Drug Development and Industrial Pharmacy, 25(3), 353–356 (1999)
`
`COMMUNICATION
`
`Comparative Bioavailability Study of a
`Generic Naltrexone Tablet Preparation
`
`Kah Hay Yuen,* Kok Khiang Peh, and Nashiru Billa
`
`SchoolofPharmaceuticalSciences,UniversityofScienceMalaysia,
`11800Penang,Malaysia
`
`ABSTRACT
`
`The bioavailability of a generic preparation of naltrexone (Narpan) was compared
`with the innovator product, Trexan. Twelve healthy volunteers participated in the
`study, conducted according to a completely randomized, two-way crossover design.
`The preparations were compared using the parameters area under the plasma con-
`centration–time curve AUC0–∞, peak plasma concentration Cmax, and time to reach
`peak plasma concentration Tmax. No statistically significant difference was observed
`between the logarithmic transformed AUC0–∞and the logarithmically transformed
`Cmax values of the two preparations. Also, no statistically significant difference was
`observed between the untransformed Tmax values. In addition, the 90% confidence
`interval for the ratio of the logarithmic transformed AUC0–∞values of Narpan over
`those of Trexan was found to lie between 0.87 and 1.01, while that of the logarithmic
`transformed Cmax values was between 0.94 and 1.23, both being within the bioequiva-
`lence limit of 0.80–1.25. The numerical values of the elimination half-life (t1/2) ob-
`tained with the two preparations were also not significantly different and were com-
`parable to those reported in the literature.
`
`INTRODUCTION
`
`Naltrexone is a long-acting, potent, and nonaddictive
`narcotic antagonist (1–3) suggested for the treatment of
`narcotic addiction (1). When administered orally, only
`approximately 40% of the dose is bioavailable, attribut-
`able to its high first-pass metabolism (4). The expiration
`
`of its patent has prompted manufacturing of generic ver-
`sions of the drug. However, it is essential that the generic
`preparations have similar bioavailability characteristics
`to the innovator preparation before they can be safely
`used as a substitute for it.
`Therefore, the present study was conducted to com-
`pare the bioavailability of Narpan, a local generic prepa-
`
`* To whom correspondence should be addressed.
`
`353
`
`Copyright © 1999 by Marcel Dekker, Inc.
`
`www.dekker.com
`
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`

`Yuen, Peh, and Billa
`
`Pharmacokinetic Analysis
`
`The two preparations were compared using the param-
`eters peak plasma concentration Cmax, time to reach peak
`plasma concentration Tmax, and area under the plasma
`concentration–time curve AUC0–∞, estimated from the
`plasma concentration–time profiles of the two prepara-
`tions. Both Cmax and Tmax were obtained directly from
`the plasma data, while the AUC0–∞ was calculated by
`adding the area from time zero to the last sampling time t
`(AUC0–t) and the area from time t to infinity (AUCt–∞).
`The former was calculated using the trapezoidal formula
`and the latter by dividing the last measurable plasma drug
`concentration by the elimination rate constant ke. The ke
`was estimated from the terminal slope of the plasma con-
`centration–time curve after logarithmic transformation
`and application of linear regression (6), while the elimi-
`nation half-life t1/2 was calculated using ln 2/ke. For each
`of the parameters (AUC0-4, Cmax, andt 1/2), the values ob-
`tained for the two preparations were analyzed statistically
`using an analysis of variance (ANOVA) procedure ap-
`propriate for the study design (7). The AUC0–∞ and Cmax
`values were logarithmically transformed prior to the sta-
`tistical analysis. On the other hand, the Tmax values were
`analyzed using the Wilcoxon signed-rank test for paired
`samples. A statistically significant difference was consid-
`ered at p ⬍ .05.
`
`RESULTS AND DISCUSSION
`
`The mean plasma concentration–time curves of nal-
`trexone obtained with Narpan and Trexan are shown in
`Fig. 1. Although the mean peak plasma concentration of
`
`354
`
`ration of naltrexone, with that of the innovator prepara-
`tion, Trexan. In addition, an attempt was also made to
`study the pharmacokinetics of naltrexone in the local
`population of Asian origin, which have not been investi-
`gated.
`
`MATERIALS AND METHODS
`Products Studied
`
`Narpan (50 mg naltrexone HCl) tablets (batch no.
`95253A, manufacturing date August 1995, expiration
`date August 1998) were manufactured by Duopharma,
`Malaysia. Trexan (50 mg naltrexone HCl) tablets (lot no.
`KA006A, manufacturing date July 1995, expiration date
`July 1998, registration no. PBKD/930054A) were manu-
`factured by Du Pont (United States). Both naltrexone and
`naloxone HCl standards were obtained from Diosynth
`BV, The Netherlands.
`
`Study Design
`
`The study protocol was approved by an ethics commit-
`tee. After providing written informed consent, 12 healthy
`adult male volunteers between 21 and 43 years old (mean
`⫽ 34 years, SD ⫽ 7 years) and weighing from 54 to 76
`kg (mean ⫽ 65 kg, SD ⫽ 7 kg) participated in the study.
`All were judged to be healthy and were not receiving any
`medication during the study period. The protocol used
`was a conventional, two-way, split groups, crossover
`study with 6 subjects in each of the two treatment groups
`and a washout period of 1 week. The volunteers were
`selected randomly to receive two tablets (100 mg) of
`Trexan or Narpan. Both preparations were administered
`with 150 ml of water in the morning at 10:00 a.m. after
`a 12-hr overnight fast. Food and drinks were withheld
`for at least 2 hr after dosing. Lunch and dinner of chicken
`with rice were served at 4 and 9 hr after dosing, respec-
`tively, and water was given ad libitum. Blood samples
`of 5 ml volume were collected in vacutainers (containing
`sodium heparin as an anticoagulant) at 0 (predose), 15
`min, 30 min, 45 min and 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and
`24 hr after dosing. The blood samples were centrifuged
`for 15 min at 3500 rpm, and the plasma was transferred to
`separate glass containers to be kept frozen until analysis.
`
`Analysis of Plasma Naltrexone
`Concentration
`
`The plasma samples were analyzed using a reversed-
`phase high-performance liquid chromatographic (HPLC)
`method described by Peh, Billa, and Yuen (5).
`
`Figure 1. Mean plasma naltrexone concentration versus time
`curves of Narpan and Trexan (mean ⫾ SD, N ⫽ 12).
`
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`Comparative Bioavailability of Naltrexone Tablet
`
`Table 1
`Numerical Values of Tmax, Cmax, AUC0–∞, and t1/2
`Trexan
`
`Narpan
`
`Subjects
`
`MN
`BN
`SD
`MD
`CM
`RV
`MA
`HM
`SV
`YS
`AD
`WT
`Mean
`SD
`
`Tmax
`(hr)
`
`0.25
`0.25
`0.75
`0.50
`1.00
`0.50
`1.50
`0.75
`1.50
`0.50
`0.50
`0.75
`0.73
`0.42
`
`Cmax
`(ng/ml)
`
`31.78
`10.11
`14.50
`26.24
`13.62
`34.07
`14.74
`10.53
`16.90
`19.68
`37.38
`12.66
`20.18
`9.66
`
`AUC0–∞
`(hr ⋅ ng/ml)
`50.87
`58.09
`61.77
`69.72
`90.00
`124.68
`46.50
`54.17
`74.15
`51.75
`82.87
`46.77
`67.61
`22.87
`
`t1/2
`(hr)
`
`2.4
`2.9
`3.5
`3.7
`3.7
`3.4
`3.3
`4.3
`3.2
`2.8
`4.5
`3.5
`3.4
`0.6
`
`Tmax
`(hr)
`
`0.25
`0.75
`0.50
`0.50
`0.50
`0.25
`1.00
`0.50
`1.00
`0.50
`1.00
`0.75
`0.63
`0.27
`
`Cmax
`(ng/ml)
`
`22.20
`8.60
`20.56
`26.98
`16.84
`48.60
`11.22
`13.14
`21.04
`22.84
`34.71
`15.81
`21.88
`11.02
`
`AUC0–∞
`(hr ⋅ ng/ml)
`42.02
`58.80
`48.07
`65.02
`82.21
`127.52
`36.64
`55.50
`68.46
`47.14
`103.44
`44.10
`64.91
`27.30
`
`355
`
`t1/2
`(hr)
`
`2.4
`3.2
`2.7
`3.7
`4.6
`4.6
`3.7
`3.9
`3.9
`3.0
`5.1
`3.2
`3.7
`0.8
`
`Narpan was observed to be slightly higher than that of
`Trexan, the two plots appeared to be almost superimpos-
`able. Both products achieved rapid absorption, producing
`peak plasma concentrations at approximately 1 hr after
`dosing, and no lag time in absorption was observed.
`Table 1 gives the individual values of Tmax, Cmax, and
`AUC0–∞ obtained with Trexan and Narpan. No statisti-
`cally significant difference (p ⬎ .10) was obtained be-
`tween the Tmax values of Trexan (0.73 ⫾ 0.42 hr) and
`Narpan (0.63 ⫾ 0.27 hr). Also, the values obtained are
`in good agreement with those reported by other workers
`(8,9). It can also be seen from Table 1 that the mean Cmax
`and AUC0–∞ values of Narpan were comparable to those
`of Trexan. No statistically significant difference was ob-
`served between the logarithmically transformed Cmax (p
`⫽ .3321) and the logarithmically transformed AUC0–∞
`(p ⫽ .1204) values of the two preparations. In addition,
`the 90% confidence interval for the ratio of the logarith-
`mically transformed AUC0–∞ values of Narpan over those
`of Trexan was found to lie between 0.87 and 1.01, while
`that of the logarithmically transformed Cmax values was
`between 0.94 and 1.23, both being within the acceptable
`bioequivalence limit of 0.80–1.25 (10,11).
`Relatively wide intersubject variation was observed in
`the numerical values of the pharmacokinetic parameters
`AUC and Cmax, which can be attributed to differences in
`body weight and drug disposition among the volunteers.
`However, the intrasubject variability of the parameter
`AUC was relatively small. When estimated using the
`mean square error obtained from the ANOVA analysis
`
`(12), the coefficient of variation was estimated to be
`9.4%. Based on this value, 12 volunteers were found to
`be sufficient to provide a power (1 – β) of greater than
`80% for detecting a statistically significant difference in
`AUC between the two products at a type 1 error rate (α)
`of 0.05 if the true difference is equal to or greater than
`20% (13). A power of approximately 80% was also ob-
`tainable with the parameter Cmax under the same condi-
`tions. Sioufi et al. (14) have also reported that 12 volun-
`teers were sufficient
`to provide an 80% power in
`detecting a difference in the AUC of greater than 16% in
`their study.
`The numerical values of the pharmacokinetic parame-
`ter t1/2 of the two preparations are given in Table 1. The
`mean values of the two preparations were closely similar
`and not significantly different statistically (p ⫽ .2084).
`Also, the values, which varied between 2.4 and 5.1 hr
`with a mean of 3.5 hr (Table 1), were comparable to those
`reported in the literature (9,15).
`
`CONCLUSION
`
`In conclusion, Narpan was found to be comparable
`to Trexan in both the rate and extent of bioavailability.
`Moreover, the numerical values of the parameter t1/2 esti-
`mated from administration of the two products were not
`significantly different and were comparable to those re-
`ported in the literature.
`
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`356
`
`REFERENCES
`
`1. National Clearinghouse for Drug Abuse Information,
`Fact Sheet on Naltrexone, Series 38(1), National Institute
`on Drug Abuse, Rockville, MD, December 1978.
`2. W. R. Martin and D. R. Jasinki, Clin. Pharm. Ther., 14,
`142 (1973).
`3. S. Taylor, R. Rodgers, R. Lynn, and N. Gerber, J. Phar-
`macol. Exp. Ther., 213, 289 (1980).
`4. M. E. Wall, D. R. Brian, and M. Perez-Reyes, Drug
`Metab. Disposition, 9, 370 (1981).
`5. K. K. Peh, N. Billa, and K. H. Yuen, J. Chromatogr. B,
`701, 140 (1997).
`6. M. Gibaldi and D. Perrier, Pharmacokinetics, 2nd ed.,
`Marcel Dekker, New York, 1982, p. 145.
`J. G. Wagner, in Fundamentals of Clinical Pharmacoki-
`netics, 1st ed., Drug Intelligence Publication, Hamilton,
`IL, 1975, p. 285.
`8. K. Verebey, J. Volavka, S. J. Mule, and R. B. Resnick,
`Clin. Pharmacol. Ther., 20, 315 (1980).
`
`7.
`
`Yuen, Peh, and Billa
`
`9. U.S. Pharmacopoeial Convention, USP D1, in Drug In-
`formation for the Health Care Professional, 14th ed., Au-
`thor, Rockville, MD, 1994, p. 1982.
`10. W. J. Westlake, in Biopharmaceutical Statistics for Drug
`Development (K. E. Peace, ed.), Marcel Dekker, New
`York, 1988, p. 329.
`11. U.S. Pharmacopoeial Convention, The United States
`Pharmacopoeia XXXIII, Author, Rockville, MD,
`1995.
`12. E. Diletti, D. Haushcke, and V. W. Steinijans, Int. J. Clin.
`Pharmacol. Ther. Toxicol., 29, 1 (1991).
`13. D. L. Weiner, in Statistics in the Pharmaceutical Industry
`(C. R. Buncher and J. Y. Tsay, eds.), Marcel Dekker, New
`York, 1981, p. 205.
`14. A. Sioufi, N. Sandrenan, J. Godbillon, P. Trunet, C.
`Czendlik, H. Howald, Ch. Pfister, and F. Ezzet, Bio-
`pharm. Drug Disp., 18(6), 489 (1997).
`15. C. N. Chiang, L. E. Hollister, A. Kishimoto, and
`G. Barnett, Clin.
`Pharmacol. Ther.,
`36,
`704
`(1984).
`
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`IPR2018-00943
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`Copyright© 2002 EBSCO Publishing
`
`AMN1088
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
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