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Relative Bioavailability of Rimantadine HCI Tablet and Syrup Formulations in Healthy Subjects
Relative Bioavailability of Rimantadine HCI Tablet and Syrup Formulations in Healthy Subjects ROBERT J. WILLS", NADIA CHÔMA, GERARD BUONPANE, A M Y LIN, AND NANCY KEIGHER
Received April 23,1987, from Hoffmann-La Roche, Inc., Nutley, NJ 07110. Abstract D Twenty healthy male subjects completed an open-label randomized crossover design to assess the bioavailability of 100 mg of rimantadine HCI in tablet and syrup forms relative to an oral solution. Blood samples were drawn and rimantadine plasma concentrations were determined by a GC-MS method. The maximum plasma concen tration (Cmax), the time to Cm« (im«), the area under the plasma concentration-time curve (AUC), and k were compared among treat ments using an analysis of variance and the Hauck-Anderson test for bioequivalence. The Hauck-Anderson test was satisfied when the syrup and solution were compared. The relative bioavailability of the syrup was 96%. Both Cm4x and AUC were significantly (p < 0.05) increased (23 and 17%, respectively) when the tablet was compared with the solution. The relative bioavailability of the tablet was 117%. This outcome was unusual and could not be explained. However, this was not anticipated to be of clinical consequence since the majority of the safety and efficacy ofrimantadineHCI was established using a tablet.
Rimantadine (a-methyl-1-adamantanemethylamine hydrochloride), an analogue of amantadine with more potent antiviral activity, 1 · 2 is currently being evaluated for prophy laxis and treatment against influenza-A viral infections. 3 - 9 To date, little pharmacokinetic information has been pub lished. Hayden et al. 10 reported on the pharmacokinetics of rimantadine following a single 200-mg dose in both young and elderly adults. No age-related alterations in the disposi tion of rimantadine were evident. Maximum concentrations ranged from 170 to 340 ng/mL at 2-10 h. The elimination half-life ranged from 19 to 64 h. On average, <10% of the dose was excreted unchanged with a renal clearance of 75 mL/min. Anderson et al. 11 assessed the pharmacokinetics of rimantadine in 10 healthy pédiatrie subjects ( 4 - 8 years) following an oral dose of 6.6 mg/kg administered as a syrup. The pharmacokinetic profile, adjusting for dose, was similar to that reported in adults. 10 Two other reports 5 · 12 contained serum concentrations drawn at a single point in time per patient during a multiple-dose regimen in nursing home patients 5 and hospitalized infants. 12 It is clear that children, adults, and the elderly are all likely to receive rimantadine HCI, either for prophylaxis or treatment. Two dosage forms, a tablet and a syrup, have been formulated for use in all populations. However, information regarding the relative bioavailability of these formulations has not been reported. The present study was conducted to determine the relative bioavailability of the tablet and syrup following single doses to healthy adults.
Experimental Section Subjects—Twenty healthy male subjects between the ages of 18 and 43 years and within +10% of ideal body weight completed the study. The subjects demonstrated good general health as determined by baseline history, physical examination including an electrocar diogram, a complete blood count, a platelet count, serum chemistries, and a urinalysis. Subjects with clinically significant abnormal base line findings, or who had a significant history of gastrointestinal, renal, hepatic, pulmonary, cardiac, hématologie, endocrinologie, or 886 / Journal of Pharmaceutical Sciences Vol. 76, No. 12, December 1987
Accepted for publication July 30,1987.
CNS disease were excluded. Subjects who had taken any medication, either prescription or over-the-counter, within three weeks of initia tion of the study or who anticipated the need for such medication during the course of the study were ineligible for participation. Volunteers with a history of drug or alcohol abuse or a history of hypersensitivity to adamantanes were also excluded. In addition, alcohol was excluded for 72 h prior to drug administration and for 120 h after each drug administration. The protocol was approved by the Investigational Review Board at Hazleton Laboratories America, Inc., and subjects gave written, informed consent to participate in the study. Study Design—Subjects reported to the Research Unit 12 h prior to treatment. Ten hours prior to treatment, a light snack was served after which all subjects fasted until dosing. In the morning, each subject received either a single 100-mg tablet of rimantadine HCI (Flumadine, lot no. 143466) with 240 mL of water, 10 mL of a syrup containing 10 mg/mL of rimantadine HCI (Flumadine, lot no. 143766) followed by two 115-mL water washings of the dispensing cup, or 100 mg of rimantadine HCI in 30 mL of water followed by two 105-mL water washings of the dispensing bottle according to an open-label, four-way randomized crossover design. All solutions were administered at room temperature. The fourth treatment involved an experimental formulation which is not being presented herein. Water was permitted ad libitum until dosing, then withheld until the 4-h blood sample was obtained. Subjects remained seated or ambulatory for at least 4 h after dosing. After collection of the 4-h sample, lunch was served followed by an absolute fast except for water. Dinner was served 10 h after drug administration. All blood samples were obtained through an indwelling catheter placed in the arm or by venipuncture. Ten-milliliter blood samples were drawn into heparinized vacutainer tubes prior to the drug administration and at 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, and 120 h post dose. The subjects remained under observation for 24 h after each dose and any adverse experiences were recorded. Subjects reported to the study site for withdrawal of the remaining blood samples. Sitting blood pressure and pulse were measured 2,12, and 24 h after administration of each treatment. A two-week period separated treatments. The physical examination, ECG, and labora tory determinations which were performed for entry into the study were repeated within one week of completion of the study. Rimantadine Assay—Plasma concentrations of rimantadine free base were determined by GC-MS.13 The calibration range was 4.2 to 416 ng/mL. The overall coefficient of variation for interassay preci sion was 5.4%, and the mean coefficient of variation for intra-assay precision was 8.3%. Data Analysis—Pharmacokinetic parameters were determined from the plasma concentration-time data and used to assess the relative bioavailability of 100-mg tablets and syrup of rimantadine-HCl compared with an oral solution. The maximum concentration (Cm«) and the time to reach the maximum concentration (*„„„) were read directly from the plasma concentration-time data. The appar ent terminal elimination rate constant, k, was calculated using leastsquares regression analysis on the terminal portion of the log plasma concentration-time profile. The terminal half-life Um) was calculat ed by dividing In 2 by k. The areas under the plasma concentrationtime curve from time zero to the time of the last measurable plasma concentration point (AUC,) were calculated using linear trapezoidal summation. Extrapolation to time infinity (AUC) was determined by dividing the last measurable plasma concentration point by k and adding the result to the corresponding AUC,. Statistical Analysis—Each bioavailability parameter was ana lyzed separately. In each case, an analysis of variance of the raw data 0022-3549/87/1200-0886$01.00/0 © 1987, American Pharmaceutical Association
was performed accounting for the effects of subjects, treatments, time periods, and possible carryover effects from the preceding treatment. Sequence effects were not included because no two subjects had the same sequence of treatment administration. The four values of a given parameter for each participant were subjected to an analysis of variance (ANOVA) using a model taken from Hedayat and Afsarinejad.14 Pairwise comparisons between treatments were made where appropriate. In addition, the Hauck-Anderson test16 for bioequivalency was performed on each parameter.
Results Clinical—There were no adverse experiences reported oth er than one incidence of headache. Subject 12 was dropped from the study after failing to show up for the third interval. Subject 12A replaced Subject 12 and completed the study under the same treatment sequence as Subject 12. Overall, rimantadine was well tolerated in these subjects. Relative Bioavailability—Mean plasma concentrations are presented in Figure 1. The pharmacokinetic parameters and the statistical results from the ANOVA and the HauckAnderson bioequivalency tests are found in Table I. The pharmacokinetic parameters C max and AUC of riman tadine following the administration of a 100-mg tablet were significantly increased (p < 0.05) over the corresponding values following administration of a 100-mg solution (Table I). There were no significant differences in i max and k values. There were no significant carryover effects and the power to detect a 20% difference was 76 and 71% for C max and AUC, respectively. The mean C max and AUC following the admin istration of the tablet were, respectively, 23 and 17% greater than the corresponding values of the solution. This suggests a bioavailability of 117% from the tablet relative to that from a solution, based on AUC. In addition, the Hauck-Anderson test suggested that neither C max nor AUC could be consid ered equivalent. The power of this test was 71 and 63% for Cmax and AUC, respectively. There were no significant differences between C max , i max , AUC, and k values when comparing the 10 mL of a 10-mg/mL syrup with a 100-mg dose of solution (Table I). The mean Cmax and AUC following the administration of the syrup were 1% and 4% less, respectively, than the corresponding values of the solution, suggesting a bioavailability of 96% from the syrup relative to a solution. Both C max and AUC were considered to be equivalent according to the Hauck-
>ς
Anderson test.
Discussion This study was designed to determine the relative bioavail ability of a tablet and a syrup formulation compared with a solution following single 100-mg doses in healthy subjects. The relative bioavailability of the tablet exceeded that of the solution by 17%. This could not be explained by correcting for salt content, since the dose of each form was based on 100 mg of the HC1 salt, nor could this be explained by overage in the tablet which did not exceed 1%. The dissolution of the tablet was relatively fast, 100% in 30 min using the USP method II in water. Rimantadine HC1 solubility in water was >50 mg/mL at 25 °C. Mass balance recovery of rimantadine and t1 nü]rimantadine from a single 200-mg dose containing 54.8 /¿Ci of 14C-labeled rimantadine indicated complete absorp tion from the oral route.16 However, an apparent plasma clearance of 500 mL/min in humans and a 30-40% first-pass effect in dogs would suggest a moderate first-pass effect in humans. In this present study, the similarity in i max between the tablet and solution, along with the fast dissolution of the tablet relative to a ¿max of 5 h, would not readily support an explanation due to a first-pass effect, although it is conceiv able that some component of the tablet may be reducing the intrinsic oral clearance. The outcome was unusual and could Table l·—Pharmacokinetic Parameters"following Administration of a Single 100-mg Dose of Rimantadine HCI as a Tablet, Syrup, and Solution Parameter
Tablet
Cmax. ng/mL
Syrup 70 (26) 43-109 6(17) 3—8 2910 (34) c 1220-5010 0.0273 (35) 0.0118-0.0454 25.4" 15.3-58.7
86 (38) " 43-192 5(28) 3—8 3540 (47)" 1580-9250 0.0278 (33) 0.0118-0.0487 25 " 14.2-58.7
tnax, h AUC, ng-h-mL" If, 1/h f
vs· n
Solution c
70 (23) 46-92 6(21) 3—8 3020 (36) 1701-4810 0.0266 (30) 0.0145-0.0405 26.1 d 17.1-47.8
"Mean (± %CV) and range. "Significantly different from solution (p < 0.05) according to ANOVA. c Bioequivalent to solution (p < 0.05) according to Hauck-Anderson. ^Harmonic mean.
no
1,00 (J
z o o < 2
CO
< z o Í z < "l 10
1 20
1 30
I 40
1 1 BO 8 0
1 70
_!
1 r BO 80 100
0
10
!
!
r
!
20
30
40
60
j
1
BO 70
p
ΘΟ 90 100
TIME (hrs) Figure λ—Left Panel: mean ± SD of rimantadine plasma concentrations versus time after administration of the 100-mg tablet (■) and 100-mg solution ( · ) to 20 subjects. Right Panel: mean ± SD of rimantadine plasma concentrations versus time after administration of 100 mg of syrup (A) and a 100-mg solution ( · ) to 20 subjects.
Journal of Pharmaceutical Sciences Vol. 76, No. 12, December 1987
887
not be readily explained. Overall, this was not anticipated to be óf clinical consequence since the majority of the safety and efficacy of rimantadine HC1 was established using a tablet. The mean plasma concentration-time profiles of the syrup and solution were superimposable (Figure 1). The statistical analyses showed no significant differences between the re spective parameters for the syrup and solution. The bioavailability of syrup was 96% relative to the solution. The pharmacokinetic profiles reported herein compared favorably with that reported by Hayden et al. 10 and by Anderson et al." after adjusting the necessary parameters for dose. In those studies, maximum concentrations were reached on average in 5 and 6 h, with elimination half-lives averaging 37 and 25 h, respectively. Elimination half-lives averaged 25 to 26 h in this study, independent of formulation. In conclusion, the bioavailability of the tablet and syrup was 117% and 96% relative to a solution following a single 100-mg dose to healthy adults. In addition, rimantadine was well tolerated in these subjects.
References and Notes 1. Hayden, F. G.; Cote, K. M.; Douglas, R. G., Jr. Antimicrob. Agents Chemother. 1980,17, 865-870. 2. Indulin, M. K.; Kalninya, V. A. In Development in Antiviral Therapy; Collier, L. H.; Oxford, J. S., Eds., Academic: London, 1980; pp 107-108.
888 / Journal of Pharmaceutical Sciences Vol. 76, No. 12, December 1987
3. Dawkins, A. T., Jr.; Gallager, L. R.; Togo, Y.; Hornick, R. B.; Harris, B. A. JAMA 1968,203,1095-1099. 4. Dolin, R.; Reichman, R. C; Madore, H. P.; Maynard, R.; Union, P. N.; Weber-Jones, J. N. Eng. J. Med. 1982,307, 580-584. 5. Patriarca, P. A.; Kater, N. A.; Kendal, A. P.; Bregman, D. J.; Smith, J. D.; Sikes, R. K. Antimicrob. Agents Chemother. 1984, 26,101-103. 6. Quarles, J. M.; Couch, R. B.; Cate, T. R.; Goswick, C. B. Antivi ral Res. 1981, i, 149-155. 7. Rabinovich, S.; Baldini, J. T.; Bannister, R. Am. J. Med. Sei. 1969,257,328-335. 8. Van Voris, L. P.; Betts, R. F.; Hayden, F. G.; Christman, W. A.; Douglas, R. G., Jr. JAMA 1981,245, 1128-1131. 9. Wingfield, W. L.; Pollack, D.; Grunert, R. R. N. Eng. J. Med. 1969,281, 579-584. 10. Hayden, F. G.; Minocha, A.; Spyker, D. A.; Hoffman, H. E. Antimicrob. Agents Chemother. 1985, 28, 216-221. 11. Anderson, E. L.; Belshe, R. B.; Hoffman, H. E. In Recent Ad vances in Chemotherapy: Antimicrobial Section 3; Ishigami, J., Ed., University of Tokyo: Tokyo, 1985; pp 1955-1956. 12. Nahata, M. C; Brady, M. T. Ear. J. Clin. Pharmacol. 1986,30, 719—722 13. Fukuda, E. K.; Rodriguez, L. C; Chôma, N.; Keigher, N.; DeGrazia, F.; Garland, W. A. Biomed. Environ. Mass Spectrom. 1987, in press. 14. Hedayat, A.; Afsrinejad, K. Ann. Stat. 1978, 6, 619-628. 15. Hauck, W. W.; Anderson, S. J. Pharmacokinet. Biopharm. 1984, 12, 83-91. 16. Wills, R. J., unpublished results.
Acknowledgments The authors thank Dr. Marion Oakes for her safety evaluation, Mr. Roy Bloch for his technical assistance, and Ms. Patricia Seymore for her assistance in the preparation of this manuscript.
Received April 23,1987, from Hoffmann-La Roche, Inc., Nutley, NJ 07110. Abstract D Twenty healthy male subjects completed an open-label randomized crossover design to assess the bioavailability of 100 mg of rimantadine HCI in tablet and syrup forms relative to an oral solution. Blood samples were drawn and rimantadine plasma concentrations were determined by a GC-MS method. The maximum plasma concen tration (Cmax), the time to Cm« (im«), the area under the plasma concentration-time curve (AUC), and k were compared among treat ments using an analysis of variance and the Hauck-Anderson test for bioequivalence. The Hauck-Anderson test was satisfied when the syrup and solution were compared. The relative bioavailability of the syrup was 96%. Both Cm4x and AUC were significantly (p < 0.05) increased (23 and 17%, respectively) when the tablet was compared with the solution. The relative bioavailability of the tablet was 117%. This outcome was unusual and could not be explained. However, this was not anticipated to be of clinical consequence since the majority of the safety and efficacy ofrimantadineHCI was established using a tablet.
Rimantadine (a-methyl-1-adamantanemethylamine hydrochloride), an analogue of amantadine with more potent antiviral activity, 1 · 2 is currently being evaluated for prophy laxis and treatment against influenza-A viral infections. 3 - 9 To date, little pharmacokinetic information has been pub lished. Hayden et al. 10 reported on the pharmacokinetics of rimantadine following a single 200-mg dose in both young and elderly adults. No age-related alterations in the disposi tion of rimantadine were evident. Maximum concentrations ranged from 170 to 340 ng/mL at 2-10 h. The elimination half-life ranged from 19 to 64 h. On average, <10% of the dose was excreted unchanged with a renal clearance of 75 mL/min. Anderson et al. 11 assessed the pharmacokinetics of rimantadine in 10 healthy pédiatrie subjects ( 4 - 8 years) following an oral dose of 6.6 mg/kg administered as a syrup. The pharmacokinetic profile, adjusting for dose, was similar to that reported in adults. 10 Two other reports 5 · 12 contained serum concentrations drawn at a single point in time per patient during a multiple-dose regimen in nursing home patients 5 and hospitalized infants. 12 It is clear that children, adults, and the elderly are all likely to receive rimantadine HCI, either for prophylaxis or treatment. Two dosage forms, a tablet and a syrup, have been formulated for use in all populations. However, information regarding the relative bioavailability of these formulations has not been reported. The present study was conducted to determine the relative bioavailability of the tablet and syrup following single doses to healthy adults.
Experimental Section Subjects—Twenty healthy male subjects between the ages of 18 and 43 years and within +10% of ideal body weight completed the study. The subjects demonstrated good general health as determined by baseline history, physical examination including an electrocar diogram, a complete blood count, a platelet count, serum chemistries, and a urinalysis. Subjects with clinically significant abnormal base line findings, or who had a significant history of gastrointestinal, renal, hepatic, pulmonary, cardiac, hématologie, endocrinologie, or 886 / Journal of Pharmaceutical Sciences Vol. 76, No. 12, December 1987
Accepted for publication July 30,1987.
CNS disease were excluded. Subjects who had taken any medication, either prescription or over-the-counter, within three weeks of initia tion of the study or who anticipated the need for such medication during the course of the study were ineligible for participation. Volunteers with a history of drug or alcohol abuse or a history of hypersensitivity to adamantanes were also excluded. In addition, alcohol was excluded for 72 h prior to drug administration and for 120 h after each drug administration. The protocol was approved by the Investigational Review Board at Hazleton Laboratories America, Inc., and subjects gave written, informed consent to participate in the study. Study Design—Subjects reported to the Research Unit 12 h prior to treatment. Ten hours prior to treatment, a light snack was served after which all subjects fasted until dosing. In the morning, each subject received either a single 100-mg tablet of rimantadine HCI (Flumadine, lot no. 143466) with 240 mL of water, 10 mL of a syrup containing 10 mg/mL of rimantadine HCI (Flumadine, lot no. 143766) followed by two 115-mL water washings of the dispensing cup, or 100 mg of rimantadine HCI in 30 mL of water followed by two 105-mL water washings of the dispensing bottle according to an open-label, four-way randomized crossover design. All solutions were administered at room temperature. The fourth treatment involved an experimental formulation which is not being presented herein. Water was permitted ad libitum until dosing, then withheld until the 4-h blood sample was obtained. Subjects remained seated or ambulatory for at least 4 h after dosing. After collection of the 4-h sample, lunch was served followed by an absolute fast except for water. Dinner was served 10 h after drug administration. All blood samples were obtained through an indwelling catheter placed in the arm or by venipuncture. Ten-milliliter blood samples were drawn into heparinized vacutainer tubes prior to the drug administration and at 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, and 120 h post dose. The subjects remained under observation for 24 h after each dose and any adverse experiences were recorded. Subjects reported to the study site for withdrawal of the remaining blood samples. Sitting blood pressure and pulse were measured 2,12, and 24 h after administration of each treatment. A two-week period separated treatments. The physical examination, ECG, and labora tory determinations which were performed for entry into the study were repeated within one week of completion of the study. Rimantadine Assay—Plasma concentrations of rimantadine free base were determined by GC-MS.13 The calibration range was 4.2 to 416 ng/mL. The overall coefficient of variation for interassay preci sion was 5.4%, and the mean coefficient of variation for intra-assay precision was 8.3%. Data Analysis—Pharmacokinetic parameters were determined from the plasma concentration-time data and used to assess the relative bioavailability of 100-mg tablets and syrup of rimantadine-HCl compared with an oral solution. The maximum concentration (Cm«) and the time to reach the maximum concentration (*„„„) were read directly from the plasma concentration-time data. The appar ent terminal elimination rate constant, k, was calculated using leastsquares regression analysis on the terminal portion of the log plasma concentration-time profile. The terminal half-life Um) was calculat ed by dividing In 2 by k. The areas under the plasma concentrationtime curve from time zero to the time of the last measurable plasma concentration point (AUC,) were calculated using linear trapezoidal summation. Extrapolation to time infinity (AUC) was determined by dividing the last measurable plasma concentration point by k and adding the result to the corresponding AUC,. Statistical Analysis—Each bioavailability parameter was ana lyzed separately. In each case, an analysis of variance of the raw data 0022-3549/87/1200-0886$01.00/0 © 1987, American Pharmaceutical Association
was performed accounting for the effects of subjects, treatments, time periods, and possible carryover effects from the preceding treatment. Sequence effects were not included because no two subjects had the same sequence of treatment administration. The four values of a given parameter for each participant were subjected to an analysis of variance (ANOVA) using a model taken from Hedayat and Afsarinejad.14 Pairwise comparisons between treatments were made where appropriate. In addition, the Hauck-Anderson test16 for bioequivalency was performed on each parameter.
Results Clinical—There were no adverse experiences reported oth er than one incidence of headache. Subject 12 was dropped from the study after failing to show up for the third interval. Subject 12A replaced Subject 12 and completed the study under the same treatment sequence as Subject 12. Overall, rimantadine was well tolerated in these subjects. Relative Bioavailability—Mean plasma concentrations are presented in Figure 1. The pharmacokinetic parameters and the statistical results from the ANOVA and the HauckAnderson bioequivalency tests are found in Table I. The pharmacokinetic parameters C max and AUC of riman tadine following the administration of a 100-mg tablet were significantly increased (p < 0.05) over the corresponding values following administration of a 100-mg solution (Table I). There were no significant differences in i max and k values. There were no significant carryover effects and the power to detect a 20% difference was 76 and 71% for C max and AUC, respectively. The mean C max and AUC following the admin istration of the tablet were, respectively, 23 and 17% greater than the corresponding values of the solution. This suggests a bioavailability of 117% from the tablet relative to that from a solution, based on AUC. In addition, the Hauck-Anderson test suggested that neither C max nor AUC could be consid ered equivalent. The power of this test was 71 and 63% for Cmax and AUC, respectively. There were no significant differences between C max , i max , AUC, and k values when comparing the 10 mL of a 10-mg/mL syrup with a 100-mg dose of solution (Table I). The mean Cmax and AUC following the administration of the syrup were 1% and 4% less, respectively, than the corresponding values of the solution, suggesting a bioavailability of 96% from the syrup relative to a solution. Both C max and AUC were considered to be equivalent according to the Hauck-
>ς
Anderson test.
Discussion This study was designed to determine the relative bioavail ability of a tablet and a syrup formulation compared with a solution following single 100-mg doses in healthy subjects. The relative bioavailability of the tablet exceeded that of the solution by 17%. This could not be explained by correcting for salt content, since the dose of each form was based on 100 mg of the HC1 salt, nor could this be explained by overage in the tablet which did not exceed 1%. The dissolution of the tablet was relatively fast, 100% in 30 min using the USP method II in water. Rimantadine HC1 solubility in water was >50 mg/mL at 25 °C. Mass balance recovery of rimantadine and t1 nü]rimantadine from a single 200-mg dose containing 54.8 /¿Ci of 14C-labeled rimantadine indicated complete absorp tion from the oral route.16 However, an apparent plasma clearance of 500 mL/min in humans and a 30-40% first-pass effect in dogs would suggest a moderate first-pass effect in humans. In this present study, the similarity in i max between the tablet and solution, along with the fast dissolution of the tablet relative to a ¿max of 5 h, would not readily support an explanation due to a first-pass effect, although it is conceiv able that some component of the tablet may be reducing the intrinsic oral clearance. The outcome was unusual and could Table l·—Pharmacokinetic Parameters"following Administration of a Single 100-mg Dose of Rimantadine HCI as a Tablet, Syrup, and Solution Parameter
Tablet
Cmax. ng/mL
Syrup 70 (26) 43-109 6(17) 3—8 2910 (34) c 1220-5010 0.0273 (35) 0.0118-0.0454 25.4" 15.3-58.7
86 (38) " 43-192 5(28) 3—8 3540 (47)" 1580-9250 0.0278 (33) 0.0118-0.0487 25 " 14.2-58.7
tnax, h AUC, ng-h-mL" If, 1/h f
vs· n
Solution c
70 (23) 46-92 6(21) 3—8 3020 (36) 1701-4810 0.0266 (30) 0.0145-0.0405 26.1 d 17.1-47.8
"Mean (± %CV) and range. "Significantly different from solution (p < 0.05) according to ANOVA. c Bioequivalent to solution (p < 0.05) according to Hauck-Anderson. ^Harmonic mean.
no
1,00 (J
z o o < 2
CO
< z o Í z < "l 10
1 20
1 30
I 40
1 1 BO 8 0
1 70
_!
1 r BO 80 100
0
10
!
!
r
!
20
30
40
60
j
1
BO 70
p
ΘΟ 90 100
TIME (hrs) Figure λ—Left Panel: mean ± SD of rimantadine plasma concentrations versus time after administration of the 100-mg tablet (■) and 100-mg solution ( · ) to 20 subjects. Right Panel: mean ± SD of rimantadine plasma concentrations versus time after administration of 100 mg of syrup (A) and a 100-mg solution ( · ) to 20 subjects.
Journal of Pharmaceutical Sciences Vol. 76, No. 12, December 1987
887
not be readily explained. Overall, this was not anticipated to be óf clinical consequence since the majority of the safety and efficacy of rimantadine HC1 was established using a tablet. The mean plasma concentration-time profiles of the syrup and solution were superimposable (Figure 1). The statistical analyses showed no significant differences between the re spective parameters for the syrup and solution. The bioavailability of syrup was 96% relative to the solution. The pharmacokinetic profiles reported herein compared favorably with that reported by Hayden et al. 10 and by Anderson et al." after adjusting the necessary parameters for dose. In those studies, maximum concentrations were reached on average in 5 and 6 h, with elimination half-lives averaging 37 and 25 h, respectively. Elimination half-lives averaged 25 to 26 h in this study, independent of formulation. In conclusion, the bioavailability of the tablet and syrup was 117% and 96% relative to a solution following a single 100-mg dose to healthy adults. In addition, rimantadine was well tolerated in these subjects.
References and Notes 1. Hayden, F. G.; Cote, K. M.; Douglas, R. G., Jr. Antimicrob. Agents Chemother. 1980,17, 865-870. 2. Indulin, M. K.; Kalninya, V. A. In Development in Antiviral Therapy; Collier, L. H.; Oxford, J. S., Eds., Academic: London, 1980; pp 107-108.
888 / Journal of Pharmaceutical Sciences Vol. 76, No. 12, December 1987
3. Dawkins, A. T., Jr.; Gallager, L. R.; Togo, Y.; Hornick, R. B.; Harris, B. A. JAMA 1968,203,1095-1099. 4. Dolin, R.; Reichman, R. C; Madore, H. P.; Maynard, R.; Union, P. N.; Weber-Jones, J. N. Eng. J. Med. 1982,307, 580-584. 5. Patriarca, P. A.; Kater, N. A.; Kendal, A. P.; Bregman, D. J.; Smith, J. D.; Sikes, R. K. Antimicrob. Agents Chemother. 1984, 26,101-103. 6. Quarles, J. M.; Couch, R. B.; Cate, T. R.; Goswick, C. B. Antivi ral Res. 1981, i, 149-155. 7. Rabinovich, S.; Baldini, J. T.; Bannister, R. Am. J. Med. Sei. 1969,257,328-335. 8. Van Voris, L. P.; Betts, R. F.; Hayden, F. G.; Christman, W. A.; Douglas, R. G., Jr. JAMA 1981,245, 1128-1131. 9. Wingfield, W. L.; Pollack, D.; Grunert, R. R. N. Eng. J. Med. 1969,281, 579-584. 10. Hayden, F. G.; Minocha, A.; Spyker, D. A.; Hoffman, H. E. Antimicrob. Agents Chemother. 1985, 28, 216-221. 11. Anderson, E. L.; Belshe, R. B.; Hoffman, H. E. In Recent Ad vances in Chemotherapy: Antimicrobial Section 3; Ishigami, J., Ed., University of Tokyo: Tokyo, 1985; pp 1955-1956. 12. Nahata, M. C; Brady, M. T. Ear. J. Clin. Pharmacol. 1986,30, 719—722 13. Fukuda, E. K.; Rodriguez, L. C; Chôma, N.; Keigher, N.; DeGrazia, F.; Garland, W. A. Biomed. Environ. Mass Spectrom. 1987, in press. 14. Hedayat, A.; Afsrinejad, K. Ann. Stat. 1978, 6, 619-628. 15. Hauck, W. W.; Anderson, S. J. Pharmacokinet. Biopharm. 1984, 12, 83-91. 16. Wills, R. J., unpublished results.
Acknowledgments The authors thank Dr. Marion Oakes for her safety evaluation, Mr. Roy Bloch for his technical assistance, and Ms. Patricia Seymore for her assistance in the preparation of this manuscript.