The Statistical Analysis of Pharmacokinetic Parameters in the Context of Bioequivalence Testing of Two Anthelmintic Formulas Based on Ivermectine and Triclabendazole in Sheep

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Abstract

Conducting bioequivalence studies is an essential step during the market authorization process of generic pharmaceutical formulations, for both human or veterinary use. The aim of the present study was to evaluate the pharmacokinetics of triclabendazole sulphoxide, the main metabolite of triclabendazole, and ivermectin in order to evaluate the bioavailability and bioequivalence of a novel sheep anthelmintic formulation of oral suspension for sheep treatment containing triclabendazole 50 mg/mL and ivermectin 1 mg/mL compared to the reference product. In order to determine relative bioavailability of the test product with respect to the reference product the study was conducted on 36 clinically healthy sheep, following an unicentric, randomized, cross-over, two-sequence, two-treatment and 14-day wash-out study design. For the determination of triclabendazole sulphoxide and ivermectin sheep plasma concentrations, two rapid, selective high performance liquid chromatography coupled with mass spectrometry (LC-MS/MS) methods were developed and validated. The measured plasma concentrations of triclabendazole sulphoxide and ivermectin were used for the pharmacokinetic analysis and the determination of bioequivalence between the test product with regards to the reference product. The noncompartmental analysis of the pharmacokinetic data for both triclabendazole sulphoxide and ivermectin showed similarities between first-order kinetics of the test and reference product. The relevant pharmacokinetic parameters (Cmax, AUClast, AUCtot) were determined and the bioequivalence between the test and reference product could be concluded.

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  • 1. Barrera B Otero JA Egido E et al. The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP. Antimicrob Agents Chemother 2012; 56(7): 3535-3543.

  • 2. Halferty L Brennan GP Trudgett A Hoey L Fairweather I. Relative activity of triclabendazole metabolites against the liver fluke Fasciola hepatica. Vet Parasitol 2009; 159:126–138.

  • 3. González Canga A Sahagún Prieto AM José Diez Liébana M Martínez NF Vega MS Vieitez JJ. The pharmacokinetics and metabolism of ivermectin in domestic animal species. Vet J 2009; 179: 25–37.

  • 4. Lifschitz A Virkel G Ballent M Sallovitz J Lanusse C. Combined use of ivermectin and triclabendazole in sheep: In vitroand in vivo characterisation of their pharmacological interaction. Vet J 2009; 182: 261–268.

  • 5. Stevenson CR Mahoney RH Fisara P Strehlau G Reichel MP. The efficacy of formulations of triclabendazole and ivermectin in combination against liver fluke (Fasciolahepatica) and gastro-intestinal nematodes in cattle andsheep and sucking lice species in cattle. Aust Vet J. 2002; 80(11): 698-701

  • 6. International Committee for Harmonization. GUIDELINE FOR GOOD CLINICAL PRACTICE E6 (R1). https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf [retrieved March 22nd 2019]

  • 7. The European Agency for the Evaluation of Medicinal Products. CVMP Guideline on the Conduct of Bioequivalence Studies for Veterinary Medicinal Products EMA/CVMP/016/00-Rev.2.

  • 8. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-conduct-bioequivalence-studies-veterinary-medicinal-products-revision-2_en.pdf [retrieved March 22nd 2019]

  • 9. The European Agency for the Evaluation of Medicinal Products. CVMP Guidelines for the Conduct of Bioequivalence Studies for Veterinary Medicinal Products EMEA/CVMP/016/00-corr-FINAL.

  • 10. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-conduct-bioequivalence-studies-veterinary-medicinal-products-revision-1_en.pdf [retrieved March 22nd 2019]

  • 11. The European Agency for the Evaluation of Medicinal Products. VICH GL52 Bioequivalence: Blood Level Bioequivalence Study EMA/CMVP/VICH/751935/2013-Corr. https://www.ema.europa.eu/en/documents/scientific-guideline/international-cooperation-harmonisation-technical-requirements-registration-veterinary-medicinal_en-3.pdf [retrieved March 22nd 2019]

  • 12. http://kineticadownload.com/Kinetica5.0/data/Kinetica%20User%20Manual.pdf [retrieved March 22nd 2019]

  • 13. U.S. Department of Health and Human Services Food and Drug Administration Bioavailability and Bioequivalence Studies for Orally Administrated Drug Products – General Considerations Rockville USA 2003 https://www.fda.gov/downloads/Drugs/Guidances/ucm154838 [retrieved March 22nd 2019]

  • 14. The European Agency for the Evaluation of Medicinal Products. Note for Guidance on the Investigation of Bioavailability and Bioequivalence London UK 2001 (CPMP/EWP/QWP/1401/98). https://www.ema.europa.eu/en/documents/scientific-guideline/draft-note-guidance-investigation-bioavailability-bioequivalence_en.pdf [retrieved March 22nd 2019]

  • 15. The European Agency for the Evaluation of Medicinal Products. Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf [retrieved March 22nd 2019]

  • 16. U.S. Department of Health and Human Services Food and Drug Administration. Bioanalytical Method ValidationGuidance for Industry. https://www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf [retrieved March 22nd 2019]

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