The steady-state pharmacokinetics of atazanavir/ritonavir in HIV-1-infected adult outpatients is not affected by gender-related co-factors

Hentig, Nils von; Babacan, Errol; Lennemann, Tessa; Knecht, G; Carlebach, Amina; Harder, Sebastian; Staszewski, Schlomo; Haberl, Annette

doi:10.1093/jac/dkn204

Cited by 28 publications

(30 citation statements)

References 7 publications

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“…It is possible that the viscous liquid formulation impedes the absorption of atazanavir by forming dissoluble complexes with atazanavir to some extent in the stomach, when administered at the same time. In general, the combination of atazanavir/ ritonavir is a pharmacokinetically safe regimen which shows little pharmacokinetic differences between gender and is not affected by demographic differences, such as age, gender, weight, or tenofovir co-medication [18,19], which can affect the pharmacokinetics of other protease inhibitors [16], such as lopinavir [3], amprenavir [8], or saquinavir [13]. It often is used in situations where a once-daily (observed) application of ART is warranted.…”

Section: Resultsmentioning

confidence: 99%

Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting

Haberl

Moesch

Nisius

et al. 2009

Eur J Clin Pharmacol

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Objective The human immundeficiency virus (HIV) protease inhibitor atazanavir is often used in once-daily observed therapy of methadone substituted former opiate drug users. We performed a matched-pairs analysis on 24 patients (12 men/women) taking atazanavir/ritonavir 300/100 mg daily plus reverse transcriptase inhibitors, with (n=12) or without (n=12) methadone co-administration. Methods Twenty-four-hour pharmacokinetic profiles of atazanavir/ritonavir were assessed at steady-state and measured by liquid chromatography-tandem mass spectrometry. The geometric mean (GM, t test) minimum and maximum plasma drug concentrations (C min , C max ), area under the concentration-time curve (AUC), and total clearance (CL total ) were compared between the groups of pairs, which were matched for age, sex, weight, and ethnicity. Results The GM [90% confidence interval (CI)] of the atazanavir C min , C max , and AUC of patients taking the methadone oral solution at doses of 20-175 mg/day simultaneously with antiretroviral therapy were impaired compared to patients not taking methadone oral solution: C min =315 (range 197-448) vs. 519 (279-793) ng/mL [GM ratio (GMR)=0.61, p=0.229]; C max =1714 (1238-2262) vs. 3190 (2412-4076) ng/mL (GMR=0.54, p=0.018); AUC=21,987 (15,870-29,327) vs. 35,572 (26,211-46,728) ng h/mL (GMR=0.62, p=0.074). Methadone dose, which is proportional to the amount of methadone oral solution (10 mg/mL), was significantly correlated to atazanavir C max (r 2 =0.40, p=0.001) and AUC (r 2 =0.32, p=0.006). Ritonavir pharmacokinetics was similar between the groups with C min , C max , and AUC GMR of 1.01, 0.80, and 0.96, respectively. Conclusion The partial decrease in atazanavir plasma concentrations in patients concomitantly taking racemic methadone oral solution in this daily observed therapy setting deserves further attention, and therapeutic drug monitoring should be considered.

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Section: Resultsmentioning

confidence: 99%

Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting

Haberl

Moesch

Nisius

et al. 2009

Eur J Clin Pharmacol

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“…However, previous studies of ATV/r 300/100 mg have showed no significant pharmacokinetic differences by gender [38] or differences in clinical outcome by race [39].…”

Section: Table 2 (Continued)mentioning

confidence: 99%

Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women

et al. 2011

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ObjectiveThere are limited antiretroviral options for use in the treatment of HIV infection during pregnancy. The purpose of this study was to assess the safety, efficacy and appropriate dosing regimen for ritonavir (RTV)-boosted atazanavir in HIV-1-infected pregnant women. MethodsIn this nonrandomized, open-label study, HIV-infected pregnant women were dosed with either 300/ 100 mg (n 5 20) or 400/100 mg (n 5 21) atazanavir/RTV once-daily (qd) in combination with zidovudine (300 mg) and lamivudine (150 mg) twice daily in the third trimester. Pharmacokinetic parameters [maximum observed plasma concentration (C max ), trough observed plasma concentration 24 hour post dose (C min ) and area under concentration-time curve in one dosing interval (AUC t )] were determined and compared with historical values (300/100 mg atazanavir/RTV) for HIV-infected nonpregnant adults (n 5 23). ResultsAt or before delivery, all mothers achieved HIV RNA o50 HIV-1 RNA copies/mL and all infants were HIV DNA negative at 6 months of age. The third trimester AUC t for atazanavir/RTV 300/100 mg was 21% lower than historical data, but the C min values were comparable. The C min value for atazanavir/RTV 400/100 mg was 39% higher than the C min for atazanavir/RTV 300/100 mg in historical controls, but the AUC t values were comparable. Twice as many patients in the 400/100 mg group (62%) had an increase in total bilirubin (42.5 times the upper limit of normal) as in the 300/100 mg group (30%). Atazanavir (ATV) was well tolerated with no unanticipated adverse events. ConclusionsIn this study, use of atazanavir/RTV 300/100 mg qd produced C min comparable to historical data in nonpregnant HIV-infected adults. When used in combination with zidovudine/lamivudine, it suppressed HIV RNA in all mothers and prevented mother-to-child transmission of HIV-1 infection. During pregnancy, the pharmacokinetics, safety and efficacy demonstrated that a dose adjustment is not required for ATV.Keywords: atazanavir, HIV, pregnancy, prevention of mother-to-child transmission, protease inhibitor IntroductionTreatment guidelines for HIV-1 infection in pregnant women recommend highly active antiretroviral (ARV) therapy (HAART) with two nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine) plus the nonnucleoside reverse transcriptase inhibitor nevirapine [1][2][3]. Some guidelines also recommend the ritonavir (RTV)-boosted protease inhibitor lopinavir as an optional third agent [1], although others recommend several boosted protease inhibitors as optional agents [2]. All other ARV DOI: 10.1111/j.1468-1293.2011.00927.x HIV Medicine (2011 r 2011 British HIV Association 570 drugs are alternative agents or for use in special circumstances [1,4]. However, there are questions and concerns regarding the two most frequently recommended third agents: treatment initiation with nevirapine is associated with an increased risk of symptomatic liver toxicity, often accompanied by a rash, which is potentially fatal [1,5]. Concerns with RTV-boosted lopinavir inclu...

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“…A steady state is reached between 4 days and 8 days, and it has nonlinear pharmacokinetics and clearance, which allow for once-daily (od) dosing. 2 Administration of ATV with food enhances bioavailability and reduces pharmacokinetic variability. In the presence of a light meal, the exposure measured as area under the curve (AUC) was increased by 70%, with a 57% increase in maximum observed plasma concentration (C max ) compared with the fasting state.…”

Section: Introduction To Hiv-1 Management: Choice Of Agent and Resistmentioning

confidence: 99%

“…For similar reasons, didanosine (DDI)-buffered tablets should be dosed at least 1 hours before or 2 hours after ATV and on an empty stomach. 2 ATV is extensively metabolized by the liver, via the cytochrome P450 family 3, subfamily A (CYP3A) enzyme pathway. 2 The CYP3A locus includes all the known members of the 3A subfamily of the cytochrome P450 superfamily of genes (CYP3A4, CYP3A5, CYP3A7, and CYP3A43).…”

Section: Introduction To Hiv-1 Management: Choice Of Agent and Resistmentioning

confidence: 99%

“…2 ATV is extensively metabolized by the liver, via the cytochrome P450 family 3, subfamily A (CYP3A) enzyme pathway. 2 The CYP3A locus includes all the known members of the 3A subfamily of the cytochrome P450 superfamily of genes (CYP3A4, CYP3A5, CYP3A7, and CYP3A43). CYP3A is affected by many other commonly prescribed drugs and is also an important enzyme in the metabolism of many medications.…”

Section: Introduction To Hiv-1 Management: Choice Of Agent and Resistmentioning

confidence: 99%

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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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The steady-state pharmacokinetics of atazanavir/ritonavir in HIV-1-infected adult outpatients is not affected by gender-related co-factors

Cited by 28 publications

References 7 publications

Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting

Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting

Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women

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

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