0, 24.0, 26.0, 30.0,
`and 34.0 hours post dose administration. Blood samples were analyzed for serum naltrexone and
`6-β-naltrexol (naltrexone's major metabolite) concentrations.
`Safety: Adverse events (AEs) and vital signs (blood pressure, temperature, pulse, and
`respiratory rate) were monitored.
`
`Lot number
`
`
`
`AMN1038
`IPR of Patent No. 7,919,499
`
`

`

`SYNOPSIS
`(PAGE 2 of 5)
`
`
`
`Company: ALZA Corporation
`Investigational Product: Naltrexone HCl 50 mg tablet
`and naltrexone HCl 1 mg solution
`Active ingredient: Naltrexone HCl
`
`Statistical methods:
`Pharmacokinetic Measures: Descriptive statistics for the pharmacokinetic parameters (Cmax,
`Tmax, k, t1/2, AUCt, and AUCinf ) were calculated for each treatment for both naltrexone and its
`major metabolite, 6-β-naltrexol. Absolute bioavailability of naltrexone following the oral route
`of naltrexone administration was calculated for subjects who completed both treatments. The
`90% CIs for mean oral bioavailability are presented. Dose-normalized 6-β-naltrexol AUC ratios
`after IV and oral naltrexone treatments were calculated for subjects who completed both
`treatments, and the 90% CIs for the mean AUC ratios were presented. Serum 6-β-
`naltrexol/naltrexone concentration ratios at different time points and 6-β-naltrexol/naltrexone
`AUC ratios following naltrexone IV and oral treatments were also summarized.
`Safety Measures: Data were summarized and descriptive statistics were calculated.
`Pharmacokinetic results:
`Naltrexone: Mean (SD) values for serum naltrexone pharmacokinetic parameters are
`summarized below for both treatment periods. Following the IV infusion, as expected, peak
`serum naltrexone concentrations were observed in most subjects when the infusion was stopped
`at 15 minutes post-initiation. The decline in serum-concentration profile generally appears to be
`biexponential. The mean terminal half-life was 2.5 hours.
`After oral dosing, serum naltrexone concentrations rose fairly rapidly, reaching a peak
`concentration by 0.86 hours. Half-life values were greater after oral dosing (mean 5.8 hours)
`than those observed following IV treatment (mean 2.5 hours). Secondary peaks were observed
`between the 2- and 12-hour time points after oral dosing, possibly due to biliary recycling,
`which has been reported in the literature for naltrexone (Kleber 1985). Mean absolute
`bioavailability after oral administration was estimated to be 5.3%. The dose-normalized AUCinf
`ratio was estimated to be 4.9% using log-transformed values in the ANOVA model.
`
`
`
`
`AMN1038
`IPR of Patent No. 7,919,499
`
`

`

`SYNOPSIS
`(PAGE 3 OF 5)
`
`
`
`Reference
`
`Company: ALZA Corporation
`Investigational Product: Naltrexone HCl 50 mg tablet and
`naltrexone HCl 1 mg solution
`Active ingredient: Naltrexone HCl
`
`Pharmacokinetic results, continued:
`Mean (SD) Values for Serum Naltrexone Pharmacokinetic Parameters
`Treatment
`Naltrexone HCl 1 mg
`Naltrexone HCl 50 mg
`IV
`Oral
`(n=18)
`(n=18)
`11.26 (2.87)
`8.82 (3.9)
`0.25 (0.01)
`0.86 (0.5)
`2.5 (0.5)
`5.8 (2)
`8.01 (1.3)
`20.36 (6.87)
`8.05 (1.3)
`20.37 (6.87)
`8.07 (1.3)
`20.61 (7.04)
`Reference
`5.26 (2.2)
`4.4 - 6.2
`4.94
`4.3 - 5.7
`
`
`
`Parameter
`Cmax (ng/mL)
`Tmax (h)
`t1/2 (h)
`AUCt (ng·h/mL)
`AUC(0-34) (ng·h/mL)
`AUCinf (ng·h/mL)
`Mean % bioavailability (SD)
`90% confidence interval (CI)
`Dose-normalized AUCinf
`Ratio
`90% CI (Log scale using
`ANOVA model)
`
` A
`
` 2-compartment disposition model best described the observed IV naltrexone concentration-
`time profile. The estimates for clearance were similar for the compartmental (136 L/h) and the
`noncompartmental analyses (127 L/h). The estimates for V1 (central compartment) and Vss
`(steady state) were 44 and 216 L, respectively. For each subject, the estimated disposition
`parameters from the 2-compartment IV model were fixed and the absorption parameters were
`estimated for oral treatment: absorption rate constant [Ka] 1.17 hours-1, absorption lag time
`0.24 hours, and bioavailability 4.6%. The bioavailability estimate was similar following
`noncompartmental analysis.
`
`
`
`AMN1038
`IPR of Patent No. 7,919,499
`
`

`

`SYNOPSIS
`(PAGE 4 OF 5)
`
`
`
`Reference
`
`Company: ALZA Corporation
`Investigational Product: Naltrexone HCl 50 mg tablet and
`naltrexone HCl 1 mg solution
`Active ingredient: Naltrexone HCl
`
`Pharmacokinetic results, continued:
`6-β-Naltrexol: Mean (SD) values of the pharmacokinetic parameters for serum 6-β-naltrexol
`are summarized below for both treatment periods. The mean dose-normalized 6-β-naltrexol
`AUC ratio (oral/IV) was about 93%, indicating that the extent of metabolism from naltrexone to
`6-β-naltrexol is similar with both IV and oral treatments. The mean 6-β-naltrexol t1/2 value was
`about 11.4 hours, approximately 5 times that of naltrexone (2.5 hours) after IV administration.
`These results suggest that the elimination rate of 6-β-naltrexol is slower than its formation rate
`from naltrexone. As a result, the serum 6-β-naltrexol/naltrexone concentration ratios increase
`over time following naltrexone treatments. The 6-β-naltrexol/naltrexone AUC ratio was higher
`with oral than with IV treatment (40 vs 2.1, respectively), suggesting high first-pass metabolism
`of naltrexone following oral administration.
`Mean (SD) Values for Serum 6-β-naltrexol Pharmacokinetic Parameters
`Treatment
`Naltrexone HCl 1 mg
`Naltrexone HCl 50 mg
`IV
`Oral
`(n=18)
`(n=18)
`1.53 (0.52)
`122.56 (48.22)
`0.82 (0.7)
`0.94 (0.5)
`11.43 (3.07)
`11.71 (3.12)
`14.59 (3.39)
`677.31 (128.1)
`14.59 (3.39)
`677.31 (128.1)
`16.88 (3.97)
`775.71 (160.6)
`Reference
`93.1 (12)
`88.2 - 98.0
`92.38
`87.9 - 97.1
`
`
`
`Parameter
`Cmax (ng/mL)
`Tmax (h)
`t1/2 (h)
`AUCt (ng·h/mL)
`AUC(0-34) (ng·h/mL)
`AUCinf (ng·h/mL)
`Mean % dose-normalized
`AUC ratio (SD); 90% CI
`Dose-normalized AUCinf
`ratio; 90% CI (Log scale
`using ANOVA model)
`
`
`
`
`
`
`AMN1038
`IPR of Patent No. 7,919,499
`
`

`

`SYNOPSIS
`(PAGE 5 OF 5)
`
`
`
`Company: ALZA Corporation
`Investigational Product: Naltrexone HCl 50 mg tablet and
`naltrexone HCl 1 mg solution
`Active ingredient: Naltrexone HCl
`
`Safety results:
`No serious adverse events were reported in this study, and no subjects discontinued from the
`study. After each naltrexone treatment, 10 subjects (55.6%) reported at least 1 AE, and the AEs
`tended to be those known to be associated with naltrexone treatment. All but 1 of the AEs was
`of mild or moderate severity.
`Headache was the most frequently reported AE after naltrexone IV (6 subjects, 33.3%) or oral
`treatment (6 subjects, 33.3%). Other AEs reported by ≥10% of subjects were: dizziness (3,
`16.7%) and nausea, thirst, and rash (each 2, 11.1%) after naltrexone IV treatment, and nausea
`and dizziness (each 3, 16.7%) and asthenia and somnolence (each 2, 11.1%) after naltrexone
`oral treatment.
`Conclusions:
`Following IV administration of naltrexone, the serum naltrexone concentration decline appears
`to be biexponential with a mean half-life of 2.5 hours and total clearance of 127 L/h; the
`clearance estimate following compartmental analysis was similar. The estimates of V1 (central
`compartment) and Vss (steady state) were 44 and 216 L, respectively. After oral administration,
`the mean terminal half-life value (5.8 hours) was greater than that after IV administration. The
`mean absolute bioavailability values from noncompartmental and compartmental analyses were
`estimated to be 5.3% and 4.6%, respectively.
`The extent of metabolism from naltrexone to 6-β-naltrexol was similar with IV and oral
`treatments. 6-β-naltrexol's longer half-life (11.4 hours) compared with that of naltrexone after
`naltrexone IV administration suggests that the elimination rate of the metabolite is slower
`than its formation rate from naltrexone. The 6-β-naltrexol/naltrexone AUC ratio was higher
`with oral than with IV administration, suggesting high first-pass metabolism of naltrexone
`following oral administration.
`Both intravenous and oral administrations of naltrexone were well tolerated and no new safety
`issues were identified in the study population.
`Date of the report: 3 November 2003
`
`
`
`
`AMN1038
`IPR of Patent No. 7,919,499
`
`

`

`Disclaimer
`
`Information in this posting shall not be considered to be a claim for any marketed
`product. Some information in this posting may differ from, or not be included in,
`the approved labeling for the product. Please refer to the full prescribing
`information for indications and proper use of the product.
`
`
`AMN1038
`IPR of Patent No. 7,919,499
`
`