Pharmacokinetic Analysis of Two Different Doses of Duloxetine Following Oral Administration in Dogs

Abstract

Background:

Duloxetine is a potent and balanced dual inhibitor of serotonin and norepinephrine reuptake that is being investigated for the treatment of depression and urinary incontinence. The purpose of this study was to investigate the pharmacokinetic properties of duloxetine in 20 beagle dogs following a single oral administration of a 30- or 60-mg enteric-coated pellet in a capsule (Cymbalta).

Method:

Following the administration of 30 or 60 mg of Cymbalta to 20 beagle dogs, the plasma concentration of duloxetine was measured using LC-MS/MS. Pharmacokinetic parameters were analyzed using both noncompartmental and compartmental approaches.

Results:

The values of C _max and AUC increased in proportion to the dose of duloxetine. The one compartment model with first-order absorption and a lag time was used successfully for pharmacokinetic analysis of duloxetine following a single oral administration of Cymbalta 30 mg or 60 mg.

Conclusion:

The studies described here are the first to report the pharmacokinetics of oral duloxetine in dogs, and these findings provide important information for pharmaceutical formulation research of duloxetine using dogs.

Key words

cymbalta - LC-MS/MS - ADAPT 5 - compartmental analysis - lag time - enteric-coated capsule

• References

• 1 Bymaster FP, Lee TC, Knadler MP et al. The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des 2005; 11: 1475-1493
• 2 Detke MJ, Lu Y, Goldstein DJ et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry 2002; 63: 308-315
• 3 Knadler MP, Lobo E, Chappell J et al. Duloxetine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet 2011; 50: 281-294
• 4 Chan C, Yeo KP, Pan AX et al. Duloxetine pharmacokinetics are similar in Japanese and Caucasian subjects. Br J Clin Pharmacol 2007; 63: 310-314
• 5 Skinner MH, Kuan HY, Pan A et al. Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003; 73: 170-177
• 6 Murata K, Noda K. Pharmacokinetic analysis of an oral sustained-release diltiazem preparation using multifraction absorption models. Pharm Res 1993; 10: 757-762
• 7 Jansen PJ, Oren PL, Kemp CA et al. Characterization of impurities formed by interaction of duloxetine HCl with enteric polymers hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate. J Pharm Sci 1998; 87: 81-85
• 8 Akaike HA. New Look at the Statistical Model Identification. IEEE Trans Automat Contr 1974; 19: 716-723
• 9 D’Argenio DZ, Schumitzky A. ADAPT II User’s Guide: Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Biomedical Simulations Resource; Los Angeles: 1997
• 10 Lantz RJ, Gillespie TA, Rash TJ et al. Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects. Drug Metab Dispos 2003; 31: 1142-1150
• 11 Senthamil SP, Gowda KV, Mandal U et al. Determination of duloxetine in human plasma by liquid chromatography with atmospheric pressure ionization-tandem mass spectrometry and its application to pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 858: 269-275
• 12 US Food and Drug Administration . Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. Center for Drug Evaluation and Research; Rockville: 2005
• 13 Sutton SC. Companion animal physiology and dosage form performance. Adv Drug Deliv Rev 2004; 56: 1383-1398
• 14 Patel K, Padhye S, Nagarsenker M. Duloxetine HCl lipid nanoparticles: preparation, characterization, and dosage form design. AAPS PharmSciTech 2012; 13: 125-133