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DRUG METABOLISM

Pharmacokinetics of a Newly Identified Active Metabolite of Buspirone After Administration of Buspirone Over Its Therapeutic Dose Range

Randy C. Dockens, PhD, Daniel E. Salazar, PhD, I. Edgar Fulmor, BS, Michele Wehling, BS, Mark E. Arnold, PhD and Robert Croop, MD

From Bristol-Myers Squibb Company, Princeton, New Jersey (Dr Dockens, Dr Salazar, Mr Fulmor, Dr Arnold, Dr Croop), and MDS Pharma Services, Lincoln, Nebraska (Ms Wehling). Dr Salazar is currently with Daiichi-Sankyo Pharma Development, Edison, New Jersey.

Address for reprints: Randy C. Dockens, PhD, Bristol-Myers Squibb, Clinical Discovery, Route 206 & Province Line Road, Princeton, NJ 08543; e-mail: randy.dockens{at}bms.com.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The objective of this study was to assess the pharmacokinetics of a newly identified active metabolite of buspirone, 6-hydroxybuspirone (6OHB), over the therapeutic dose range of buspirone. A 26-day, open-label, nonrandomized, single-sequence, dose-escalation study in normal healthy volunteers was conducted (N = 13). Subjects received escalating doses of buspirone with each dose administered for 5 days starting at a dose of 5 mg twice daily and increasing up to 30 mg twice daily. Plasma concentrations of 6OHB were approximately 40-fold greater than those of buspirone. 6OHB was rapidly formed following buspirone administration, and exposure increased proportionally with buspirone dose. Further research regarding the safety and efficacy of 6OHB itself is warranted.

Key Words: Buspirone • 6-hydroxybuspirone • 1-PP • anxiety • pharmacokinetics

Buspirone is a potent partial agonist of 5-HT1A receptors and was approved by the Food and Drug Administration in 1986 for the treatment of generalized anxiety disorder.1,2 Buspirone may, potentially, be beneficial in depression,3,4 but its main use in depression has been as augmentation therapy5,6 or decreasing sexual dysfunction symptoms from other antidepressants.7,8 Buspirone has also shown positive results in other indications as well.9-12 After administration, buspirone itself is completely absorbed13,14 but undergoes extensive first-pass metabolism, resulting in many metabolites14,15 with an oral bioavailability of < 5%.13 Urinary excretion is the major elimination pathway in humans, accounting for 60% of the total oral dose of [14C]buspirone.13 The metabolites 1-(2-pyrimidinyl)-piperazine (1-PP) and 6-hydroxybuspirone (6OHB) were the 2 major metabolites identified, along with numerous other secondary metabolites, although buspirone accounted for less than 1% of the total urinary radioactivity.16 However, human plasma metabolite profiles after oral administration of radio-labeled buspirone have not been reported. To date, only 1-PP, 5-hydroxybuspirone, and its conjugate have been reported in human plasma.14 Of these, only 1-PP had activity.14,17 More recently, further in vitro human liver microsomal metabolism studies have been performed in which other major metabolites were identified to be an N-oxidation on the piperazine ring and 3 hydroxylated metabolites, all of which were formed via CYP3A4 metabolism of buspirone.18 One of these hydroxylated metabolites, 6OHB (BMS-528215, 6-hydroxy-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione), was found to have partial agonist activity at the 5-HT1A receptors and may potentially contribute to the clinical efficacy of buspirone as an anxiolytic agent (Y-W Li, H Wong, RC Dockens, et al, unpublished data). Therefore, adequate plasma exposure to 6OHB (and, presumably, central nervous system exposure) after buspirone administration could indicate its ability to play a major role in the anxiolytic effect of buspirone.

The study reported here is the first investigation to see if 6OHB is present in human plasma after the administration of buspirone. It also assessed whether 6OHB was a major plasma metabolite of buspirone and thereby may potentially contribute to the overall activity of buspirone. If present, the pharmacokinetics of 6OHB (as the racemate) and 1-PP after the administration of buspirone over its therapeutic dose range of 5 mg twice daily to 30 mg twice daily were to be evaluated.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Study Design
This study was a 26-day, open-label, nonrandomized, single-sequence, dose-escalation study in normal healthy volunteers. The study was conducted at MDS Harris, Lincoln, Nebraska, and was approved by the MDS Harris Institutional Review Board prior to subjects signing informed consent.

Normal, healthy subjects between the ages of 19 and 45 with a body mass index of 18 to 30 kg/m2, inclusive, were allowed to participate in the study. The following tests and procedures were done at baseline and at regular intervals during the trial: physical examination, vital signs, clinical laboratory, and electrocardiogram (ECG). Subjects were monitored for adverse events throughout the study.

The subjects were administered buspirone orally for 25 days. Total daily doses of buspirone ranged from 10 mg to 60 mg using BuSpar® Dividose® 15-mg tablets (Bristol-Myers Squibb Company, Princeton, NJ). All doses were administered in the clinic. The subjects received BuSpar® 5.0 mg twice daily for 5 days. Serial samples for pharmacokinetic analysis were obtained on day 5. On days 6 through 10, the subjects were administered BuSpar® 7.5 mg twice daily, and pharmacokinetics were determined on day 10. On days 11 through 15, the subjects were administered BuSpar® 15 mg twice daily, and pharmacokinetics were determined on day 15. On days 16 through 20, the subjects were administered BuSpar® 20 mg twice daily, and pharmacokinetics were determined on day 20. On days 21 through 25, the subjects were administered BuSpar® 30 mg twice daily, and pharmacokinetics were determined on day 25.

Pharmacokinetic sample collection was accomplished by collecting venous blood at each of the following time points relative to buspirone dosing on days 5, 10, 15, 20, and 25 of the study: 0 (prior to dosing), and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours postdose. Trough concentrations (Cmin) were measured prior to dosing on days 4, 6, 9, 11, 14, 16, 19, 21, 24, and 26. Pharmacokinetic measures for orally administered buspirone and its metabolites, 6OHB, and 1-PP were determined on days 5, 10, 15, 20, and 25.

Analyte Extraction Method
Assays for buspirone, 6OHB, and 1-PP, and their pharmacokinetic analyses were performed by MDS Harris under the supervision of the Bioanalytical Sciences and Clinical Discovery Departments at Bristol-Myers Squibb.

After the addition of 100 µL of internal standards ([13C,15N2,D4]buspirone and [13C,15N2,D4]1-PP: 10 ng/mL in methanol for buspirone, 6OHB, and 1-PP analysis), the samples were centrifuged prior to being loaded onto a preconditioned C18 (EC) solid phase extraction column (Isolute, Biotage, Charlottesville, Va). The loaded samples were first washed with 3 mL 10 mM ammonium acetate and then with 3 mL methanol/water (50/50 volume/volume). The compounds were eluted with 3 mL of a 3% ammonium hydroxide in acetonitrile solution, and the eluate evaporated to dryness under nitrogen in a 37°C water bath. The residue was reconstituted in 200 µL of 90:10:1 solution of acetonitrile, water, and formic acid. The samples were transferred into limited volume inserts and injected into the liquid chromatography/tandem mass spectrometry (LC/MS/MS) system (API 3000, MDS Sciex, Foster City, Calif).

Chromatographic Conditions
For buspirone, 6OHB, and 1-PP, chromatographic separation was achieved isocratically on a Hypersil Silica precolumn (Keystone Scientific, Penn, 3 x 50 mm, 3 µm) and a Cyclobond I TM 2000 analytical column (Astec, Whippany, NJ: 2.0 x 150 mm, 3 µm). The mobile phase, containing 80% acetonitrile, 20% 20 mM ammonium acetate (pH 2.5), was pumped at 0.3 mL/min. Detection was by positive ion electrospray tandem mass spectrometry (API 3000). For selected reaction monitoring, the transitions monitored were mass-to-charge ratio (m/z) 402 to m/z 122 for 6OHB, m/z 386 to m/z 122 for buspirone, m/z 165 to m/z 122 for 1-PP, m/z 393 to m/z 127 for [13C,15N2,D4]buspirone and m/z 172 to m/z 127 for [13C,15N2,D4]1-PP. The standard curves, which ranged from 0.0050 to 10.0 ng/mL for buspirone, 0.010 to 10.0 ng/mL for 6OHB, and 0.050 ng/mL for 1-PP, were fitted to a 1/x2 weighted linear regression model using peak area ratios of the analyte to the internal standards. The interassay precision was within 7.8% coefficient of variation for all analytes. The assay accuracy was within ±4.7% of the nominal values.

Pharmacokinetic Analysis
Pharmacokinetic parameters for 6OHB, buspirone, and 1-PP were determined using noncompartmental methods19,20: peak plasma concentration (Cmax), time to reach Cmax (tmax), area under the plasma concentration-time curve from dosing to 12 hours or to the last measurable time point within the dosing interval (AUC0-t), half-life (t1/2), metabolite ratio (ratio of the AUC of each metabolite to the AUC of buspirone, corrected for molecular weight), and AUC ratio for each analyte (AUC at each dose of buspirone compared to the 5-mg dose of buspirone). Geometric means and coefficients of variation for Cmax, AUC0-t, and metabolite ratio were determined. AUC ratio was based on the mean AUC at each dose. Medians and ranges were calculated for tmax. Means and standard deviations were determined for t1/2.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The study enrolled 13 subjects (12 men and 1 woman), and all enrolled subjects completed the study. The mean age was 28 years (range, 20-42 years), with 10 of white ethnicity, 2 Hispanic, and 1 American Indian. Mean weight was 75.2 kg (range, 59.9-93.5 kg), mean height was 178.9 cm (range, 165-191 cm), and mean body mass index was 23.5 kg/m2 (range, 19.3-28.8 kg/m2).

The pharmacokinetics of 1-PP and 6OHB appeared to be dose proportional, whereas the Cmax and AUC of buspirone tended to increase slightly greater than the dose increment at the higher doses (Table I). The exposure to 1-PP was approximately 20-fold greater than that of the parent drug buspirone, and that of 6OHB was approximately 40-fold greater (Table I and Figure 1). This fact, and the large metabolite ratio values, indicated that both 1-PP and 6OHB were major metabolites of buspirone. The Cmin values indicated that steady state was reached at each dose for each analyte within 4 days of buspirone dosing. The tmax values of these metabolites were not much longer than that of buspirone itself.


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  		Table I Pharmacokinetic Parameters for Buspirone, 1-(2-pyrimidinyl)-piperazine (1-PP), and 6-hydroxybuspirone (6OHB) After 5 Days of Dosing at the Corresponding Buspirone Dosesa

 

Figure 1
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  		Figure 1. Mean plasma concentration versus time profiles of buspirone, 1-(2-pyrimidinyl)-piperazine (1-PP), and 6-hydroxybuspirone (6OHB) after a 5-day oral administration of 5, 7.5, 15, 20, and 30 mg buspirone HCl on a twice-daily dosing reimen.

 

Because of the small sample size in this study, safety could not be robustly assessed. However, there were no untoward effects seen in ECG or clinical laboratory monitoring, and the doses were generally well tolerated. There were no adverse events reported in this study that were different from those already known following BuSpar® administration.1


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
This study indicated that 6OHB was a major metabolite of buspirone. Its concentrations were approximately 40-fold greater than those of buspirone and were about twice those observed from the metabolite 1-PP. Exposure to 6OHB appeared to be proportional to the dose of buspirone administered. However, the metabolite ratio of 6OHB to busprione appeared to be slightly less at the higher buspirone doses, probably because of buspirone exposure being slightly greater than the dose increment increase at these higher doses. Both 1-PP and 6OHB were rapidly formed, as indicated by their tmax values being not much different from those of buspirone itself.

CONCLUSIONS
The steady-state AUC and Cmax of buspirone increased greater than the dose increment across its dose range, whereas those of 1-PP and 6OHB increased approximately proportionally to the buspirone dose increment. Because of the 40-fold greater exposure to 6OHB compared to buspirone following buspirone dosing, 6OHB may be a significant contributor to the efficacy of buspirone. The multiple dosing of buspirone, ranging from 5 mg twice daily to 30 mg twice daily, was safe and generally well tolerated. Further research regarding the safety and efficacy of 6OHB itself is warranted.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
Financial disclosure: Bristol-Myers Squibb sponsored this study. See also author employment.

DOI: 10.1177/0091270006292250


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Bristol-Myers Squibb Company. BuSpar (buspirone HCl) tablets. In: Physicians' Desk Reference. 53 rd ed. Montvale, NJ: Thomson PDR, 1999: 823-825.

2. Gorman JM. Treating generalized anxiety disorder. J Clin Psychiatry. 2003;64(suppl 2): 24-29.

3. Robinson DS, Rickels K, Feighner J, et al. Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression. J Clin Psychopharmacol. 1990;10(suppl): 67S-76S.[Medline] [Order article via Infotrieve]

4. Blier P, Ward NM. Is there a role for 5-HT1A agonists in the treatment of depression? Biol Pshychiatry. 2003;53: 193-203.

5. Marangell LB. Augmentation of standard depression therapy. Clin Ther. 2000;22(suppl A): A25-A38; discussion A39-A41.

6. Appelberg BG, Syvalahti EK, Koskinen TE, Mehtonen OP, Muhonen TT, Naukkarinen HH. Patients with severe depression may benefit from buspirone augmentation of selected serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study. J Clin Psychiatry. 2001;62: 448-452.[Web of Science][Medline] [Order article via Infotrieve]

7. Rothschild AJ. New direction in the treatment of antidepressantinduced sexual dysfunction. Clin Ther. 2000;22(suppl A): A42-A47; discussion A58-A61.

8. Gitlin M. Sexual dysfunction with psychotropic drugs. Expert Opin Pharmacother. 2003;4: 2259-2269.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Niederhofer H. An open trial of buspirone in the treatment of attention-deficit disorder. Hum Psychopharmacol. 2003;18: 489-492.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

10. Rynn M, Garcia-Espana F, Greenblatt DJ, Mandos LA, Schjweizer E, Rickels K. Imipramine and buspirone in patients with panic disorder who are discontinuing long-term benzodiazepine therapy. J Clin Psychopharmacol. 2003;23: 505-508.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Cooper JP. Buspirone for anxiety and agitation in dementia. J Psychiatry Neurosci. 2003;28: 469.[Web of Science][Medline] [Order article via Infotrieve]

12. Cornelius JR, Bukstein O, Salloum I, Clark D. Alcohol and psychiatric comorbidity. Recent Dev Alcohol. 2003;16: 361-374.[Medline] [Order article via Infotrieve]

13. Mayol RF, Adamson DS, Gammans RE, LaBudde JA. Pharmacokinetic disposition of 14C-buspirone HCl after intravenous and oral dosing in man. Clin Pharmacol Ther. 1985;37: 210.

14. Gammans RE, Mayol RF, LaBudde JA. Metabolism and disposition of buspirone. Am J Med. 1986;80(suppl 3B): 41-51.[Web of Science][Medline] [Order article via Infotrieve]

15. Gammans RE, Johnston RE. Metabolism, pharmacokinetics and toxicology of buspirone. In: Tunnicliff G, Eison A, Taylor D. Buspirone: Mechanisms and Clinical Aspects. San Diego, Calif: Academic Press; 1995: 223-260.

16. Jajoo HK, Mayol RF, LaBudde JA, Blair IA. Metabolism of the antianxiety drug buspirone in human subjects. Drug Metab Dispos. 1989;17: 634-640.[Abstract]

17. Caccia S, Conti J, Vigano G, Garattini S. 1-(2-pyrimidinyl)-piperazine as active metabolite of buspirone in man and rat. Pharmacology. 1986;33: 46-51.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

18. Zhu M, Zhao W, Jimenez H, et al. Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes. Drug Metab Dispos. 2005;33: 500-507.[Abstract/Free Full Text]

19. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York, NY: Marcel-Dekker; 1982: 409-417.

20. Riegelman S, Collier P. The application of statistical moment theory to the evaluation of in vivo dissolution time and absorption time. J Pharmacokinet Biopharm. 1980;8: 509-534.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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