Abstract

Our current work has involved development of a pharmacokinetic model for the drug delavirdien (DLV), a recently-approved reverse transcriptase inhibitor, used in combination regimens to treat AIDS. During development, the drug was dosed, in several trials, using adaptive feedback control of 'trough' plasma concentrations. A typical starting regimen is 876.1 (moles (400 mg), given orally, every 8 hours. Both parent DLV (also called U90) and metabolite (N-DLV or U96) concentrations were assayed as feedback. The kinetic model has bolus inputs into an absorptive site, then first order absorption (ka) after a lag time. DLV distributes into central and peripheral compartments with rate of equilibration governed by Cld (Cld = Vc(kcp = Vp(kpc). DLV is eliminated, from the central compartment, by parallel capacity-limited (saturable) and first order clearance pathways (CL90). We parameterize the saturable pathway by Km and intrinsic clearance (CLi = Vmax/Km). DLV which is cleared by the saturable pathway is metabolized to N-DLV, which we modeled as distributing into a single compartment from which drug is cleared by a first order process (CL96). This model is currently being used to analyze data from 40 patients as part of a Phase 2 clinical trial of DLV in HIV infected patients.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001861-18
Application #
6611244
Study Section
Project Start
2002-09-01
Project End
2003-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
18
Fiscal Year
2002
Total Cost
$155,764
Indirect Cost

  Institution

Name
University of Southern California
Department
Type
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Song, Dong; Wang, Haonan; Tu, Catherine Y et al. (2013) Identification of sparse neural functional connectivity using penalized likelihood estimation and basis functions. J Comput Neurosci 35:335-57
Hoppenbrouwers, Toke; Oliveira, Flavia; Sandarupa, Stanislaus et al. (2012) The development of the circadian heart rate rhythm (CHR) in Asian infants. Early Hum Dev 88:555-61
Wang, Xiaoning; Schumitzky, Alan; D'Argenio, David Z (2007) Nonlinear Random Effects Mixture Models: Maximum Likelihood Estimation via the EM Algorithm. Comput Stat Data Anal 51:6614-6623
Gholmieh, Ghassan; Courellis, Spiros; Marmarelis, Vasilis et al. (2007) Nonlinear dynamic model of CA1 short-term plasticity using random impulse train stimulation. Ann Biomed Eng 35:847-57
Gholmieh, Ghassan; Courellis, Spiros; Dimoka, Angelika et al. (2004) An algorithm for real-time extraction of population EPSP and population spike amplitudes from hippocampal field potential recordings. J Neurosci Methods 136:111-21
Ashjian, Peter; Elbarbary, Amir; Zuk, Patricia et al. (2004) Noninvasive in situ evaluation of osteogenic differentiation by time-resolved laser-induced fluorescence spectroscopy. Tissue Eng 10:411-20
Blasi, Anna; Jo, Javier; Valladares, Edwin et al. (2003) Cardiovascular variability after arousal from sleep: time-varying spectral analysis. J Appl Physiol 95:1394-404
Jo, Javier A; Blasi, Anna; Valladares, Edwin et al. (2003) Model-based assessment of autonomic control in obstructive sleep apnea syndrome during sleep. Am J Respir Crit Care Med 167:128-36
Belozeroff, Vasily; Berry, Richard B; Khoo, Michael C K (2003) Model-based assessment of autonomic control in obstructive sleep apnea syndrome. Sleep 26:65-73
Bading, James R; Yoo, Paul B; Fissekis, John D et al. (2003) Kinetic modeling of 5-fluorouracil anabolism in colorectal adenocarcinoma: a positron emission tomography study in rats. Cancer Res 63:3667-74

Showing the most recent 10 out of 84 publications