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Pharmacokinetic Evaluation of Gepirone Immediate-Release Capsules and Gepirone Extended-Release Tablets in Healthy Volunteers
Pharmacokinetic Evaluation of Gepirone Immediate-Release Capsules and Gepirone Extended-Release Tablets in Healthy Volunteers C.J. TIMMER,1 J.M.A. SITSEN2 1
Department of Drug Metabolism and Kinetics, NV Organon, Molenstraat 110, P.O. Box 20, 5340 BH Oss, The Netherlands
2
Clinical Development Department, NV Organon, Molenstraat 110, P.O. Box 20, 5340 BH Oss, The Netherlands
Received 7 January 2003; revised 11 February 2003; accepted 17 February 2003
ABSTRACT: In an open-label, randomized, crossover study, the pharmacokinetics of gepirone immediate-release (gepirone-IR) and different gepirone extended-release (gepirone-ER, types 1, 2, and 3) formulations were compared. Mean maximum concentration (Cmax) was 6.1 ng/mL for gepirone-IR, which was statistically significantly ( p < 0.05) higher than that of two of the ER-formulations (3.7 and 3.6 ng/mL, respectively, for types 2 and 3). The mean time to Cmax (mean Tmax) was 1.3 h for gepirone-IR and ranged from 4.8 to 5.6 h for gepirone-ER. The mean area under the curve of concentration versus time (AUC30) was similar and not statistically significantly different between gepirone-IR and ER. For the 1-(2-pyrimidinyl)-piperazine (1-PP) metabolite, Cmax and AUC30 were statistically significantly ( p < 0.05) higher and Tmax was lower for gepironeIR compared with ER. No significant differences in bioavailability were observed between the IR and the three gepirone-ER formulations, indicating that any of the once-daily gepirone-ER formulations could be substituted for gepirone-IR. This study revealed a reduction in the peak-to-trough fluctuations in plasma gepirone concentrations and maintenance of consistent plasma levels with gepirone-ER. ß 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1773–1778, 2003
Keywords: gepirone; extended release; immediate release; CNS; controlled release; metabolite kinetics; clinical pharmacokinetics; bioavailability
INTRODUCTION Gepirone is a 5-HT1A agonist of the azapirone class that has been studied for the treatment of major depression.1,2 Gepirone has a half-life of 3 h and good oral bioavailability, and undergoes extensive first-pass metabolism with formation of two major pharmacologically active metabolites, 1-(2-pyrimidinyl)-piperazine (1-PP) and 30 -OHgepirone.3 1-PP, a common azapirone metabolite, is a presynaptic a2-adrenoceptor antagonist4 that in animal models of depression does not elicit signiCorrespondence to: C.J. Timmer (Telephone: 31-412-662782; Fax: 31-412-662542; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 92, 1773–1778 (2003) ß 2003 Wiley-Liss, Inc. and the American Pharmacists Association
ficant effects.5 30 -OH-gepirone is an agonist at 5-HT1A receptors and exhibits antidepressant and anxiolytic characteristics in animal models.6,7 Most clinical studies of gepirone were undertaken with the immediate-release formulation (gepirone-IR).8–19 Because of its rapid absorption and short half-life, the gepirone-IR must be administered at least twice daily. This regimen results in high peak concentrations and marked peak-to-trough fluctuations in plasma concentrations. These fluctuations may contribute to an increased incidence of adverse events, such as nausea, dizziness, headache, and somnolence, and have the potential to result in lower patient compliance and reduced effectiveness.8 To address these limitations of the IR formulation, an extended-release gepirone formulation
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(gepirone-ER) has been developed with the goal of reducing peak plasma concentrations and plasma level fluctuations and allowing once-daily administration while maintaining the same total exposure [area under the curve of concentration versus time (AUC)] to active drug. The ER formulation should thereby allow higher dosages of gepirone to be administered with improved efficacy and better patient compliance. The objective of this study was to compare the bioavailability and pharmacokinetics of gepirone and its 1-PP metabolite after administration of gepirone-IR and three gepironeER formulations in healthy male subjects.
and 30 h after the dose. The 12-h blood sample was obtained prior to administering the second dose of gepirone-IR. Plasma samples were analyzed for gepirone and 1-PP concentrations using a specific and validated gas chromatography/mass spectrometry method.11 The lower and upper limits of quantitation for both gepirone and 1-PP were 0.1 and 25 ng/mL, respectively. All subjects were screened for inclusion and exclusion criteria prior to entering the study. Vital signs and clinical laboratory tests were measured at screening, predose, and at the completion of each session. A physical examination was performed and an electrocardiogram was obtained at screening and at the completion of the study.
METHODS This open, randomized, four-session crossover study balanced for first-order residual effects was conducted at a single study center (Meriter Hospital, Madison, WI). An appropriate institutional review board (Meriter Hospital, Madison, WI) approved the study protocol. All subjects provided written informed consent prior to participation. Healthy male subjects aged 19 to 36 years were eligible to participate in the study. All subjects underwent a baseline evaluation, which included a medical history, physical examination, and clinical laboratory test. After baseline screening, subjects were randomly assigned to one of four groups using a 4 4 Latin square design. Each group received, in random order, each of the following treatments: gepirone-ER, two 10-mg tablets (ER1); gepirone-ER, two 10-mg tablets (ER-2); gepirone-ER, one 25-mg tablet (ER-3); and gepirone-IR, two 5-mg capsules in the morning and two in the evening (IR). The ER formulations differed in the time at which 50% of the drug is released from the formulation in vitro (T-50). The T-50 values were 2.5 h for ER-1, 5.0 h for ER-2, and 5.0 h for ER-3. Each treatment was separated by a 7-day washout period. All doses of gepirone were administered with 200 mL of water in the morning for gepirone-ER formulations and in the morning and evening for the gepirone-IR formulation. All subjects fasted from 10:00 p.m. the night before dosing until 4 h after dosing for each session. For gepirone-IR, blood samples were obtained prior to the first dose (time 0) and at 0.5, 0.75, 1, 1.25, 2, 4, 5, 6, 8, 12, 12.5, 13, 13.5, 14, 16, 18, 20, 24, and 30 h. For gepirone-ER groups, blood samples were obtained prior to dose administration (time 0) and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 9, SEPTEMBER 2003
Pharmacokinetic Analysis Plasma gepirone and 1-PP concentrations versus time data were evaluated by noncompartmental methods.12,13 The highest observed plasma concentration during a dosing interval and the corresponding sampling time were defined as Cmax and Tmax, respectively. The AUC and the area under the first moment of the concentration versus time curve were calculated with the trapezoidal rule. The absorption kinetics for gepirone was evaluated by the method of Wagner and Nelson.14 Because gepirone-ER-3 was administered as a 25-mg once-daily dose, the AUC (0 to 30 h) and Cmax were dose-normalized to 20 mg. Sequence, period, and treatment effects were evaluated by analysis of variance (ANOVA) for both gepirone and 1-PP. If the test for treatment effects was significant ( p < 0.05), all pairwise comparisons of the means were performed using Tukey’s multiple comparisons procedure. Homogeneity of variance was evaluated by Levene’s test. If there was significant heterogeneity of variance, a weighted ANOVA was performed. A Bonferroni adjustment was made to the significance level to account for multiple comparisons. Comparisons of mean Tmax between groups were made with an unequal variance t-test. Comparisons of mean Cmax and AUC30 were made with a Tukey’s test. All tests of significance were two-sided at the a ¼ 0.05 level.
RESULTS Twelve healthy adult male subjects participated in the study; 10 were Caucasian, 1 AfricanAmerican, and 1 Asian. The mean age was
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24.1 6.0 years (range 19–36 years) and mean weight was 72.8 9.7 kg (range 56.6–86.0 kg). One subject was discontinued from the study after session 2 because of an automobile accident that was unrelated to the study and was replaced by a subject who completed the entire study. Gepirone Tmax and Cmax Mean Tmax was 1.3 0.9 h for the gepirone-IR formulation (Table 1). A second Tmax was obtained at 14.3 1.1 h, or 2 h after the second dose of gepirone-IR. Mean Tmax ranged from 4.8 to 5.6 h for the three gepirone-ER formulations. An earlier but smaller peak plasma concentration of gepirone occurred at 3 h after dosing with each of the gepirone-ER formulations. Measurable plasma concentrations of gepirone were observed at 24 h after dosing with the three ER formulations in 11 of 12 subjects (Figure 1). Mean Cmax was statistically significantly ( p < 0.05, Tukey’s test) greater with gepirone-IR (6.1 3.1 ng/mL) than with two of the three gepirone-ER formulations (3.7 and 3.6 ng/mL for types 2 and 3, respectively). Mean dose-normalized Cmax ranged from 3.6 to 4.3 ng/mL for the three gepirone-ER formulations. There were no significant differences in Cmax among ER formulations. No statistically significant differences were observed between any of the three gepirone-ER formulations and the gepirone-IR formulation for mean AUC30 after adjusting for dose.
Figure 1. Mean gepirone plasma concentrations following administration of gepirone-IR formulations (10 mg q12 h, n ¼ 12) or gepirone-ER formulations (ER-1: 20 mg q24 h, n ¼ 12; ER-2: 20 mg q24 h, n ¼ 12; ER-3: 25 mg q24 h, n ¼ 12).
gepirone-IR. For 1-PP, mean Tmax ranged from 5.1 to 5.7 h for the three gepirone-ER formulations. A second Tmax after the second dose of gepirone-IR was obtained at 15.1 1.4 h, or 3 h after the second dose. Mean plasma concentrations of 1-PP are shown in Figure 2. For 1-PP, mean Cmax was statistically significantly ( p < 0.05) greater with gepirone-IR than with any of the gepirone-ER formulations (Table 1). However, there were no significant differences in mean dose-normalized Cmax among the three ER formulations. Mean dose-normalized AUC30 was statistically significantly ( p < 0.05) greater with gepirone-IR than with gepirone-ER formulations; however, no significant differences were observed for AUC30 among the three gepirone-ER
1-PP Tmax and Cmax Pharmacokinetic parameters for 1-PP with each of the four gepirone formulations are summarized in Table 1. Mean Tmax was 1.7 0.8 h with
Table 1. Pharmacokinetic Parameters for Four Formulations of Gepirone Gepirone Formulations (mean standard deviation) Parameter Gepirone Cmax (ng/mL) Tmax (h) AUC(30) (hng/mL) 1-PP Cmax (ng/mL) Tmax (h) AUC(30) (hng/mL)
IR
ER-1
ER-2
ER-3
6.1 3.1b 1.3 0.9 54.9 25.6
4.3 2.8 5.1 1.6 55.3 28.2
3.7 2.2 5.6 2.5 55.0 33.7
3.6 1.6a 4.8 1.9 51.8 27.3a
6.3 2.1c 1.7 0.8 92.8 56.8c
4.2 1.6 5.7 1.6 74.0 40.8
3.7 1.6 5.1 2.0 68.3 40.2
3.6 1.8a 5.6 2.5 67.6 41.6a
a
Dose-normalized to gepirone 20 mg. Gepirone-IR > gepirone-ER-(2,3); p < 0.05; Tukey’s test. Gepirone-IR > gepirone-ER-(1,2,3); p < 0.05; Tukey’s test.
b c
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Table 2. Gepirone
Figure 2. Mean 1-PP plasma concentrations following administration of gepirone-IR formulations (10 mg q12 h, n ¼ 12) or gepirone-ER formulations (ER1: 20 mg q24 h, n ¼ 12; ER-2: 20 mg q24 h, n ¼ 12; ER-3: 25 mg q24 h, n ¼ 12).
formulations. Thus, significantly less 1-PP was formed after administration of gepirone-ER than after gepirone-IR. The fraction of gepirone absorbed after each dosage regimen was calculated by the Wagner– Nelson method.14 Absorption from the gepironeER formulations was slower than that from the gepirone-IR capsule, however, there were no differences in absorption among the three gepironeER formulations. The difference in release rates (T-50 of 2.5 or 5.0 h) among the three gepirone-ER formulations did not affect the absorption of gepirone. The majority of the dose was absorbed from gepirone-IR within 1 to 1.5 h. In contrast, 18 to 24 h were required for absorption of 90–95% of gepirone-ER. Tolerability Six of 12 subjects reported adverse events during the study after treatments with gepirone-IR, ER1, and ER-2 (Table 2). No adverse events were reported with gepirone-ER-3. All adverse events were of mild severity. A single subject reported four of five adverse events with gepirone-ER-1, and four of eight adverse events with gepirone-IR. No clinically significant changes in vital signs, laboratory tests, or electrocardiogram were reported with any formulation.
DISCUSSION The results of this pharmacokinetic study in healthy subjects revealed markedly reduced peak plasma concentrations of gepirone and 1-PP, its JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 9, SEPTEMBER 2003
Number of Adverse Events Reported with
Adverse Event
IR
ER-1
ER-2
ER-3
Dizziness Headache Hot flashes Lightheadedness Nausea Shakiness Sinus headache Sleepiness Tiredness Total
1 3 1 1 1 0 0 1 0 8
0 1 0 1 1 1 0 0 1 5
0 0 0 1 0 0 1 0 0 2
0 0 0 0 0 0 0 0 0 0
major metabolite, when administered as three different ER formulations versus an IR formulation. The rate of absorption of gepirone also was markedly reduced with gepirone-ER versus gepirone-IR, as evidenced by significantly prolonged time-to-peak plasma concentrations with the ER formulations. The majority of gepirone was absorbed from the IR formulation in 1–1.5 h, whereas 90–95% of gepirone was absorbed from the three ER formulations in 18–24 h. For the ER formulations, the plasma concentration–time curve revealed two peaks for gepirone, the first occurring at 3 h and the second at 4–6 h. It is possible that the first peak represents the true Tmax for gepirone, and the second peak was due to the effect of food delaying absorption. Alternatively, the two peak plasma gepirone concentrations with the ER formulations could be the result of enterohepatic recirculation of unchanged drug. A third explanation is that the second peak at 4–6 h could have occurred from absorption in the distal portion of the small intestine. Results from AUC30 data demonstrated no significant differences between gepirone-ER formulations dosed once daily and gepirone-IR dosed twice daily. Significantly less 1-PP was formed from all three gepirone-ER formulations than from the gepirone-IR formulation. This effect can be explained by the fact that a larger portion of the ER formulation will be absorbed in the distal part of the small intestine compared with the IR formulation. The distal part of the small intestine contains less CYP3A4, which mediates the formation of 1-PP from gepirone, than the proximal part, so less 1-PP is formed pre-systemically for the ER formulation compared with the IR formulation.15 Altogether these results show that the gepironeER formulations were able to reduce the high peak plasma concentrations observed with gepirone-IR
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without impacting on the total exposure to active drug (AUC). Significantly lower mean peak plasma concentrations and delayed time-to-peak concentrations of gepirone and 1-PP, which were observed with the ER formulations, and continued absorption of gepirone 20 h post dose are characteristics of an extended-release formulation. Despite differences in the rate of release, absorption from the ER formulations was similar and there was no indication of premature release or dose dumping, which occurs when a bolus of drug is released from an extended-release formulation. Few adverse effects were reported with the gepirone-ER formulations, which suggests an improved tolerability profile compared with the IR formulation. An adverse effect such as dizziness is likely to be attributed to the 5HT1A agonistic effect of gepirone itself and/or the 30 -OH-gepirone metabolite. The higher incidence of side effects with gepirone-IR may be attributed to the higher peak plasma levels compared with the ER formulations. A high incidence of adverse events may contribute to reduced patient compliance and lower therapeutic effectiveness. Similar findings of a reduced incidence of adverse events related to the use of an ER formulation have been reported with another drug (i.e., venlafaxine16,17). It has been suggested that the use of an ER formulation, which results in improved tolerability, also may contribute to greater effectiveness.18,19 An ER formulation of gepirone has been selected for final clinical development. Thus, these results indicate that an ER formulation of gepirone reduces peak plasma concentrations while maintaining overall exposure to active drug. This combination of effects allows once-daily administration of therapeutic doses of gepirone, which may result in improved efficacy and tolerability and, therefore, better patient compliance.
ACKNOWLEDGMENTS This study was supported by NV Organon, Oss, The Netherlands.
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REFERENCES 14. 1. Heiser JF, Wilcox CS. 1998. Serotonin 5-HT receptor agonists as antidepressants: pharmacological
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rationale and evidence for efficacy. CNS Drugs 10: 343–353. Robinson DS, Sitsen JMA, Gibertini M. Gepirone: Efficacy and tolerability of immediate-release and extended-release formulations. Clin Ther, in press. Tay LK, Sciacca MA, Sostrin MB, Farmen RH, Pittman KA. 1993. Effect of food on the bioavailability of gepirone in humans. J Clin Pharmacol 33: 631–635. Bianchi G, Garattini S. 1988. Blockade of alpha 2-adrenoceptors by 1-(2-pyrimidinyl)-piperazine (PmP) in vivo and its relation to the activity of buspirone. Eur J Pharmacol 147:343–350. Lucki I. 1991. Behavioral studies of serotonin receptor agonists as antidepressant drugs. J Clin Psychiatr 52(Suppl):24–31. Blier P, Haddjeri N, Dong J. 2002. Effect of the 5HT1A agonist gepirone HCl and its metabolite 30 OH-gepirone on the 5-HT system in the rat brain. Int J Neuropsychopharmacol 5:S68. Ward NM, Drinkenburg WHIM, Shahid M, Walker GB, Westwood PJ, Elands CE, Hill DR. 2002. The preclinical antidepressant-like profile of the 5HT1A receptor agonist gepirone and its metabolites 30 -OH-gepirone. Int J Neuropsychopharmacol 5: S68. Jenkins SW, Robinson DS, Fabre LF, Andary JJ, Messina ME, Reich LA. 1990. Gepirone in the treatment of major depression. J Clin Psychopharmacol 10(Suppl 3):77S–85S. Amsterdam JD. 2000. Gepirone prevents relapse in major depressive disorder: A double-blind placebo substitution trial. Paper presented at: American College of Neuropsychopharmacology Annual Meeting, San Juan, Puerto Rico. McGrath PJ, Stewart JW, Quitkin FM, Wager S, Jenkins SW, Archibald DG, et al. 1994. Gepirone treatment of atypical depression: Preliminary evidence of serotonergic involvement. J Clin Psychopharmacol 14:347–352. Sciacca MA, Duncan GF, Shea JP, Faulkner HC 3rd, Farmen RH, Pittman KA. 1988. Simultaneous quantitation of buspirone and 1-(2-pyrimidinyl)piperazine in human plasma and urine by capillary gas chromatography-mass spectrometry. J Chromatogr 428:265–274. Gibaldi M, Perrier D. 1982. Noncompartmental analysis based on statistical moment theory. Pharmacokinetics, 2nd ed. New York: Marcel Dekker. pp 409–417. Riegelman S, Collier P. 1980. The application of statistical moment theory to the evaluation of in vivo dissolution time and absorption time. J Pharmacokinet Biopharm 8:509–534. Gibaldi M, Perrier D. 1982. Absorption kinetics and bioavailability. Pharmacokinetics, 2nd ed. New York: Marcel Dekker. pp 145–198.
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15. Tay LK, Dixon F Jr., Sostrin MB, Barr WH, Farmen RH, Pittman KA. 1992. The site of gastrointestinal absorption of gepirone in humans. J Clin Pharmacol 32:827–832. 16. Troy SM, DiLea C, Martin PT, Leister CA, Fruncillo RJ, Chiang ST. 1997. Pharmacokinetics of once daily venlafaxine extended release (XR) in healthy volunteers. Curr Ther Res 58:504–514. 17. Troy SM, DiLea C, Martin PT, Rosen AS, Fruncillo RJ, Chiang ST. 1997. Bioavailability of once-daily venlafaxine extended release (XR) compared with
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the immediate release formulation in healthy adult volunteers. Curr Ther Res 58:492–503. 18. Thase ME. 1997. Efficacy and tolerability of oncedaily venlafaxine extended release (XR) in outpatients with major depression. The Venlafaxine XR 209 Study Group. J Clin Psychiatr 58:393–398. 19. Cunningham LA. 1997. Once-daily venlafaxine extended release (XR) and venlafaxine immediate release (IR) in outpatients with major depression. Venlafaxine XR 208 Study Group. Ann Clin Psychiatr 9:157–164.
Department of Drug Metabolism and Kinetics, NV Organon, Molenstraat 110, P.O. Box 20, 5340 BH Oss, The Netherlands
2
Clinical Development Department, NV Organon, Molenstraat 110, P.O. Box 20, 5340 BH Oss, The Netherlands
Received 7 January 2003; revised 11 February 2003; accepted 17 February 2003
ABSTRACT: In an open-label, randomized, crossover study, the pharmacokinetics of gepirone immediate-release (gepirone-IR) and different gepirone extended-release (gepirone-ER, types 1, 2, and 3) formulations were compared. Mean maximum concentration (Cmax) was 6.1 ng/mL for gepirone-IR, which was statistically significantly ( p < 0.05) higher than that of two of the ER-formulations (3.7 and 3.6 ng/mL, respectively, for types 2 and 3). The mean time to Cmax (mean Tmax) was 1.3 h for gepirone-IR and ranged from 4.8 to 5.6 h for gepirone-ER. The mean area under the curve of concentration versus time (AUC30) was similar and not statistically significantly different between gepirone-IR and ER. For the 1-(2-pyrimidinyl)-piperazine (1-PP) metabolite, Cmax and AUC30 were statistically significantly ( p < 0.05) higher and Tmax was lower for gepironeIR compared with ER. No significant differences in bioavailability were observed between the IR and the three gepirone-ER formulations, indicating that any of the once-daily gepirone-ER formulations could be substituted for gepirone-IR. This study revealed a reduction in the peak-to-trough fluctuations in plasma gepirone concentrations and maintenance of consistent plasma levels with gepirone-ER. ß 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1773–1778, 2003
Keywords: gepirone; extended release; immediate release; CNS; controlled release; metabolite kinetics; clinical pharmacokinetics; bioavailability
INTRODUCTION Gepirone is a 5-HT1A agonist of the azapirone class that has been studied for the treatment of major depression.1,2 Gepirone has a half-life of 3 h and good oral bioavailability, and undergoes extensive first-pass metabolism with formation of two major pharmacologically active metabolites, 1-(2-pyrimidinyl)-piperazine (1-PP) and 30 -OHgepirone.3 1-PP, a common azapirone metabolite, is a presynaptic a2-adrenoceptor antagonist4 that in animal models of depression does not elicit signiCorrespondence to: C.J. Timmer (Telephone: 31-412-662782; Fax: 31-412-662542; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 92, 1773–1778 (2003) ß 2003 Wiley-Liss, Inc. and the American Pharmacists Association
ficant effects.5 30 -OH-gepirone is an agonist at 5-HT1A receptors and exhibits antidepressant and anxiolytic characteristics in animal models.6,7 Most clinical studies of gepirone were undertaken with the immediate-release formulation (gepirone-IR).8–19 Because of its rapid absorption and short half-life, the gepirone-IR must be administered at least twice daily. This regimen results in high peak concentrations and marked peak-to-trough fluctuations in plasma concentrations. These fluctuations may contribute to an increased incidence of adverse events, such as nausea, dizziness, headache, and somnolence, and have the potential to result in lower patient compliance and reduced effectiveness.8 To address these limitations of the IR formulation, an extended-release gepirone formulation
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(gepirone-ER) has been developed with the goal of reducing peak plasma concentrations and plasma level fluctuations and allowing once-daily administration while maintaining the same total exposure [area under the curve of concentration versus time (AUC)] to active drug. The ER formulation should thereby allow higher dosages of gepirone to be administered with improved efficacy and better patient compliance. The objective of this study was to compare the bioavailability and pharmacokinetics of gepirone and its 1-PP metabolite after administration of gepirone-IR and three gepironeER formulations in healthy male subjects.
and 30 h after the dose. The 12-h blood sample was obtained prior to administering the second dose of gepirone-IR. Plasma samples were analyzed for gepirone and 1-PP concentrations using a specific and validated gas chromatography/mass spectrometry method.11 The lower and upper limits of quantitation for both gepirone and 1-PP were 0.1 and 25 ng/mL, respectively. All subjects were screened for inclusion and exclusion criteria prior to entering the study. Vital signs and clinical laboratory tests were measured at screening, predose, and at the completion of each session. A physical examination was performed and an electrocardiogram was obtained at screening and at the completion of the study.
METHODS This open, randomized, four-session crossover study balanced for first-order residual effects was conducted at a single study center (Meriter Hospital, Madison, WI). An appropriate institutional review board (Meriter Hospital, Madison, WI) approved the study protocol. All subjects provided written informed consent prior to participation. Healthy male subjects aged 19 to 36 years were eligible to participate in the study. All subjects underwent a baseline evaluation, which included a medical history, physical examination, and clinical laboratory test. After baseline screening, subjects were randomly assigned to one of four groups using a 4 4 Latin square design. Each group received, in random order, each of the following treatments: gepirone-ER, two 10-mg tablets (ER1); gepirone-ER, two 10-mg tablets (ER-2); gepirone-ER, one 25-mg tablet (ER-3); and gepirone-IR, two 5-mg capsules in the morning and two in the evening (IR). The ER formulations differed in the time at which 50% of the drug is released from the formulation in vitro (T-50). The T-50 values were 2.5 h for ER-1, 5.0 h for ER-2, and 5.0 h for ER-3. Each treatment was separated by a 7-day washout period. All doses of gepirone were administered with 200 mL of water in the morning for gepirone-ER formulations and in the morning and evening for the gepirone-IR formulation. All subjects fasted from 10:00 p.m. the night before dosing until 4 h after dosing for each session. For gepirone-IR, blood samples were obtained prior to the first dose (time 0) and at 0.5, 0.75, 1, 1.25, 2, 4, 5, 6, 8, 12, 12.5, 13, 13.5, 14, 16, 18, 20, 24, and 30 h. For gepirone-ER groups, blood samples were obtained prior to dose administration (time 0) and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 9, SEPTEMBER 2003
Pharmacokinetic Analysis Plasma gepirone and 1-PP concentrations versus time data were evaluated by noncompartmental methods.12,13 The highest observed plasma concentration during a dosing interval and the corresponding sampling time were defined as Cmax and Tmax, respectively. The AUC and the area under the first moment of the concentration versus time curve were calculated with the trapezoidal rule. The absorption kinetics for gepirone was evaluated by the method of Wagner and Nelson.14 Because gepirone-ER-3 was administered as a 25-mg once-daily dose, the AUC (0 to 30 h) and Cmax were dose-normalized to 20 mg. Sequence, period, and treatment effects were evaluated by analysis of variance (ANOVA) for both gepirone and 1-PP. If the test for treatment effects was significant ( p < 0.05), all pairwise comparisons of the means were performed using Tukey’s multiple comparisons procedure. Homogeneity of variance was evaluated by Levene’s test. If there was significant heterogeneity of variance, a weighted ANOVA was performed. A Bonferroni adjustment was made to the significance level to account for multiple comparisons. Comparisons of mean Tmax between groups were made with an unequal variance t-test. Comparisons of mean Cmax and AUC30 were made with a Tukey’s test. All tests of significance were two-sided at the a ¼ 0.05 level.
RESULTS Twelve healthy adult male subjects participated in the study; 10 were Caucasian, 1 AfricanAmerican, and 1 Asian. The mean age was
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24.1 6.0 years (range 19–36 years) and mean weight was 72.8 9.7 kg (range 56.6–86.0 kg). One subject was discontinued from the study after session 2 because of an automobile accident that was unrelated to the study and was replaced by a subject who completed the entire study. Gepirone Tmax and Cmax Mean Tmax was 1.3 0.9 h for the gepirone-IR formulation (Table 1). A second Tmax was obtained at 14.3 1.1 h, or 2 h after the second dose of gepirone-IR. Mean Tmax ranged from 4.8 to 5.6 h for the three gepirone-ER formulations. An earlier but smaller peak plasma concentration of gepirone occurred at 3 h after dosing with each of the gepirone-ER formulations. Measurable plasma concentrations of gepirone were observed at 24 h after dosing with the three ER formulations in 11 of 12 subjects (Figure 1). Mean Cmax was statistically significantly ( p < 0.05, Tukey’s test) greater with gepirone-IR (6.1 3.1 ng/mL) than with two of the three gepirone-ER formulations (3.7 and 3.6 ng/mL for types 2 and 3, respectively). Mean dose-normalized Cmax ranged from 3.6 to 4.3 ng/mL for the three gepirone-ER formulations. There were no significant differences in Cmax among ER formulations. No statistically significant differences were observed between any of the three gepirone-ER formulations and the gepirone-IR formulation for mean AUC30 after adjusting for dose.
Figure 1. Mean gepirone plasma concentrations following administration of gepirone-IR formulations (10 mg q12 h, n ¼ 12) or gepirone-ER formulations (ER-1: 20 mg q24 h, n ¼ 12; ER-2: 20 mg q24 h, n ¼ 12; ER-3: 25 mg q24 h, n ¼ 12).
gepirone-IR. For 1-PP, mean Tmax ranged from 5.1 to 5.7 h for the three gepirone-ER formulations. A second Tmax after the second dose of gepirone-IR was obtained at 15.1 1.4 h, or 3 h after the second dose. Mean plasma concentrations of 1-PP are shown in Figure 2. For 1-PP, mean Cmax was statistically significantly ( p < 0.05) greater with gepirone-IR than with any of the gepirone-ER formulations (Table 1). However, there were no significant differences in mean dose-normalized Cmax among the three ER formulations. Mean dose-normalized AUC30 was statistically significantly ( p < 0.05) greater with gepirone-IR than with gepirone-ER formulations; however, no significant differences were observed for AUC30 among the three gepirone-ER
1-PP Tmax and Cmax Pharmacokinetic parameters for 1-PP with each of the four gepirone formulations are summarized in Table 1. Mean Tmax was 1.7 0.8 h with
Table 1. Pharmacokinetic Parameters for Four Formulations of Gepirone Gepirone Formulations (mean standard deviation) Parameter Gepirone Cmax (ng/mL) Tmax (h) AUC(30) (hng/mL) 1-PP Cmax (ng/mL) Tmax (h) AUC(30) (hng/mL)
IR
ER-1
ER-2
ER-3
6.1 3.1b 1.3 0.9 54.9 25.6
4.3 2.8 5.1 1.6 55.3 28.2
3.7 2.2 5.6 2.5 55.0 33.7
3.6 1.6a 4.8 1.9 51.8 27.3a
6.3 2.1c 1.7 0.8 92.8 56.8c
4.2 1.6 5.7 1.6 74.0 40.8
3.7 1.6 5.1 2.0 68.3 40.2
3.6 1.8a 5.6 2.5 67.6 41.6a
a
Dose-normalized to gepirone 20 mg. Gepirone-IR > gepirone-ER-(2,3); p < 0.05; Tukey’s test. Gepirone-IR > gepirone-ER-(1,2,3); p < 0.05; Tukey’s test.
b c
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Table 2. Gepirone
Figure 2. Mean 1-PP plasma concentrations following administration of gepirone-IR formulations (10 mg q12 h, n ¼ 12) or gepirone-ER formulations (ER1: 20 mg q24 h, n ¼ 12; ER-2: 20 mg q24 h, n ¼ 12; ER-3: 25 mg q24 h, n ¼ 12).
formulations. Thus, significantly less 1-PP was formed after administration of gepirone-ER than after gepirone-IR. The fraction of gepirone absorbed after each dosage regimen was calculated by the Wagner– Nelson method.14 Absorption from the gepironeER formulations was slower than that from the gepirone-IR capsule, however, there were no differences in absorption among the three gepironeER formulations. The difference in release rates (T-50 of 2.5 or 5.0 h) among the three gepirone-ER formulations did not affect the absorption of gepirone. The majority of the dose was absorbed from gepirone-IR within 1 to 1.5 h. In contrast, 18 to 24 h were required for absorption of 90–95% of gepirone-ER. Tolerability Six of 12 subjects reported adverse events during the study after treatments with gepirone-IR, ER1, and ER-2 (Table 2). No adverse events were reported with gepirone-ER-3. All adverse events were of mild severity. A single subject reported four of five adverse events with gepirone-ER-1, and four of eight adverse events with gepirone-IR. No clinically significant changes in vital signs, laboratory tests, or electrocardiogram were reported with any formulation.
DISCUSSION The results of this pharmacokinetic study in healthy subjects revealed markedly reduced peak plasma concentrations of gepirone and 1-PP, its JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 9, SEPTEMBER 2003
Number of Adverse Events Reported with
Adverse Event
IR
ER-1
ER-2
ER-3
Dizziness Headache Hot flashes Lightheadedness Nausea Shakiness Sinus headache Sleepiness Tiredness Total
1 3 1 1 1 0 0 1 0 8
0 1 0 1 1 1 0 0 1 5
0 0 0 1 0 0 1 0 0 2
0 0 0 0 0 0 0 0 0 0
major metabolite, when administered as three different ER formulations versus an IR formulation. The rate of absorption of gepirone also was markedly reduced with gepirone-ER versus gepirone-IR, as evidenced by significantly prolonged time-to-peak plasma concentrations with the ER formulations. The majority of gepirone was absorbed from the IR formulation in 1–1.5 h, whereas 90–95% of gepirone was absorbed from the three ER formulations in 18–24 h. For the ER formulations, the plasma concentration–time curve revealed two peaks for gepirone, the first occurring at 3 h and the second at 4–6 h. It is possible that the first peak represents the true Tmax for gepirone, and the second peak was due to the effect of food delaying absorption. Alternatively, the two peak plasma gepirone concentrations with the ER formulations could be the result of enterohepatic recirculation of unchanged drug. A third explanation is that the second peak at 4–6 h could have occurred from absorption in the distal portion of the small intestine. Results from AUC30 data demonstrated no significant differences between gepirone-ER formulations dosed once daily and gepirone-IR dosed twice daily. Significantly less 1-PP was formed from all three gepirone-ER formulations than from the gepirone-IR formulation. This effect can be explained by the fact that a larger portion of the ER formulation will be absorbed in the distal part of the small intestine compared with the IR formulation. The distal part of the small intestine contains less CYP3A4, which mediates the formation of 1-PP from gepirone, than the proximal part, so less 1-PP is formed pre-systemically for the ER formulation compared with the IR formulation.15 Altogether these results show that the gepironeER formulations were able to reduce the high peak plasma concentrations observed with gepirone-IR
PHARMACOKINETICS OF GEPIRONE IMMEDIATE- AND EXTENDED-RELEASE CAPSULES
without impacting on the total exposure to active drug (AUC). Significantly lower mean peak plasma concentrations and delayed time-to-peak concentrations of gepirone and 1-PP, which were observed with the ER formulations, and continued absorption of gepirone 20 h post dose are characteristics of an extended-release formulation. Despite differences in the rate of release, absorption from the ER formulations was similar and there was no indication of premature release or dose dumping, which occurs when a bolus of drug is released from an extended-release formulation. Few adverse effects were reported with the gepirone-ER formulations, which suggests an improved tolerability profile compared with the IR formulation. An adverse effect such as dizziness is likely to be attributed to the 5HT1A agonistic effect of gepirone itself and/or the 30 -OH-gepirone metabolite. The higher incidence of side effects with gepirone-IR may be attributed to the higher peak plasma levels compared with the ER formulations. A high incidence of adverse events may contribute to reduced patient compliance and lower therapeutic effectiveness. Similar findings of a reduced incidence of adverse events related to the use of an ER formulation have been reported with another drug (i.e., venlafaxine16,17). It has been suggested that the use of an ER formulation, which results in improved tolerability, also may contribute to greater effectiveness.18,19 An ER formulation of gepirone has been selected for final clinical development. Thus, these results indicate that an ER formulation of gepirone reduces peak plasma concentrations while maintaining overall exposure to active drug. This combination of effects allows once-daily administration of therapeutic doses of gepirone, which may result in improved efficacy and tolerability and, therefore, better patient compliance.
ACKNOWLEDGMENTS This study was supported by NV Organon, Oss, The Netherlands.
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