Identification of Mechanism and Pathway of the Interaction between the African Traditional Medicine, Sutherlandia Frutescens, and the Antiretroviral Protease Inhibitor, Atazanavir, in Human Subjects Using Population Pharmacokinetic (PK) Analysis
DOI:
https://doi.org/10.18433/jpps30068Abstract
Although the use of the indigenous Southern African plant, Sutherlandia frutescens (SF) for the treatment of HIV/AIDS has previously been described, the risk which it may pose to the safety and efficacy of ARVs and the potential mechanisms which underlie such effects may have clinical significance and relevance. The protease inhibitor (PI), atazanavir (ATV) is a substrate of the efflux transporter, P-gp which modulates absorption in the small intestine, as well as CYP3A4 and CYP3A5enzymes which facilitate metabolism in the small intestine and liver. The objective of this study was to investigate the effect of SF on the pharmacokinetics (PK) of atazanavir (ATV) and to use a population PK analysis to fit and explain plasma concentration vs. time profiles of ATV generated in a previously conducted study in healthy male subjects in order to understand and postulate on the potential mechanism(s) of the drug-drug interaction. The population PK Compartmental Analysis of ATV before and after a two-week regimen of Phyto Nova Sutherlandia SU1 tablets which contain SF plant material indicated that a two compartment model with a dual absorption mechanism best explained the data. The dual absorption mechanism is hypothesized to reflect “passive” (first-order, Ka parameter) and “active” (zero-order, K0 parameter) absorption processes. The model suggested that the mechanism by which SF reduced the overall bioavailability of ATV may be modulated via the inhibition of the “active” absorption process. This study has highlighted the utility of population PK analyses in postulating probable mechanism(s) whereby an ATM or a herbal medicine interacts with an allopathic drug.
Downloads
References
Babb DA, Pemba L, Seatlanyane P, Charalambous S, Churchyard GJ, Grant AD. Use of traditional medicine in the era of antiretroviral therapy: experience from South Africa. 15th International Conference on AIDS 2004; Bangkok, Thailand abstract no. B10640. http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102276492.html;
Langlois-Klassen D, Kipp W, Jhangri GS, Rubaale T. Use of traditional herbal medicine by AIDS patients in Kabarole district, western Uganda. Am J Trop Med Hyg, 2007; 77: 757–763.
Malangu N. Self-reported use of traditional, complementary and over-the-counter medicines
by HIV-infected patients on antiretroviral therapy in Pretoria, South Africa. Afr J Tradit Complement Altern Med 2007; 4: 273–278.
Peltzer K, du Preez NFD, Ramlagan S, Fomundam H. Use of traditional complementary and alternative medicine for HIV patients in KwaZulu-Natal, South Africa. BMC Publ Health, 2008; 8: 255.
Watson RR, Stanaway, JD. African medicinal plants for the treatment of HIV/AIDS, in: Medicine in Clinical Practice, 2008; 13-30, GAB International.
Bousquet L, Roucairol C, Hembury A, Nevers MC, Creminon C, Farinotti R, Mabondzo, A. Comparison of ABC transporter modulation by atazanavir in lymphocytes and human brain endothelial cells: ABC transporters are involved in the atazanavir-limited passage across an in vitro human model of the blood-brain barrier. AIDS Research and Human Retroviruses, 2008; 24: 1147-1154.
Janneh O, Anwar T, Jungbauer C, Kopp S, Khoo SH, Back DJ, Chiba P. P-glycoprotein, multidrug resistance-associated proteins and human organic anion transporting polypeptide influence the intracellular accumulation of atazanavir. Antiviral Therapy, 2009; 14: 965-974.
Le Tiec C, Barrail A, Goujard U, Taburet AM, Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Clinical Pharmacokinetics, 2005; 44: 1035-1050.
Müller AC, Patnala S, Kis O, Bendayan R, Kanfer I. Interactions between phytochemical components of Sutherlandia frutescens and the antiretroviral, atazanavir in vitro: implications for absorption and metabolism. Journal of Pharmacy and Pharmaceutical Sciences, 2012; 15: 221- 233.
van Wyk BE, Albrecht C. A review of the taxonomy, ethnobotany, chemistry and pharmacology of Sutherlandia frutescens (Fabaceae). Journal of Ethnopharmacology, 2008; 119: 620-629.
Fu X, Li XC, Smillie TJ, Carvalho P, Mabusela W, Syce J, Johnson Q, Folk W, Avery MA, Khan IA. Cycloartane glycosides from Sutherlandia frutescens. Journal of Natural Products, 2008; 71: 1749-1753.
Fu X, Li XC, Wang YB, Avula B, Smillie TJ, Mabusela, W, Syce J, Johnson Q, Folk W. Khan IA. Flavonol glycosides from the South African medicinal plant Sutherlandia frutescens, Planta Medica, 2010; 76: 178-181.
Avula B, Wang YH, Smillie TJ, Fu X, Li XC, Mabusela W, Syce J, Johnson Q, Folk W, . Khan IA. Quantitative determination of flavonoids and cycloartanol glycosides from aerial parts of Sutherlandia frutescens (L.) R. BR. by using LC-UV/ELSD methods and confirmation by using LC-MS method, Journal of Pharmaceutical and Biomedical Analysis, 2010; 52: 173-180.
Committee for Proprietary Medicinal Products, Note for Guidance on the Investigation of Drug Interactions, European Medicines Agency, London, 1997.
US Food and Drug Administration, Guidance for industry: In vivo drug metabolism/drug interaction studies-study design, data analysis, and recommendations for dosing and labeling. 1999.
Strnad, C F, Therapeutics Products Programme Guidance Document, Drug-drug interactions: Studies In Vitro and In Vivo, Health Canada, 2000.
US Department of Health and Human Services, Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. Food and Drug Administration, Rockville, MD, 2001.
Zhang P. A simple formula for sample size calculation in equivalence Studies. Journal of Biopharmaceutical Statistics, 2003; 13: 529.
Müller, A.C, Skinner, M.F. and Kanfer, I. Effect of the African Traditional Medicine, Sutherlandia frutescens, on the bioavailability of the antiretroviral protease inhibitor, atazanavir. Evidence-based Complementary and Alternative Medicine, 2013; 4: 324618.
Colucci P, Pottage JC, Robison H, Turgeon J, Ducharme MP. Effect of a single dose of ritonavir on the pharmacokinetic behavior of elvucitabine, a nucleoside reverse transcriptase inhibitor, administered in heathy volunteers. Antimicrob Agents Chemother 2009; 53(2):646-50.
Colucci P, Pottage JC, Robison H, Turgeon J, Schurmann D, Hoepelman IM, Ducharme MP. Antimicrob Agents Chemother 2009; 53(2):662-9.
Bonate PL, Ahamadi M, Budha N, et al. Methods and strategies for assessing uncontrolled drug-drug interactions in population pharmacokinetic analyses: results from the International Society of Pharmacometrics (ISOP) Working Group. J Pharmacokinet Pharmacodyn 2016;43:123-135.
Department of Health: Pretoria, South Africa. Guidelines for good practice in the conduct of clinical trials with human participants in South Africa,, 2006; 2nd Edition.
Declaration of Helsinki, Ethical principles for medical research involving human subjects, adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964. Amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975; 35th WMA General Assembly, Venice, Italy, October 1983; 41st WMA General Assembly, Hong Kong, September1989; 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996, 52nd WMA General Assembly, Edinburgh, Scotland, October 2000, 59th WMA General Assembly, Seoul, Republic of Korea October 2008 and 64th WMA General Assembly, Fortazela, Brazil, Oxctober 2013.
Müller AC, Kanfer I. An efficient HPLC method for the quantitative determination of atazanavir in human plasma suitable for bioequivalence and pharmacokinetic studies in healthy human subjects. Journal of Pharmaceutical and Biomedical Analysis, 2010; 53, 113-118.
D’Argenio DZ, Schumitzky A, Wang X. ADAPT 5 User’s guide: Pharmacokinetic/Pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los Angeles, 2009.
Downloads
Published
How to Cite
Issue
Section
License
This is an open access journal with free of charge non-commercial download. At the time of submission, authors will be asked to transfer the copyright to the accepted article to the Journal of Pharmacy and Pharmaceutical Sciences. The author may purchase the copyright for $500 upon which he/she will have the exclusive copyright to the article. Nevertheless, acceptance of a manuscript for publication in the Journal is with the authors' approval of the terms and conditions of the Creative Commons copyright license Creative Common license (Attribution-ShareAlike) License for non-commercial uses.
CLOCKSS system has permission to collect, preserve, and serve this Archival Unit.
