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JAC Advance Access published online on January 25, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl516
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© The Author 2007. 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

Saquinavir, nelfinavir and M8 pharmacokinetics following combined saquinavir, ritonavir and nelfinavir administration

Hartmut Stocker1,2,*, Christian Herzmann3, Antje Breske4, Guido Kruse4, Marcel Berger1,2, Hubert Schulbin1,2, Andrew Hill5, Jutta Steinmüller5, Mark Becker5, Keikawus Arastéh1,2 and Michael Kurowski4

1 Vivantes Auguste-Viktoria Klinikum, Rubensstraße 125, 12157 Berlin, Germany 2 Kompetenznetz HIV/AIDS, Ruhr-Universität Bochum, Gudrunstraße 56, 44791 Bochum, Germany 3 Epimed GmbH, c/o Vivantes Auguste-Viktoria Klinikum, Rubensstraße 125, 12157 Berlin, Germany 4 Therapia GmbH, c/o Vivantes Auguste-Viktoria Klinikum, Rubensstraße 125, 12157 Berlin, Germany 5 Hoffmann-La Roche AG, Grenzacherstraße 124, 4070 Basel, Switzerland

Received 27 June 2006; returned 2 August 2006; revised 25 October 2006; accepted 15 November 2006

* Correspondence address. Vivantes Auguste-Viktoria Klinikum, Rubensstr. 125, 12157 Berlin, Germany. Tel: +49-30-79033939; Fax: +49-30-79033938; E-mail: hartmut.stocker{at}vivantes.de

OBJECTIVES: This study evaluated the steady-state pharmacokinetic interaction between ritonavir-boosted saquinavir and nelfinavir.

METHODS: Open label, multiple-dose, two parallel-groups, single crossover study conducted in 24 HIV-infected patients (12 in each group). Patients in the nelfinavir group added saquinavir/ritonavir, 1000/100 mg twice daily to their ongoing stable treatment regimen consisting of nelfinavir, 1250 mg twice daily and two nucleoside reverse transcriptase inhibitors (NRTIs). Patients in the saquinavir group added nelfinavir, 1250 mg twice daily to their ongoing stable treatment regimen consisting of saquinavir/ritonavir, 1000/100 mg twice daily and two NRTIs. Pharmacokinetic assessments were performed before and 7 days after the start of combined treatment with nelfinavir/saquinavir/ritonavir. Blood samples were collected before and 1, 2, 3, 4, 6, 8, 10 and 12 h after dosing for measurement of nelfinavir, the nelfinavir metabolite M8 and saquinavir using liquid chromatography tandem mass spectrometry (LC-MS/MS).

RESULTS: The addition of saquinavir/ritonavir to the nelfinavir-containing regimen resulted in significant increases in the M8 pharmacokinetic parameters AUC0–12, Cmax and C12; geometric mean ratios (90% confidence intervals) of 2.25 ng·h/mL (1.47–3.44), 1.74 ng/mL (1.25–2.40) and 4.21 ng/mL (2.10–8.47), respectively. The intra-individual changes in nelfinavir and saquinavir concentrations were highly variable. Statistical analysis could not discard a relevant interaction but includes the possibility that some parameters may be halved, others more than doubled. At the same time the analysis failed to show any directed change.

CONCLUSIONS: The co-administration of nelfinavir and saquinavir/ritonavir leads to unpredictable changes in concentrations of both drugs. It is unclear whether the increased concentrations of M8 are associated with a clinical benefit.

Key Words: HIV , AIDS , double boosting , drug interactions , cytochromes


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