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 (approximately 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.
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 (approximately 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.
Authors: 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; A T Haase Journal: Science Date: 1997-05-09 Impact factor: 47.728
Authors: G Pantaleo; C Graziosi; J F Demarest; L Butini; M Montroni; C H Fox; J M Orenstein; D P Kotler; A S Fauci Journal: Nature Date: 1993-03-25 Impact factor: 49.962
Authors: Loren Kinman; Scott J Brodie; Che Chung Tsai; Tot Bui; Kay Larsen; Ann Schmidt; David Anderson; William R Morton; Shiu-Lok Hu; Rodney J Y Ho Journal: J Acquir Immune Defic Syndr Date: 2003-12-01 Impact factor: 3.731
Authors: 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; R T D'Aquila Journal: Proc Natl Acad Sci U S A Date: 2000-09-26 Impact factor: 11.205
Authors: Bhavesh D Kevadiya; Brendan Ottemann; Insiya Z Mukadam; Laura Castellanos; Kristen Sikora; James R Hilaire; Jatin Machhi; Jonathan Herskovitz; Dhruvkumar Soni; Mahmudul Hasan; Wenting Zhang; Sarella Anandakumar; Jered Garrison; JoEllyn McMillan; Benson Edagwa; R Lee Mosley; Richard W Vachet; Howard E Gendelman Journal: Theranostics Date: 2020-01-01 Impact factor: 11.556