TDM & Drug Interactions in HIVinfected Substance Abusers

Summary

Principal Investigator: Gene Morse
Abstract: 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.
Funding Period: 2003-06-15 - 2009-05-31
more information: NIH RePORT

Top Publications

  1. pmc Therapeutic drug monitoring of protease inhibitors and efavirenz in HIV-infected individuals with active substance-related disorders
    Qing Ma
    Translational Pharmacology Research Core, NYS Center of Excellence in Bioinformatics and Life Sciences, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14203, USA
    Ther Drug Monit 33:309-14. 2011
  2. pmc Pharmacogenomics of CYP3A: considerations for HIV treatment
    Sukhwinder S Lakhman
    Department of Pharmaceutical Sciences, DYC School of Pharmacy, Buffalo, NY 14201 USA
    Pharmacogenomics 10:1323-39. 2009
  3. ncbi Antiretroviral therapy : pharmacokinetic considerations in patients with renal or hepatic impairment
    Sarah M McCabe
    Department of Pharmacy Practice and Pharmacotherapy Research Center, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA
    Clin Pharmacokinet 47:153-72. 2008
  4. ncbi Factors associated with altered pharmacokinetics in substance users and non-substance users receiving lopinavir and atazanavir
    Niamh Higgins
    Pharmacotherapy Research Center, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Amherst, New York 14260, USA
    Am J Addict 16:488-94. 2007
  5. ncbi Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers
    Qing Ma
    Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14260, USA
    Biopharm Drug Dispos 29:91-101. 2008
  6. ncbi Advances in pharmacogenomics of antiretrovirals: an update
    Qing Ma
    Pharmacotherapy Research Center, University at Buffalo, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY 14260, USA
    Pharmacogenomics 8:1169-78. 2007
  7. ncbi Assessing the impact of substance use and hepatitis coinfection on atazanavir and lopinavir trough concentrations in HIV-infected patients during therapeutic drug monitoring
    Judianne Slish
    Pharmacotherapy Research Center, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Amherst, New York 14260, USA
    Ther Drug Monit 29:560-5. 2007
  8. ncbi Determination of lopinavir cerebral spinal fluid and plasma ultrafiltrate concentrations by liquid chromatography coupled to tandem mass spectrometry
    Robin DiFrancesco
    Department of Pharmacy Practice, University at Buffalo, NY 14260, United States
    J Pharm Biomed Anal 44:1139-46. 2007
  9. ncbi HIV pharmacotherapy issues, challenges, and priorities in sub-Saharan African countries
    Charles C Maponga
    University of Zimbabwe College of Health Science, Avondale, Harare, Zimbabwe
    Top HIV Med 15:104-10. 2007
  10. ncbi Drug interactions between proton pump inhibitors and antiretroviral drugs
    Sarah M McCabe
    Associate Dean, Clinical Education and Research, University of Buffalo, Department of Pharmacy Practice, 317 Hochstetter Hall, Buffalo, NY 14260, USA
    Expert Opin Drug Metab Toxicol 3:197-207. 2007

Scientific Experts

  • Qing Ma
  • Gene Morse
  • Robert Douglas Bruce
  • Charles C Maponga
  • Robin DiFrancesco
  • Sarah M McCabe
  • Kim Keil
  • Richard C Reichman
  • Barry S Zingman
  • Margaret A Fischl
  • Judianne Slish
  • Barbara Gripshover
  • Sukhwinder S Lakhman
  • Linda M Catanzaro
  • Alan Forrest
  • Niamh Higgins
  • Dan Brazeau
  • Troy M Martin
  • Robert Dicenzo
  • Neha Sheth
  • Judianne C Slish
  • Kelly Tooley
  • Jill Hochreitter
  • Francesco Lliguicota
  • Patrick F Smith
  • Linda Catanzaro
  • Naomi S Boston
  • Naomi Boston
  • Karen T Tashima
  • Timothy P Flanigan
  • Jaclynn Kurpewski
  • Angela M Caliendo

Detail Information

Publications18

  1. pmc Therapeutic drug monitoring of protease inhibitors and efavirenz in HIV-infected individuals with active substance-related disorders
    Qing Ma
    Translational Pharmacology Research Core, NYS Center of Excellence in Bioinformatics and Life Sciences, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14203, USA
    Ther Drug Monit 33:309-14. 2011
    ..The objective of this study was to utilize therapeutic drug monitoring to compare efavirenz (EFV) and protease inhibitor pharmacokinetics in patients with and without SRDs...
  2. pmc Pharmacogenomics of CYP3A: considerations for HIV treatment
    Sukhwinder S Lakhman
    Department of Pharmaceutical Sciences, DYC School of Pharmacy, Buffalo, NY 14201 USA
    Pharmacogenomics 10:1323-39. 2009
    ....
  3. ncbi Antiretroviral therapy : pharmacokinetic considerations in patients with renal or hepatic impairment
    Sarah M McCabe
    Department of Pharmacy Practice and Pharmacotherapy Research Center, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA
    Clin Pharmacokinet 47:153-72. 2008
    ..This review summarizes the current knowledge of the use of antiretrovirals in patients with hepatic or renal impairment, and makes dosing recommendations for this subpopulation of HIV-infected patients...
  4. ncbi Factors associated with altered pharmacokinetics in substance users and non-substance users receiving lopinavir and atazanavir
    Niamh Higgins
    Pharmacotherapy Research Center, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Amherst, New York 14260, USA
    Am J Addict 16:488-94. 2007
    ..These data indicate that chronic HIV treatment may be assisted with plasma concentration monitoring to identify those patients who may require dosage modification and/or regimen adjustment in order to optimize antiretroviral effects...
  5. ncbi Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers
    Qing Ma
    Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14260, USA
    Biopharm Drug Dispos 29:91-101. 2008
    ..In conclusion, concomitant administration of dual PIs is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2B6 substrates in general or oral efavirenz specifically...
  6. ncbi Advances in pharmacogenomics of antiretrovirals: an update
    Qing Ma
    Pharmacotherapy Research Center, University at Buffalo, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY 14260, USA
    Pharmacogenomics 8:1169-78. 2007
    ..Future directions for research and the application of this technology to the clinical practice of individualizing treatment for HIV management are discussed...
  7. ncbi Assessing the impact of substance use and hepatitis coinfection on atazanavir and lopinavir trough concentrations in HIV-infected patients during therapeutic drug monitoring
    Judianne Slish
    Pharmacotherapy Research Center, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Amherst, New York 14260, USA
    Ther Drug Monit 29:560-5. 2007
    ..Further work is needed to assess the optimal dosing regimen when using LPV in HIV-infected substance users...
  8. ncbi Determination of lopinavir cerebral spinal fluid and plasma ultrafiltrate concentrations by liquid chromatography coupled to tandem mass spectrometry
    Robin DiFrancesco
    Department of Pharmacy Practice, University at Buffalo, NY 14260, United States
    J Pharm Biomed Anal 44:1139-46. 2007
    ..The method successfully measured LPV concentrations in CSF that were previously undetectable by HPLC as well as UF from protein binding studies...
  9. ncbi HIV pharmacotherapy issues, challenges, and priorities in sub-Saharan African countries
    Charles C Maponga
    University of Zimbabwe College of Health Science, Avondale, Harare, Zimbabwe
    Top HIV Med 15:104-10. 2007
    ..The potential for the effective international collaboration is enhanced when expertise and resources from the developed world are combined with an understanding of the unique priorities of resource-limited settings...
  10. ncbi Drug interactions between proton pump inhibitors and antiretroviral drugs
    Sarah M McCabe
    Associate Dean, Clinical Education and Research, University of Buffalo, Department of Pharmacy Practice, 317 Hochstetter Hall, Buffalo, NY 14260, USA
    Expert Opin Drug Metab Toxicol 3:197-207. 2007
    ..This review summarizes the current knowledge on the interactions between proton pump inhibitors and antiretrovirals, and makes recommendations for the coadministration of proton pump inhibitors...
  11. ncbi Buprenorphine assay and plasma concentration monitoring in HIV-infected substance users
    Robin DiFrancesco
    Pharmacotherapy Research Center, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
    J Pharm Biomed Anal 44:188-95. 2007
    ..Use of this combined BUP and ARV plasma concentration monitoring approach for a representative patient receiving BUP, atazanavir and efavirenz demonstrated its clinical application...
  12. ncbi Multidrug resistance 1 polymorphisms and trough concentrations of atazanavir and lopinavir in patients with HIV
    Qing Ma
    University at Buffalo, Pharmacotherapy Research Center, School of Pharmacy and Pharmaceutical Sciences, NY, USA
    Pharmacogenomics 8:227-35. 2007
    ..We examined MDR1 single nucleotide polymorphisms in a cohort of patients in whom therapeutic drug monitoring is ongoing through a research protocol...
  13. ncbi Integration of atazanavir into an existing liquid chromatography UV method for protease inhibitors: validation and application
    Kim Keil
    Pharmacotherapy Research Center, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York 14260, USA
    Ther Drug Monit 29:103-9. 2007
    ..During 2 years, more than 100 batches of analyses have been performed and have proved the method is rugged, specific, and accurate. This assay method is currently used in the authors' clinical research program in TDM...
  14. ncbi Pharmacokinetic interactions between buprenorphine and antiretroviral medications
    R Douglas Bruce
    Yale University AIDS Program, New Haven, CT 06511, USA
    Clin Infect Dis 43:S216-23. 2006
    ..Review of the current state of knowledge regarding specific interactions between buprenorphine and antiretrovirals is followed by a review of the clinical applicability of these interactions...
  15. ncbi Determination of tipranavir in human plasma by reverse phase liquid chromatography with UV detection using photodiode array
    Kim Keil
    Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA
    Ther Drug Monit 28:512-6. 2006
    ..390 microg/mL with an interday variation in control value ranging from 2.9 to 4.6%. The method is being used in a clinical therapeutic drug monitoring program that is ongoing in our laboratory...
  16. ncbi Pharmacokinetic drug interactions with non-nucleoside reverse transcriptase inhibitors
    Qing Ma
    University at Buffalo, Pharmacotherapy Research Center, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, 317 Hochstetter Hall, Buffalo, NY 14260, USA
    Expert Opin Drug Metab Toxicol 1:473-85. 2005
    ..This review provides an updated summary of pharmacokinetic interactions with NNRTIs...
  17. ncbi Plasma and cerebrospinal pharmacokinetics and pharmacodynamics in subjects taking lopinavir/ritonavir
    Troy M Martin
    AIDS 20:1085-7. 2006
  18. ncbi Clinical pharmacodynamics of HIV-1 protease inhibitors: use of inhibitory quotients to optimise pharmacotherapy
    Gene D Morse
    Department of Pharmacy Practice, University at Buffalo, State University of New York, Amherst 14260, USA
    Lancet Infect Dis 6:215-25. 2006
    ..Current investigation is focused on examining the predictive value of this approach for clinical monitoring...