Abstract
Purpose
Compare the simulated pharmacokinetics of lipid-associated and soluble indinavir (IDV) to determine the potential for greater control of virus replication in the lymphoid tissues.
Methods
Two-compartment mathematical models were developed to simulate the human pharmacokinetics of soluble and lipid-associated forms of IDV in the central compartment and the lymphoid tissue. The lipid-associated IDV model was then used to determine the minimum dosing schedule needed to attain central or lymph drug concentrations comparable to the soluble form.
Results
Association of IDV to lipid nanoparticles has a favorable half-life and tissue distribution and allows comparable minimum drug concentration in the lymph (where the majority of viral replication occurs) to be achieved with a dosing schedule of every 95.5 h (∼4 days).
Conclusions
Presuming pharmacodynamics of lipid-associated IDV are similar to soluble IDV, estimations based on the proposed kinetic model suggest the novel delivery system could have a tremendous impact on the current standard of HIV treatment, particularly for therapy targeted to clear virus sanctuaries in lymphoid tissues. With less frequent and more effective dosing, lipid-associated indinavir delivery as an adjunct to conventional antiviral therapy could lead to better suppression of viral replication, increased immunological benefit, and fewer treatment failures.
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References
D. Finzi and R. F. Siliciano. Viral dynamics in HIV-1 infection. Cell 93:665–671 (1998).
A. T. Haase. Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu. Rev. Immunol. 17:625–656 (1999).
W. Cavert, D. W. Notermans, K. Staskus, S. W. Wietgrefe, M. Zupancic, K. Gebhard, K. Henry, Z. Q. Zhang, R. Mills, H. McDade, C. M. Schuwirth, J. Goudsmit, S. A. Danner, and A. T. Haase. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 276:960–964 (1997).
G. Pantaleo, C. Graziosi, J. F. Demarest, L. Butini, M. Montroni, C. H. Fox, J. M. Orenstein, D. P. Kotler, and A. S. Fauci. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362:355–358 (1993).
F. Mammano, V. Trouplin, V. Zennou, and F. Clavel. Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: virus fitness in the absence and in the presence of drug. J. Virol. 74:8524–8531 (2000).
J. Martinez-Picado, M. P. DePasquale, N. Kartsonis, G. J. Hanna, J. Wong, D. Finzi, E. Rosenberg, H. F. Gunthard, L. Sutton, A. Savara, C. J. Petropoulos, N. Hellmann, B. D. Walker, D. D. Richman, R. Siliciano, and R. T. D'Aquila. Antiretroviral resistance during successful therapy of HIV type 1 infection. Proc. Natl. Acad. Sci. USA. 97:10948–10953 (2000).
L. Kinman, S. J. Brodie, C. C. Tsai, T. Bui, K. Larsen, A. Schmidt, D. Anderson, W. R. Morton, S. L. Hu, and R. J. Ho. Lipid-drug association enhanced HIV-1 protease inhibitor indinavir localization in lymphoid tissues and viral load reduction: a proof of concept study in HIV-2287-infected macaques. J. Acquir. Immune Defic. Syndr. 34:387–397 (2003).
T. Lian and R. J. Ho. Trends and developments in liposome drug delivery systems. J. Pharm. Sci. 90:667–680 (2001).
C. Oussoren, J. Zuidema, D. J. Crommelin, and G. Storm. Lymphatic uptake and biodistribution of liposomes after subcutaneous injection. II. Influence of liposomal size, lipid compostion and lipid dose. Biochim. Biophys. Acta. 1328:261–272 (1997).
M. A. Boyd, R. E. Aarnoutse, K. Ruxrungtham, M. Stek, Jr., R. P. van Heeswijk, J. M. Lange, D. A. Cooper, P. Phanuphak, and D. M. Burger. Pharmacokinetics of indinavir/ritonavir (800/100 mg) in combination with efavirenz (600 mg) in HIV-1-infected subjects. J. Acquir. Immune Defic. Syndr. 34:134–139 (2003).
B. Clotet, L. Menéndez-Arias, L. Ruiz, C. Tural, A. Vandamme, D. Burger, J. Schapiro, C. A. Boucher, R. D'Aquila, and D. Richman. Guide to management of HIV resistance and pharmacokinetics of drug therapy 94–96 (2000).
Yoffey and Courtice. Lymphatics, lymph and lymphoid tissue, 2nd edn. London, 26–27 (1956).
Merck & Co., Inc. Crixivan® Prescribing Information, (2004).
B. D. M. C. Khoo S. Pharmacology. In G. G. J. Boucher C. A. (ed.), Practical Guidelines in Antiviral Therapy, Elsevier, 2002.
C. Solas, A. Lafeuillade, P. Halfon, S. Chadapaud, G. Hittinger, and B. Lacarelle. Discrepancies between protease inhibitor concentrations and viral load in reservoirs and sanctuary sites in human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 47:238–243 (2003).
Acknowledgments
This study was supported by a grant from the UNCF-Merck Science initiative (S.J.S.) and NIH grants #AI52663 and #RR00166 (R.J.Y.H). The authors wish to thank Elliot M. Landaw and Guenther Hochhaus for critical reading and helpful comments.
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Snedecor, S.J., Sullivan, S.M. & Ho, R.J.Y. Feasibility of Weekly HIV Drug Delivery to Enhance Drug Localization in Lymphoid Tissues Based on Pharmacokinetic Models of Lipid-Associated Indinavir. Pharm Res 23, 1750–1755 (2006). https://doi.org/10.1007/s11095-006-9026-1
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DOI: https://doi.org/10.1007/s11095-006-9026-1