(provided by candidate): Candidate: Dr. Neely is an Assistant Professor of Clinical Pediatrics with subspecialty training in infectious diseases and clinical pharmacology. For the last 4 years he has been using population pharmacokinetic (PK) modeling to measure adherence to antiretroviral therapy by women, adolescents, and children, as well as finding that non-nucleoside reverse transcriptase inhibitors (NNRTIs) may be more associated with shedding of HIV RNA from the cervix than are protease inhibitors (PIs). His immediate aims are to prospectively explore this finding using advanced population modeling techniques to compare NNRTI or PI pharmacodynamic (PD) effects on HIV replication in plasma and the female genital tract. His long-term objective is to develop a research center of excellence, using PK-PD modeling to pose and answer therapeutic and scientific questions, particularly in women and children. The University of Southern California is ideally suited for this goal, having a Master's program in Clinical Investigation, the Laboratory of Applied Pharmacokinetics (LAPK), the Biomedical Simulations Resource (BMSR), and over 3500 HIV-infected patients, with the Maternal Child Adolescent (MCA) clinic focused specifically on the needs of HIV- infected women and children. Dr. Neely will be mentored by Dr. Roger Jelliffe (LAPK), as well as a team of advisors including Dr. Andrea Kovacs (MCA) and Dr. David D'Argenio (BMSR). Research: Repeated, paired blood-genital samples will be obtained over a 6-month period from 20 women, stratified by treatment. Blood and directly aspirated vaginal fluid will be analyzed by LC-MS/MS for drug concentrations. HIV RNA will be quantified in blood and cervical swabs by isothermal nucleic acid amplification. Population modeling methods will be used to characterize drug PK in plasma and vaginal fluid and to compare the PD effects on plasma and cervical HIV RNA shedding over time. Relevance: Data from this project will be pertinent to several important, unanswered clinical questions, including: 1) Are some agents more effective in preventing sexual or maternal-to-child transmission of HIV by effectively suppressing viral replication in the genital tract? 2) Is suppression of viral replication in the genital tract necessary to maintain suppression in plasma? 3) Can short-term models of viral dynamics be used to predict long-term responses to therapy? 4) Should women initiate antiretroviral therapy according to different virologic/immunologic criteria than for men? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI076106-02
Application #
7477089
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Gezmu, Misrak
Project Start
2007-08-15
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$90,568
Indirect Cost
Name
University of Southern California
Department
Pediatrics
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Neely, Michael; Louie, Stan; Xu, Jiaao et al. (2015) Simultaneous plasma and genital pharmacokinetics and pharmacodynamics of atazanavir and efavirenz in HIV-infected women starting therapy. J Clin Pharmacol 55:798-808
Neely, Michael; Rutstein, Richard; Del Bianco, Gabriela et al. (2013) Use of nucleoside reverse transcriptase inhibitor-only regimens in HIV-infected children and adolescents. Pediatr Infect Dis J 32:e370-6
Rakhmanina, Natella Y; Neely, Michael N; Capparelli, Edmund V (2012) High dose of darunavir in treatment-experienced HIV-infected adolescent results in virologic suppression and improved CD4 cell count. Ther Drug Monit 34:237-41
Neely, Michael N; van Guilder, Michael G; Yamada, Walter M et al. (2012) Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R. Ther Drug Monit 34:467-76
Festekjian, Ara; Neely, Michael (2011) Incidence and predictors of invasive candidiasis associated with candidaemia in children. Mycoses 54:146-53
Rakhmanina, Natella Y; Neely, Michael N; Van Schaik, Ron H N et al. (2011) CYP3A5, ABCB1, and SLCO1B1 polymorphisms and pharmacokinetics and virologic outcome of lopinavir/ritonavir in HIV-infected children. Ther Drug Monit 33:417-24
Darbari, Deepika S; Neely, Michael; van den Anker, John et al. (2011) Increased clearance of morphine in sickle cell disease: implications for pain management. J Pain 12:531-8
Neely, Michael N; Rakhmanina, Natella Y (2011) Pharmacokinetic optimization of antiretroviral therapy in children and adolescents. Clin Pharmacokinet 50:143-89
Neely, Michael; Decosterd, Laurent; Fayet, Aurélie et al. (2010) Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers. Antimicrob Agents Chemother 54:4619-25
Rakhmanina, Natella Y; van den Anker, John N; Soldin, Steven J et al. (2010) Can therapeutic drug monitoring improve pharmacotherapy of HIV infection in adolescents? Ther Drug Monit 32:273-81

Showing the most recent 10 out of 12 publications