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Non-linear mixed effects modeling of antiretroviral drug response after administration of lopinavir, atazanavir and efavirenz containing regimens to treatment-naive HIV-1 infected patients

Roshammar, Daniel; Simonsson, Ulrika S. H.; Ekvall, Hakan; Flamholc, Leo LU ; Ormaasen, Vidar; Vesterbacka, Jan; Wallmark, Eva; Ashton, Michael and Gisslen, Magnus (2011) In Journal of Pharmacokinetics and Pharmacodynamics 38(6). p.727-742
Abstract
The objective of this analysis was to compare three methods of handling HIV-RNA data below the limit of quantification (LOQ) when describing the time-course of antiretroviral drug response using a drug-disease model. Treatment naive Scandinavian HIV-positive patients (n = 242) were randomized to one of three study arms. Two nucleoside reverse transcriptase inhibitors were administrated in combination with 400/100 mg lopinavir/ritonavir twice daily, 300/100 mg atazanavir/ritonavir once a day or 600 mg efavirenz once a day. The viral response was monitored at screening, baseline and at 1, 2, 3, 4, 12, 24, 48, 96, 120, and 144 weeks after study initiation. Data up to 400 days was fitted using a viral dynamics non-linear mixed effects... (More)
The objective of this analysis was to compare three methods of handling HIV-RNA data below the limit of quantification (LOQ) when describing the time-course of antiretroviral drug response using a drug-disease model. Treatment naive Scandinavian HIV-positive patients (n = 242) were randomized to one of three study arms. Two nucleoside reverse transcriptase inhibitors were administrated in combination with 400/100 mg lopinavir/ritonavir twice daily, 300/100 mg atazanavir/ritonavir once a day or 600 mg efavirenz once a day. The viral response was monitored at screening, baseline and at 1, 2, 3, 4, 12, 24, 48, 96, 120, and 144 weeks after study initiation. Data up to 400 days was fitted using a viral dynamics non-linear mixed effects drug-disease model in NONMEM. HIV-RNA data below LOQ of 50 copies/ml plasma (39%) was omitted, replaced by LOQ/2 or included in the analysis using a likelihood-based method (M3 method). Including data below LOQ using the M3 method substantially improved the model fit. The drug response parameter expressing the fractional inhibition of viral replication was on average (95% CI) estimated to 0.787 (0.721-0.864) for lopinavir and atazanavir treatment arms and 0.868 (0.796-0.923) for the efavirenz containing regimen. At 400 days after treatment initiation 90% (76-100) of the lopinavir and atazanavir treated patients were predicted to have undetectable viral levels and 96% (89-100%) for the efavirenz containing treatment. Including viral data below the LOQ rather than omitting or replacing data provides advantages such as better model predictions and less biased parameter estimates which are of importance when quantifying antiretroviral drug response. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Antiretroviral, HIV-RNA, Limit of quantification, NONMEM
in
Journal of Pharmacokinetics and Pharmacodynamics
volume
38
issue
6
pages
727 - 742
publisher
Springer
external identifiers
  • wos:000300173500004
  • scopus:84855649399
ISSN
1567-567X
DOI
10.1007/s10928-011-9217-1
language
English
LU publication?
yes
id
e4606c60-695d-40bc-9f62-4c04815334a3 (old id 2377705)
date added to LUP
2012-04-02 09:21:06
date last changed
2017-01-01 03:26:27
@article{e4606c60-695d-40bc-9f62-4c04815334a3,
  abstract     = {The objective of this analysis was to compare three methods of handling HIV-RNA data below the limit of quantification (LOQ) when describing the time-course of antiretroviral drug response using a drug-disease model. Treatment naive Scandinavian HIV-positive patients (n = 242) were randomized to one of three study arms. Two nucleoside reverse transcriptase inhibitors were administrated in combination with 400/100 mg lopinavir/ritonavir twice daily, 300/100 mg atazanavir/ritonavir once a day or 600 mg efavirenz once a day. The viral response was monitored at screening, baseline and at 1, 2, 3, 4, 12, 24, 48, 96, 120, and 144 weeks after study initiation. Data up to 400 days was fitted using a viral dynamics non-linear mixed effects drug-disease model in NONMEM. HIV-RNA data below LOQ of 50 copies/ml plasma (39%) was omitted, replaced by LOQ/2 or included in the analysis using a likelihood-based method (M3 method). Including data below LOQ using the M3 method substantially improved the model fit. The drug response parameter expressing the fractional inhibition of viral replication was on average (95% CI) estimated to 0.787 (0.721-0.864) for lopinavir and atazanavir treatment arms and 0.868 (0.796-0.923) for the efavirenz containing regimen. At 400 days after treatment initiation 90% (76-100) of the lopinavir and atazanavir treated patients were predicted to have undetectable viral levels and 96% (89-100%) for the efavirenz containing treatment. Including viral data below the LOQ rather than omitting or replacing data provides advantages such as better model predictions and less biased parameter estimates which are of importance when quantifying antiretroviral drug response.},
  author       = {Roshammar, Daniel and Simonsson, Ulrika S. H. and Ekvall, Hakan and Flamholc, Leo and Ormaasen, Vidar and Vesterbacka, Jan and Wallmark, Eva and Ashton, Michael and Gisslen, Magnus},
  issn         = {1567-567X},
  keyword      = {Antiretroviral,HIV-RNA,Limit of quantification,NONMEM},
  language     = {eng},
  number       = {6},
  pages        = {727--742},
  publisher    = {Springer},
  series       = {Journal of Pharmacokinetics and Pharmacodynamics},
  title        = {Non-linear mixed effects modeling of antiretroviral drug response after administration of lopinavir, atazanavir and efavirenz containing regimens to treatment-naive HIV-1 infected patients},
  url          = {http://dx.doi.org/10.1007/s10928-011-9217-1},
  volume       = {38},
  year         = {2011},
}