Ritonavir and saquinavir combination therapy for the treatment of HIV infection

Cameron, D. William; Japour, Anthony J.; Xu, Yi; Hsu, Ann; Mellors, John W.; Farthing, Charles; Cohen, Calvin; Poretz, Donald M.; Markowitz, Martin; Follansbee, Stephen; Angel, Jonathan B.; McMahon, Deborah; Ho, David D.; Devanarayan, V.; Rode, Richard A.; Salgo, Miklos; Kempf, Dale J.; Granneman, R.; Leonard, John M.; Sun, Eugene

doi:10.1097/00002030-199902040-00009

Cited by 183 publications

(98 citation statements)

References 23 publications

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“…RTV, therefore, is used as a booster to increase the bioavailability of another PI in the dual protease therapy. [5][6][7][8] On the other hand, recent studies demonstrated that all PIs are potent substrates and inhibitors for Pglycoprotein (Pgp). All PIs have higher transport rates from the basolateral to apical direction than the apical to basolateral direction using in vitro models such as Caco-2 or MDR1 transfected LLC-PK1 cells.…”

mentioning

confidence: 99%

Effect of Chronic Administration of Ritonavir on Function of Cytochrome P450 3A and P-Glycoprotein in Rats

Kageyama

Namiki

Fukushima

et al. 2005

Biological & Pharmaceutical Bulletin

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confidence: 99%

Effect of Chronic Administration of Ritonavir on Function of Cytochrome P450 3A and P-Glycoprotein in Rats

Kageyama

Namiki

Fukushima

et al. 2005

Biological & Pharmaceutical Bulletin

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“…PI-based combination regimens can lead to profound and sustained suppression of viral replication (9,13,20); however, these regimens eventually fail to control replication in a significant portion of patients, leading to the eventual development of resistant viruses (10,14,18). Although failure of PIbased therapy has a complex and multifactorial etiology, inadequate drug concentrations in plasma due to poor or variable pharmacokinetics and/or inconsistent adherence appear to be important factors (1,7,16,19,26,38,42).…”

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confidence: 99%

Pharmacokinetic-Pharmacodynamic Analysis of Lopinavir-Ritonavir in Combination with Efavirenz and Two Nucleoside Reverse Transcriptase Inhibitors in Extensively Pretreated Human Immunodeficiency Virus-Infected Patients

Hsu

Isaacson

Brun

et al. 2003

Antimicrob Agents Chemother

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The steady-state pharmacokinetics and pharmacodynamics of two oral doses of lopinavir-ritonavir (lopinavir/r; 400/100 and 533/133 mg) twice daily (BID) when dosed in combination with efavirenz, plus two nucleoside reverse transcriptase inhibitors, were assessed in a phase II, open-label, randomized, parallel arm study in 57 multiple protease inhibitor-experienced but non-nucleoside reverse transcriptase inhibitor-naive human immunodeficiency virus (HIV)-infected subjects. All subjects began dosing of lopinavir/r at 400/100 mg BID; subjects in one arm increased the lopinavir/r dose to 533/133 mg BID on day 14. When codosed with efavirenz, the lopinavir/r 400/100 mg BID regimen resulted in lower lopinavir concentrations in plasma, particularly C min , than were observed in previous studies of lopinavir/r administered without efavirenz. Increasing the lopinavir/r dose to 533/133 mg increased the lopinavir area under the concentration-time curve over a 12-h dosing interval (AUC 12 ), C predose , and C min by 46, 70, and 141%, respectively. The increase in lopinavir C max (33%,) did not reach statistical significance. Ritonavir AUC 12 , C max , C predose , and C min values were increased 46 to 63%. The lopinavir predose concentrations achieved with the 533/133-mg BID dose were similar to those observed with lopinavir/r 400/100 mg BID in the absence of efavirenz. Results from univariate logistic regression analyses identified lopinavir and efavirenz inhibitory quotient (IQ) parameters, as well as the baseline lopinavir phenotypic susceptibility, as predictors of antiviral response (HIV RNA < 400 copies/ml at week 24); however, no lopinavir or efavirenz concentration parameter was identified as a predictor. Multiple stepwise logistic regressions confirmed the significance of the IQ parameters, as well as other baseline characteristics, in predicting virologic response at 24 weeks in this patient population.

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“…The bioavailability of saquinavir is low, but when it is coadministered with ritonavir, concentrations of saquinavir in plasma increase enormously (28). The first combination of PIs used was saquinavir and ritonavir, each at doses of 400 mg (3). The combination of 1,000 mg of saquinavir and 100 mg of ritonavir, both twice daily (b.i.d.…”

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Steady-State Pharmacokinetics of a Double-Boosting Regimen of Saquinavir Soft Gel plus Lopinavir plus Minidose Ritonavir in Human Immunodeficiency Virus-Infected Adults

Ribera¹,

López²,

Díaz³

et al. 2004

Antimicrob Agents Chemother

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Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC 0-12 ), 85.1 g/ml ⅐ h; maximum concentration of drug in serum (C max ), 10.0 g/ml; trough concentration of drug in serum (C trough ), 7.3 g/ml; and minimum concentration of drug in serum (C min ), 5.5 g/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC 0-12 , 22.9 g/ml ⅐ h; C max , 2.9 g/ml; C trough , 1.6 g/ml; and C min , 1.4 g/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitorbased antiretroviral regimen for patients with several prior virologic failures.

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Ritonavir and saquinavir combination therapy for the treatment of HIV infection

Cited by 183 publications

References 23 publications

Effect of Chronic Administration of Ritonavir on Function of Cytochrome P450 3A and P-Glycoprotein in Rats

Effect of Chronic Administration of Ritonavir on Function of Cytochrome P450 3A and P-Glycoprotein in Rats

Pharmacokinetic-Pharmacodynamic Analysis of Lopinavir-Ritonavir in Combination with Efavirenz and Two Nucleoside Reverse Transcriptase Inhibitors in Extensively Pretreated Human Immunodeficiency Virus-Infected Patients

Steady-State Pharmacokinetics of a Double-Boosting Regimen of Saquinavir Soft Gel plus Lopinavir plus Minidose Ritonavir in Human Immunodeficiency Virus-Infected Adults

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