Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen

Boffito, Marta; Kurowski, Michael; Kruse, Guido; Hill, Andrew; Benzie, Andrew; Nelson, Mark; Moyle, Graeme; Gazzard, Brian; Pozniak, Anton

doi:10.1097/00002030-200406180-00007

Cited by 65 publications

(45 citation statements)

References 8 publications

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“…This can be a further limitation as differences in boosted protease inhibitor exposure have been seen between HIV-positive and -negative individuals (9), suggesting that patients with HIV infection may have lower plasma concentrations than those measured in our study. However, when our findings are compared to the concentrations of both darunavir and atazanavir measured in previously published studies (historical controls), the concentrations are similar to those observed in HIV-positive subjects (3,5,18).…”

Section: Vol 55 2011 Protease Inhibitor Concentration Persistence 4221supporting

confidence: 85%

Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation

Boffito

Jackson

Amara

et al. 2011

Antimicrob Agents Chemother

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The object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavirritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavirritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0-to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0-to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC 50 ] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the proteinbinding-corrected IC 50 for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.The combination of a ritonavir-boosted protease inhibitor and two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) has shown sustained suppression of plasma HIV replication and continued immunological recovery in naïve and experienced HIV-infected individuals (11).The advantages associated to ritonavir boosting are a consequence of the increased drug exposure and prolonged halflife that allow reducing the pill burden and dosing frequency and lead to the achievement of a high genetic barrier to resistance (11, 16).Drug persistence (the presence of drug at a detectable level high enough to exert an effect) in plasma mainly depends on the half-life (which itself is dependent on clearance and volume of distribution). Long-half-life antiretroviral agents may allow for forgotten doses, especially if they are able to delay the decline in drug concentration to a subtherapeutic level for a period of time that is long enough for the concentrations to be above target until th...

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Section: Vol 55 2011 Protease Inhibitor Concentration Persistence 4221supporting

confidence: 85%

Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation

Boffito

Jackson

Amara

et al. 2011

Antimicrob Agents Chemother

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“…Plasma concentrations of ATV, SQV, and RTV were determined by validated high-pressure liquid chromatography-tandem mass spectrometry methods (equipment from Merck-Hitachi, Germany, and Applied Biosystems/Canada at Therapia GmbH, Berlin, Germany) that are described elsewhere (28). The reliable lower limit of quantification was 20 ng/ml, and the linearity of the calibration curve for all tested compounds was proved up to 20,000 ng/ml (3,28).…”

Section: Patientsmentioning

confidence: 99%

Pharmacokinetics of Saquinavir, Atazanavir, and Ritonavir in a Twice-Daily Boosted Double-Protease Inhibitor Regimen

Hentig

Müller

Rottmann

et al. 2007

Antimicrob Agents Chemother

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The objective of this study was to evaluate the pharmacokinetics of atazanavir (ATV), saquinavir (SQV), and ritonavir (RTV) in a boosted double-protease inhibitor (PI) therapy regimen without reverse transcriptase inhibitors (RTIs). The study design was as follows. Patients with limited RTI options received a PI combination of 300/100 mg ATV/RTV once daily and 1,000 mg SQV twice daily (group 1; n ‫؍‬ 49) without RTI comedication. The results were compared to the plasma concentrations of PIs of patients taking either 300 mg ATV/100 mg RTV once daily plus RTIs (group 2; n ‫؍‬ 72) or patients taking 1,000 mg SQV/100 mg RTV plus RTIs (group 3; n ‫؍‬ 90). The study methods were as follows. Patients were given a 12/24-h pharmacokinetic assessment at steady state. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. The minimum and maximum concentrations (C min and C max ), area under the concentration-time curve under steady-state conditions (AUC ss ), elimination half-life, time of maximum concentration and lag time were subject to statistical analysis. The results show that patients treated with ATV/SQV/RTV exhibited significantly high SQV concentrations and moderate enhancement of the AUC ss of ATV in comparison to those of patients of the control groups: for SQV in groups 1 and 3, the geometric mean (GM) of the AUC ss was 22,794 versus 15,759 ng ⅐ h/ml (GM ratio [GMR] ‫؍‬ 1.45; P < 0.05), the GM of the C max was 3,257 versus 2,331 ng/ml (GMR ‫؍‬ 1.40; P < 0.05), and the GM of the C min was 438 versus 437 ng/ml (GMR ‫؍‬ 1.00); for ATV in groups 1 and 2, the GM of the AUC ss was 39,154 versus 33,626 ng ⅐ h/ml (GMR ‫؍‬ 1.16), the GM of the C max was 3,488 versus 2,924 ng/ml (GMR ‫؍‬ 1.20), and the GM of the C min was 515 versus 428 ng/ml (GMR ‫؍‬ 1.21). RTV levels were comparable for all groups. A subgroup analysis detected only marginal differences in ATV plasma exposure if combined with tenofovir-disoproxilfumarate and without it. We conclude that our pharmacokinetic results support the use of a boosted double-PI regimen of ATV/SQV/RTV as a treatment option for patients who need antiretroviral therapy without RTIs.

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“…32 The best virological response at 48 weeks was found in the ATV 400 mg od group (41%) over the ATV 600 mg od (29%) or SQV/r groups (35%), and there were fewer adverse event discontinuations in the ATV/SQV groups than in those in the SQV/r arm. Salvage therapy refers to ARV regimens devised to reduce viral replication in treatment-experienced patients with virological failure on a prior regimen.…”

Section: Atv In Arv-experienced Patientsmentioning

confidence: 87%

Clinical utility and long-term use of atazanavir in the treatment of HIV-1 infection

Rampling¹,

Nelson²

2011

VAAT

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Abstract:The protease inhibitor atazanavir (ATV) now forms an integral component of many combination antiretroviral regimens. It has been shown to have a favorable side effect profile, and it does not negatively affect plasma lipids as some other protease inhibitors can. ATV also has a long half-life, which allows for a once-daily dosing schedule. Coadministration of ATV with low-dose ritonavir (RTV) potentiates the effect of ATV ("RTV boosting"), allowing for lower doses of ATV than those prescribed without RTV. ATV boosted with RTV (ATV/r) has shown noninferiority to RTV-boosted lopinavir (LPV/r), and it has been shown to be effective as a simplification strategy in switch studies. ATV/r-based regimens have also shown promise as a rescue strategy for patients failing other regimens. Several important adverse events and drug interactions have been identified, and care must be taken when administering ATV with other medications. The most commonly reported adverse effect is unconjugated hyperbilirubinemia, which occurs as a result of the metabolic pathway by which it is excreted. Resistance to ATV has been described in both treatment-experienced and treatment-naïve patients.

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Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen

Cited by 65 publications

References 8 publications

Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation

Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation

Pharmacokinetics of Saquinavir, Atazanavir, and Ritonavir in a Twice-Daily Boosted Double-Protease Inhibitor Regimen

Clinical utility and long-term use of atazanavir in the treatment of HIV-1 infection

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