Research Summary
Clinical research activities investigate the clinical pharmacology of new anti-HIV therapies and drug combinations. Specific drug classes studied include HIV reverse transcriptase inhibitors, protease inhibitors, entry inhibitors (selective CCR5 and CXCR4 antagonists), and integrase inhibitors. Scientific objectives of clinical studies include characterization of early drug activity, toxicity, and pharmacokinetics. Additional objectives are characterization of pathways of drug metabolism, and identification of clinically significant harmful and beneficial drug interactions mediated by hepatic and intestinal cytochrome P450 isoforms.
Clinical Trial Keywords
Phase 4; Phase 3; Phase 2; Phase 1; Pharmacokinetics
Clinical Trials
Flexner C, Tierney C, Gross R, Andrade A, Lalama C, Eshleman SH, Aberg J, Sanne I, Parsons T, Kashuba A, Rosenkranz SL, Kmack A, Ferguson E, Dehlinger M, Mildvan D, AIDS Clinical Trials Group A5073 Study Team. Comparison of once-daily versus twice-daily combination antiretroviral therapy in treatment-naïve patients: results of AIDS Clinical Trials Group (ACTG) A5073, a 48-week randomized controlled trial. Clin Infect Dis 2010; 50:1041–1052. [PMCID #2833234; NIHMS #168892]
Wilkin TJ, Su Z, Krambrink A, Long J, Greaves WL, Gross R, Hughes MD, Flexner C, Skolnik PR, Coakley E, Godfrey C, Hirsch M, Kuritzkes DR, Gulick RM, AIDS Clinical Trials Group A5211 Study Team. Three-year safety and efficacy of vicriviroc, a CCR5 antagonist, in HIV-1-infected, treatment-experienced patients. J Acq Immunodef Syndr 2010; 54:470–476.
Crawford KW, Spritzler J, Kalayjian R, Parsons T, Landay A, Pollard R, Stoker V, Lederman M, Flexner C. Age-related changes in the plasma concentrations of the HIV protease inhibitor lopinavir. AIDS Res Hum Retroviruses 2010; 26: 635-643.
Soon GH, Shen P, Yong E-L, Flexner C, Pham P, Lee LS. Pharmacokinetics of darunavir 900 mg and ritonavir 100 mg once daily when co-administered with efavirenz 600 mg once daily in healthy volunteers. Antimicrob Agents Chemother 2010; 54: 2775-2780.
Chen J, Garner RC, Lee LS, Seymour M, Fuchs EJ, Hubbard W, Parsons T, Pakes GE, Fletcher CV, Flexner C. Accelerator mass spectrometry measurement of intracellular concentrations of active drug metabolites in human target cells in vivo. Clin Pharmacol Ther 2010; 88: 796-800.
Wang L-Z, Lee L, Thuya W-L, Soon GH, Kong L-R, Nye P-L, Jon-Deoon E-L, Flexner C, Goh B-C. Simultaneous determination of raltegravir and raltegravir glucuronide in human plasma by liquid chromatography-tandem mass spectrometry. J Mass Spectrometry 2011; 46: 202-208.
Wang L, Soon GH, Seng K-Y, Li J, Lee E, Yong E-L, Goh B-C, Flexner C, Lee L. Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers. Antimicrob Agents Chemother 2011; 55: 4090-4095.
Dooley KE, Park J-G, Swindells S, Allen R, Haas DW, Cramer Y, Aweeka F, Wiggins I, Gupta A, Lizak P, Qasba S, van Heeswijk R, Flexner C, and the ACTG 5267 Study Team. Safety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in healthy volunteers: AIDS Clinical Trials Group Study A5267. J Acq Immunodef Syndr 2012; 59:455-462.
Chen J, Flexner C, Liberman RG, Skipper PL, Louissaint N, Tannenbaum SR, Hendrix CW, Fuchs EJ. Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study. J Acq Immunodef Syndr 2012; 61: 593-599.
Lee LS, Pham P, Flexner C. Unexpected drug-drug interactions in HIV therapy: induction of UGT1A1 and bile efflux transporters by efavirenz. Annals Acad Med (Singapore) 2012; 41: 559-562.
Dooley KE, Sayre P, Borland, J, Purdy E, Chen S, Song I, Peppercorn A, Everts S, Piscitelli S, Flexner C. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acq Immune Defic Syndr 2013; 62: 21-27. [October 15, 2012 Epub ahead of print]
Williams J, Sayles HR, Meza JL, Sayre P, Sandkovsky U, Gendelman HE, Flexner C, Swindells S. Long-acting parenteral nanoformulated antiretroviral therapy: interest and attitudes of HIV-infected patients. Nanomedicine (Lond). 2013; 8: 1807-1813. [April 23, 2013 Epub ahead of print]
Andrade A, Rosenkranz SL, Cillo A, Lu D, Daar E, Jacobson JM, Lederman M, Acosta E, Read S, Campbell T, Feinberg J, Flexner C, Mellors JW, Kuritzkes DR, AIDS Clinical Trials Group A5248 Team. Three distinct phases of HIV-1 RNA decay in treatment-naïve patients receiving raltegravir-based antiretroviral therapy: ACTG A5248 study. J Infect Dis 2013; 208:884-891.
Selected Publications
View all on PubMed
- Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C, Quinn TC, Chaisson RE, Rosenberg E, Walker B, Gange S, Gallant J, Siliciano RF. 1999. Latentinfection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Med 5:512-517.
- Hendrix CW, Flexner C, MacFarland RT, Fuchs EJ, Redpath E, Bridger G, Henson GW. 2000. Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers. Antimicrob Agents Chemother 44: 1667-1673.
- Speck RS, Flexner C, Tian C-J, Yu X-F. 2000. Comparison of human immunodeficiency virus type 1 Pr55Gag and Pr160Gag-Pol processing intermediates that accumulate in primary and transformed cells treated with peptidic and non-peptidic protease inhibitors. Antimicrob Agents Chemother 44: 1397-1403.
- Speck RR, Yu X-F, Hildreth, JE, Flexner C. 2002. Differential effects of P-glycoprotein and multidrug resistance protein-1 on productive HIV infection. J Infect Dis 186: 332-340.
- Nettles RE, Kieffer TL, Parsons T, Johnson J, Cofrancesco J, Gallant JE, , Carson K, Siliciano RF, Flexner C. Marked intraindividual variability in antiretroviral concentrations may limit the utility of therapeutic drug monitoring. Clin Infect Dis 2006; 42: 1189-1196.
- Flexner C. HIV drug development: the next 25 years. (Invited review). Nature Reviews Drug Discovery 2007; 6: 959-966.
- Crawford KW, Li C, Keung A, Su Z, Hughes MD, Greaves W, Kuritzkes D, Gulick R, Flexner C, for the ACTG A5211 Study Team. Pharmacokinetic/ pharmacodynamic modeling of the antiretroviral activity of the CCR5 antagonist vicriviroc in treatment-experienced HIV-infected patients. J Acq Immunodef Syndr 2010; 53: 598–605.
- Crawford KW, Spritzler J, Kalayjian R, Parsons T, Landay A, Pollard R, Stoker V, Lederman M, Flexner C. Age-related changes in the plasma concentrations of the HIV protease inhibitor lopinavir. AIDS Res Hum Retroviruses 2010; 26: 635-643.
- Flexner C, Tierney C, Gross R, Andrade A, Lalama C, Eshleman SH, Aberg J, Sanne I, Parsons T, Kashuba A, Rosenkranz SL, Kmack A, Ferguson E, Dehlinger M, Mildvan D, AIDS Clinical Trials Group A5073 Study Team. Comparison of once-daily versus twice-daily combination antiretroviral therapy in treatment-naïve patients: results of AIDS Clinical Trials Group (ACTG) A5073, a 48-week randomized controlled trial. Clin Infect Dis 2010; 50:1041–1052. [PMCID #2833234]
- Chen J, Garner RC, Lee LS, Seymour M, Fuchs EJ, Hubbard W, Parsons T, Pakes GE, Fletcher CV, Flexner C. Accelerator mass spectrometry measurement of intracellular concentrations of active drug metabolites in human target cells in vivo. Clin Pharmacol Ther 2010; 88: 796-800.
- Swindells S, Flexner C, Fletcher CV, Jacobson JM. The critical need for alternative antiretroviral formulations and obstacles to their development. J Infect Dis 2011; 204: 669-674.
- Wang L, Soon GH, Seng K-Y, Li J, Lee E, Yong E-L, Goh B-C, Flexner C, Lee L. Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers. Antimicrob Agents Chemother 2011; 55: 4090-4095.
- Crawford KW, Ripin DHB, Levin AD, Campbell JR, Flexner C. Optimizing the manufacturing, formulation, and dosage of antiretroviral drugs for more cost-efficient delivery in resource-limited settings: a consensus statement. Lancet Infect Dis 2012; 12: 550–60.
- Chen J, Flexner C, Liberman RG, Skipper PL, Louissaint N, Tannenbaum SR, Hendrix CW, Fuchs EJ. Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study. J Acq Immunodef Syndr 2012; 61: 593-599.
- Williams J, Sayles HR, Meza JL, Sayre P, Sandkovsky U, Gendelman HE, Flexner C, Swindells S. Long-acting parenteral nanoformulated antiretroviral therapy: interest and attitudes of HIV-infected patients. Nanomedicine (Lond). 2013; 8: 1807-1813.