Bioequivalence study of two oral tablet formulations containing saquinavir mesylate boosted with ritonavir in healthy male subjects

Abstract

Saquinavir (SAQ) mesylate (CAS 149845-06-7) is a potent inhibitor of the HIV-1 protease indicated in combination with other antiretrovirals for the management of HIV-1 infection. The objective of this study was to compare rate and extent of absorption and to assess the bioequivalence between a new pharmaceutical equivalent tablet formulation containing 500 mg of SAQ mesylate and the innovator film coated tablet formulation. A randomized, single-center, open-label, twotreatment, two-sequence, three-period, replicated crossover bioequivalence study in 40 healthy male subjects was conducted. All subjects received 100 mg ritonavir (CAS 155213-67-5) twice daily for a run-in period of 3 days before treatment. Dosing was separated by a wash-out period of 14 days. Blood samples were collected over 72 h and plasma levels of SAQ were determined by a validated HPLC/UV assay. The 90%confidence interval(CI) of the ratio of the geometric means for logtransformed Cmax, AUClast and AUCinf values were used to assess bioequivalence using the equivalence interval of 80–125%. Point estimate and 90% CI of the ratios of Cmax, AUClast and AUCinf values were 94.9 (80.9–111.3), 97.4 (82.4–115.4) and 97.4 (82.5–115.0), respectively. Both treatments exhibited similar tolerability and safety. It was concluded that the new pharmaceutical product was bioequivalent to the innovator.

Key words

Antiretroviral - Bioequivalence - Healthy volunteers - Saquinavir mesylate

• References

• 1 Product Monograph. Pr. Invirase o. Saquinavir mesylate. Film Coated Tablets - 500 mg saquinavir - Hard Gelatin Capsules 200 mg saquinavir. Pharmaceutical standard proffesed. HIV Protease Inhivitor/ Antiretroviral Agent. Hoffmann-La Roche Limited 2455 Meadowpine Boulevard, Mississauga, Ontario. Date of Revision: March 22, 2010. Availalable at: www.rochediagnostics.ca/portal/servlet/staticfilesServlettype
• 2 Eagling VA, Wiltshire H, Whitcombe IW, Back DJ. CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir in vitro. Xenobiotica. 2002; 32: 1-17
• 3 Eagling VA, Back DJ, Barry MG. Differential inhibition of cytocrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol. 1997; 44 (2) 190-4
• 4 Drewe J, Gutmann H, Fricker G, Torok M, Begliner C, Huwyler J. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Bioch Pharmacol. 1999; 57 (10) 1147-52
• 5 Van Heeswijk RP, Veldkamp A, Mulder JW, Meenhorst PL, Lange JM, Beijnen JH. Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience. Antivir Ther. 2001; 6 (4) 201-29
• 6 Kilby J, Hill A, Buss N. The effect of ritonavir on saquinavir plasma concentration is independent of ritonavir dosage: combined analysis of pharmacokinetic data from 97 subjects. HIV Med. 2002; 3: 1-8
• 7 Kurowski M, Sternfeld T, Sawyer A, Hill A, Moklinghoff C. Pharmacokinetic and tolerability profile of twice-daily saquinavir hard gelatin capsules and saquinavir soft gelatin capsules boosted with ritonavir in healthy volunteers. HIV Med. 2003; 4: 94-100
• 8 Bittner B, Riek M, Holmes B, George S. Saquinavir 500 mg film-coated tablets demonstrate bioequivalence to saquinavir 200 mg hard capsules when boosted with twice-daily ritonavir in healthy volunteers. Antivir Ther. 2005; 10 (7) 803-10
• 9 Cradiello PG, Monhaphol T, Mahanontharit A, Van Heeswijk RP, Burger D, Hill A et al Pharmacokinetics of once-daily saquinavir hard-gelatin capsules and saquinavir soft-gelatin capsules boosted with ritonavir in HIV-1 infected subjects. JAIDS. 2003; 32 (4) 375-9
• 10 Vanhove GF, Kastrissios H, Gries JM, Verotta D, Park K, Collier AC et al Pharmacokinetics of saquinavir, zidovudine, and zalcitabine in vombination therapy. Antimicrob Agents Chemother. 1997; 41 (11) 2428-2432
• 11 Thompson MA, Aberg JA, Cahn P, Montaner JS, Rizzardini G, Telenti A et al International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010; 304 (3) 321-33 Available at: http://jama.amaassn.org/content/304/3/321.full
• 12 British HIV Association (BHIVA) guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Medicine; 9, 563–608. Available at: http://www.bhiva.org/TreatmentofHIV1_2008.aspx
• 13 U.S. Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. Section V 2001. Available at: www.fda.gov/downloads/Drugs/…/Guidances/ucm070244.pdf
• 14 World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. Seoul 2008
• 15 U.S. Department of Health and human services, Food and Drug Administration Center for Drug Evaluation and Research (CDER). ICH E6. Good Clinical Practices: Consolidated Guidance 1996
• 16 U.S. Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for Industry: Bioavailability and Bioequivalence Studies for orally Administered Drug Products - General Considerations. Revision 1. Rockville, MD; 2003. Available at: http://www.fda.gov/cder/guidance/5356fnl.pdf
• 17 Shein-Chung Ch, Liu JP. Design and analysis of bioavailability and bioequivalence studies. In: power and sample size determination. Chapter 5; 2nd. ed. Vol 133. New York: Marcel Dekker; 2000
• 18 Aymard G, Legrand M, Trichereau N, Diquet B. Determination of twelve antiretroviral agents in human plasma sample using reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 2000; 744 (2) 227-40
• 19 U.S. Department of Health and Human Services, Food and drug Administration Center for Drug Evaluation and Research (CDER). Guidance for Industry: Bioanalytical Method Validation, May 2001.
• 20 Assessment Report - Invirase, INN-Saquinavir. Scientific Discussion. EMEA.2005. Available at: www.ema.europa.eu/docs/en_GB/…library/…/WC500035085.pdf
• 21 Fletcher CV, Jiang H, Brundage RC, Acosta EP, Haubrich R, Katzenstein D et al Sex-based differences in saquinavir pharamacology and virologic response in AIDS Clinical Trials Group Study 359. J Infect Dis. 2004; 189 (7) 1176-1184
• 22 Van der Lugt J, Colbers A, Molto J, Hawkins D, Van der Ende M, Vogel M et al The pharmacokinetics, safety and efficacy of boosted saquinavir tablets in HIV type-1 infected pregnant women. Antivir Ther. 2009; 14 (3) 443-450
• 23 Wisnton A, Mallon PW, Satchell C, MacRae K, Williams KM, Schultz M et al The safety, efficacy, and pharmacokinetic profile of a switch in antiretroviral therapy to saquinavir, ritonavir, and alone for 48 weeks and a