Publications by authors named "Leon J Aarons"

3 Publications

  • Page 1 of 1

Population pharmacokinetics of ritonavir-boosted saquinavir regimens in HIV-infected individuals.

J Antimicrob Chemother 2008 Dec 29;62(6):1344-55. Epub 2008 Sep 29.

NIHR National Biomedical Research Centre, Royal Liverpool and Broadgreen University Hospital Trust, Liverpool, UK.

Objectives: The aim of this study was to develop and validate a population pharmacokinetic model in order to describe ritonavir-boosted saquinavir concentrations dosed twice and once daily in human immunodeficiency virus (HIV)-infected patients from the UK, Uganda and Thailand and to identify factors that may influence saquinavir pharmacokinetics.

Methods: Pharmacokinetic data from 10 clinical studies were combined. Non-linear mixed effects modelling (NONMEM version V) was applied to determine the saquinavir pharmacokinetic parameters, interindividual/interoccasion variability (IIV/IOV) and residual error. Various covariates potentially related to saquinavir pharmacokinetics were explored, and the final model was validated by means of 95% prediction interval and testing the predictive performance of the model with data not included in the model-building process.

Results: Ninety-seven patients were included from the UK (n = 52), Uganda (n = 18) and Thailand (n = 27), contributing 347 saquinavir profiles (1-14 profiles per patient). A one-compartment model with zero-order absorption and lag-time best described the data with IIV/IOV on apparent oral clearance (CL/F) and volume of distribution (V/F) and with IIV on duration and absorption lag-time. The ritonavir area under the curve over the dosing interval was significantly associated with saquinavir CL/F and V/F. A typical patient from the UK had approximately 1.5- and 3-fold higher saquinavir CL/F compared with patients from Uganda (89.0 versus 49.8 L/h) and Thailand (89.0 versus 26.7 L/h), respectively.

Conclusions: A model to characterize ritonavir-boosted saquinavir pharmacokinetics in HIV-infected adults has been developed and validated. The model could be used for dosage adaptation following therapeutic drug monitoring and to assess patients' suitability for once-daily boosted saquinavir therapy.
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December 2008

Pharmacokinetic analysis to assess forgiveness of boosted saquinavir regimens for missed or late dosing.

J Antimicrob Chemother 2008 Jul 7;62(1):161-7. Epub 2008 May 7.

Department of Pharmacology, University of Liverpool, Liverpool, UK.

Objectives: One potential concern of once-daily protease inhibitor administration is low trough concentrations and ultimately the 'forgiveness' or robustness in comparison with the originally licensed twice-daily dose. To give an estimation of 'forgiveness', we determined the length of time plasma drug concentrations were below target in HIV-infected patients receiving saquinavir/ritonavir regimens.

Methods: Seventy-seven pharmacokinetic profiles (saquinavir/ritonavir 1000/100 mg twice daily, n = 34; 1600/100 mg once daily, n = 26; 2000/100 mg once daily, n = 17) from five studies were combined, presented as twice- and once-daily percentiles (P10-P90) and compared. At percentiles where trough concentrations fell below the alleged minimum effective concentration (MEC; 100 ng/mL), the length of time below MEC was determined.

Results: Saquinavir concentrations were below MEC at P10 for 0.7 h for twice-daily saquinavir/ritonavir when compared with 8.6 and 6.6 h for 1600/100 and 2000/100 mg once daily, respectively. At P25, 1600/100 mg once daily produced suboptimal concentrations for 5.5 h in contrast to 0.5 h for 2000/100 mg once daily.

Conclusions: Here, we provide substantive data that indicate once-daily saquinavir, in particular 1600/100 mg, is not as robust as the twice-daily regimen based on a population of UK patients; this raises concern over late or missed doses. However, pharmacokinetic data can only ever be a guide to the impact on long-term efficacy.
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July 2008

Use of nonlinear mixed-effects analysis for improved precision of early pharmacodynamic measures in tuberculosis treatment.

Antimicrob Agents Chemother 2006 Sep;50(9):3154-6

Wellcome Trust Centre for Clinical Tropical Medicine, University of Liverpool, UK.

Nonlinear mixed-effects analysis of serial sputum colony-counting data supports the existence of two bacillary subpopulations in sputum, eliminated at different rates. It distinguishes between combination regimens, removes bias, and greatly improves precision, with significant implications for the analysis of surrogate endpoints of "sterilization" in the development of new antituberculosis regimens.
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September 2006