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JAC Advance Access published online on May 7, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn187
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

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

Laura Dickinson1,*, Marta Boffito2, Saye H. Khoo1, Malte Schutz3, Leon J. Aarons4, Anton L. Pozniak2 and David J. Back1

1 Department of Pharmacology, University of Liverpool, Liverpool, UK 2 PK Research Ltd, St Stephen's Centre, Chelsea and Westminster Foundation Trust, London, UK 3 Roche Pharmaceuticals, Nutley, NJ, USA 4 School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK

Received 6 January 2008; returned 25 March 2008; revised 27 March 2008; accepted 3 April 2008

* Corresponding author. Tel: +44-151-794-5553; Fax: +44-151-794-5656; E-mail: laurad{at}liv.ac.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.

Key Words: HIV , pharmacokinetics , once daily , robustness


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