This application describes an innovative approach to the rapid assessment of complex drug interactions between protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs), and commonly prescribed medications including methadone, ethinyl estradiol, fluconazole, pravastatin, and fluoxetine in HIV-infected, substance abusers The proposed methodology employs a Therapeutic Drug Monitoring (TDM) program that will facilitate rapid determination of ART in subjects receiving multiple interacting medications Specific aims 1) Implement a TDM program that will establish a mechanism to investigate protease inhibitor (PI) and NNRTI pharmacokinetics in HIV-infected, substance abusers receiving ART, determine drug exposure parameters (Cmin, AUC) and inhibitory quotients (IQs), 2) Determine the pharmacokinetics of selected interacting medications (methadone, ethinyl estradiol, fluconazole, pravastatin, fluoxetine) in HIV-infected, substance abusers receiving ART, 3) Determine in vitro and ex vivo total and unbound plasma concentrations of protease inhibitors and NNRTIs in HIV-infected, substance abusers utilizing novel analytical approaches including HPLC, LC-MS-MS and capillary electrophoresis, 4) Develop and validate a capillary electrophoresis assay capable of enantiomeric separation to enhance the pharmacokinetic analysis of interacting medications, 5) Examine pharmacogenetic factors that may identify individuals at greater risk for insufficient or excessive systemic drug exposure while receiving complex regimens with multiple drug-drug interactions The proposed TDM-drug-drug interaction program integrates a comprehensive antiretroviral clinical pharmacology research group, an HPLC/LC-MS analytical facility, a pharmacometrics laboratory, a web-based TDM enrollment infrastructure, and four HIV clinical centers caring for substance abusers Innovative pharmacokinetic and pharmacodynamic modeling approaches to assess complex drug-drug interaction analyses of PI and NNRTIs from HIV-infected substance abusers and non-substance abusers will be conducted. Clinical sites will enroll subjects while drug measurement and data analysis will be conducted at the central pharmacology laboratory. These studies will provide insight into clinical interactions that face clinicians and patients today, and identify priority drug interactions that require more traditional pharmacokinetic trials to identify specific mechanisms of interaction. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA015024-03S2
Application #
7124908
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Khalsa, Jagjitsingh H
Project Start
2003-06-15
Project End
2007-05-31
Budget Start
2005-09-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$102,250
Indirect Cost
Name
State University of New York at Buffalo
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Bednasz, Cindy; Luque, Amneris E; Zingman, Barry S et al. (2016) Lipid-Lowering Therapy in HIV-Infected Patients: Relationship with Antiretroviral Agents and Impact of Substance-Related Disorders. Curr Vasc Pharmacol 14:280-7
Ma, Qing; Zingman, Barry S; Luque, Amneris E et al. (2011) Therapeutic drug monitoring of protease inhibitors and efavirenz in HIV-infected individuals with active substance-related disorders. Ther Drug Monit 33:309-14
Lakhman, Sukhwinder S; Ma, Qing; Morse, Gene D (2009) Pharmacogenomics of CYP3A: considerations for HIV treatment. Pharmacogenomics 10:1323-39
McCabe, Sarah M; Ma, Qing; Slish, Judianne C et al. (2008) Antiretroviral therapy : pharmacokinetic considerations in patients with renal or hepatic impairment. Clin Pharmacokinet 47:153-72
Ma, Qing; Forrest, Alan; Rosenkranz, Susan L et al. (2008) Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers. Biopharm Drug Dispos 29:91-101
DiFrancesco, Robin; DiCenzo, Robert; Vicente, Glorimar et al. (2007) Determination of lopinavir cerebral spinal fluid and plasma ultrafiltrate concentrations by liquid chromatography coupled to tandem mass spectrometry. J Pharm Biomed Anal 44:1139-46
Ma, Qing; Brazeau, Dan; Forrest, Alan et al. (2007) Advances in pharmacogenomics of antiretrovirals: an update. Pharmacogenomics 8:1169-78
Higgins, Niamh; Zingman, Barry S; Slish, Judianne et al. (2007) Factors associated with altered pharmacokinetics in substance users and non-substance users receiving lopinavir and atazanavir. Am J Addict 16:488-94
Slish, Judianne; Ma, Qing; Zingman, Barry S et al. (2007) Assessing the impact of substance use and hepatitis coinfection on atazanavir and lopinavir trough concentrations in HIV-infected patients during therapeutic drug monitoring. Ther Drug Monit 29:560-5
Ma, Qing; Brazeau, Daniel; Zingman, Barry S et al. (2007) Multidrug resistance 1 polymorphisms and trough concentrations of atazanavir and lopinavir in patients with HIV. Pharmacogenomics 8:227-35

Showing the most recent 10 out of 19 publications