Department Affiliation: Primary: Medicine; Secondary: Pharmacology and Molecular Sciences
Degree: M.D., Johns Hopkins University
Telephone Number: 410-955-9712
Fax Number: 410-955-9708
E-mail address: firstname.lastname@example.org
School of Medicine Address: 575 Osler Building, 600 N. Wolfe St., Baltimore, MD 21287-5554
Basic and clinical pharmacology of antiretroviral drugs; HIV protease inhibitors and entry inhibitors
A. Laboratory activities include the use of accelerator mass spectrometry (AMS) techniques to measure intracellular drugs and drugs metabolites. AMS is a highly sensitive method for detecting tracer amounts of radio-labeled molecules in cells, tissues, and body fluids. We have been able to measure intracellular zidovudine triphosphate (the active anabolite of zidovudine) in peripheral blood mononuclear cells from healthy volunteers given small doses of 14C-zidovudine, and have directly compared the sensitivity of AMS to traditional LC/MS methods carried out in our laboratory.
B. 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.
- Chen, J., Garner, R.C., Lee, L.S., Seymour, M., Fuchs, E.J., Hubbard, W., Parsons, T., Pakes, G.E., Fletcher, C.V., 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. Pub Med Reference
- Crawford, K.W., Li, C., Keung, A., Su, Z., Hughes, M.D., 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. Pub Med Reference
- Crawford, K.W., 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(6):635-43. Pub Med Reference
- Tsibris, A.M.N., Korber, B., Arnaout, R., Russ, R., Lo, C.-C., Leitner, T., Gaschen, B., Theiler, J., Paredes, R., Su, Z., Hughes, M.D., Gulick, R.M., Greaves, W., Coakley, E., Flexner, C., Nusbaum, C., Kuritzkes, D.R. Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo. PLoS ONE 2009; 4(5):e5683. Pub Med Reference
- Lee, L.S., Soon, G.H., Shen, P., Yong, E.-L., Flexner, C., Pham, P. Darunavir/ritonavir and efavirenz exert differential effects on MRP1 transporter expression and function in healthy volunteers. Antiviral Ther 2010; 15:275-279. Pub Med Reference
- Pham, P.A., la Porte, C.J.L., Lee, L.S., van Heeswijk, R., Sabo, J.P., Elgadi, M.M., Piliero, P.J., Barditch-Crovo, P., Fuchs, E., Flexner, C., Cameron, D.W. Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother 2009; 53:4385–4392. Pub Med Reference
Bakshi, R.P., Hamzeh, F., Frank, I., Eron, J.J., Bosch, R.J., Rosenkranz, S.L., Cramer, Y.S., Ussery, M., Flexner, C. Effect of hydroxyurea and dideoxyinosine on intracellular 3’-deoxyadenosine-5’-triphosphate concentrations in HIV-infected patients. AIDS Res Hum Retroviruses 2007; 23:1360-1365. Pub Med Reference.
- Stone, N.D., Dunaway, S.B., Flexner, C., Tierney, C., Calandra, G.B., Becker, S., Cao, Y.-J., Wiggins, I.P., Conley, J., MacFarland, R.T., Park, J.-G., Lalama, C., Snyder, S., Kallungal, B., Klingman, K.L., Hendrix, C.W. Multiple dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects (ACTG A5191). Antimicrob Agents Chemother 2007; 51:2351-2358. Pub Med Reference.
- Flexner, C. HIV drug drug development: the next 25 years. Nature Reviews Drug Discovery 2007; 6:959-966. [Reprinted in Nature Biotechnology Antivirals Supplement 2008; 26:S39-S46.] Pub Med Reference.
- Nettles, R.E., Kieffer, T.L., Kwon, P., Monie, D., Han, Y., Adnan, S., Parsons, T., Cofrancesco, J., Gallant, J.E., Quinn, T., Jackson, B., Flexner, C., Carson, K., Ray, S., Persaud, D., and Siliciano, R.F. Intermittent HIV-1 viremia and the evolution of drug resistance in patients on highly active antiretroviral therapy, JAMA 293(7):817-829, 2005. Pub Med Reference.
Other graduate programs in which Dr. Flexner participates:
Graduate Training Program in Clinical Investigation