Pharmacokinetic Parameters of Nevirapine and Efavirenz in Relation to Antiretroviral Efficacy

Leth, Frank van; Kappelhoff, Bregt S; Johnson, D. W.; Losso, Marcelo; Boroń-Kaczmarska, Anna; Saag, Michael S.; Livrozet, J.-M.; Hall, David B.; Leith, J.; Huitema, Alwin D. R.; Wit, Ferdinand W. N. M.; Beijnen, Jos H.; Lange, Joep M. A.

doi:10.1089/aid.2006.22.232

Cited by 65 publications

(50 citation statements)

References 32 publications

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“…These data are not easy to interpret because they include data from the two other studies mentioned [11,12], but the summary implication of the results is that the minimal effective concentration of EFV is likely to vary depending on the activity of the other drugs used in the combination. In the PK/PD substudy of 2NN, comprising only previously treatment-naïve patients, a C trough < 1,100 ng/ml was associated with an increased risk of virological failure, although the positive predictive value for virological failure was very low [14]. In this study, 1,100 ng/ml was the imputed median C trough of the population; thus, the EFV exposure in that study seems to be lower than in other study populations (see [7,15,16]).…”

Section: Discussionmentioning

confidence: 97%

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

Josephson

Andersson

Flamholc

et al. 2009

Eur J Clin Pharmacol

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Section: Discussionmentioning

confidence: 97%

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

Josephson

Andersson

Flamholc

et al. 2009

Eur J Clin Pharmacol

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“…Minimum plasma concentrations define therapeutic success, while maximum concentrations define the threshold for adverse drug reactions [17,18]. High intrapatient variability in efavirenz plasma trough concentration, as measured using the integrated pharmacokinetic adherence measure (IPAM) score, was associated with higher risk of viral rebound [2], while Pfister et al demonstrated that a 100% increase in clearance above the population mean was associated with clinical failure among highly active antiretroviral therapy (HAART)-naïve patients [10].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV‐infected Ugandans

et al. 2011

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BackgroundPharmacokinetic variability of the nonnucleoside reverse transcriptase inhibitor efavirenz has been documented, and high variation in trough concentrations or clearance has been found to be a risk for virological failure. Africans population exhibits greater variability in efavirenz concentrations than other ethnic groups, and so a better understanding of the pharmacokinetics of the drug is needed in this population. This study characterized efavirenz pharmacokinetics in HIV-infected Ugandans. MethodsEfavirenz plasma concentrations were obtained for 66 HIV-infected Ugandans initiating efavirenzbased regimens, with blood samples collected at eight time-points over 24 h on day 1 of treatment, and at a further eight time-points on day 14. Noncompartmental analysis was used to describe the pharmacokinetics of efavirenz. ResultsThe mean steady-state minimum plasma concentration (C min ) of efavirenz was 2.9 mg/mL, the mean area under the curve (AUC) was 278.5 h mg/mL, and mean efavirenz clearance was 7.4 L/h. Although overall mean clearance did not change over the 2 weeks, 41.9% of participants showed an average 95.8% increase in clearance. On day 14, the maximum concentration (C max ) of efavirenz was 44 mg/ mL in 96.6% of participants, while C min was o1 mg/mL in only 4.5%. Overall, 69% of participants experienced adverse central nervous system (CNS) symptoms attributable to efavirenz during the 2-week period, and 95% of these participants were found to have efavirenz plasma concentrations 44 mg/mL, although only half maintained a high concentration until at least 8 h after dosing. ConclusionThe findings of this study show that HIV-infected patients on efavirenz may exhibit autoinduction to various extents, and this needs to be taken into consideration in the clinical management of individual patients. Efavirenz CNS toxicity during the initial phase of treatment may be related to C max , regardless of the sampling time.Keywords: autoinduction, efavirenz, pharmacokinetics, Ugandans IntroductionA plasma therapeutic range of 1-4mg/mL has been established for the nonnucleoside reverse transcriptase inhibitor efavirenz [1,2], and great variation in the pharmacokinetics of the drug exists within and between patients, causing variation in drug concentrations [3][4][5][6]. Factors reported to be associated with interpatient variability in efavirenz concentration include gender, ethnicity and genetic polymorphisms [3,4,7,8,36], while autoinduction and adherence [8,9] [3,4,7], while Black patients have been reported to exhibit lower rates of clearance of the drug and hence higher plasma concentrations [10]. A recent study comparing 24-h efavirenz pharmacokinetics between HIV-infected patients and healthy volunteers after a single dose showed patients with HIV/AIDS to have lower efavirenz oral bioavailability compared with healthy volunteers when genetics and gender were controlled for [11].Certain polymorphisms of the gene encoding the major enzyme responsible for efavirenz metabolism, CYP2B6 (an enzyme belonging ...

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“…Plasma samples for drug concentrations of both ZDV/3TC and efavirenz were obtained 14 (IQR 13-15) hours and 13 (IQR [13][14] hours after the previous doses at 2 and 4 weeks, respectively. Mean plasma antiretroviral drug concentrations did not differ between patients with diarrhea and controls at Week 2 or Week 4; nor did the geometric mean values for each antiretroviral drug differ, Table 2 .…”

Section: Resultsmentioning

confidence: 99%

AIDS Diarrhea and Antiretroviral Drug Concentrations: A Matched-Pair Cohort Study in Port au Prince, Haiti

Dillingham¹,

Leger²,

Beauharnais³

et al. 2011

The American Society of Tropical Medicine and Hygiene

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Diarrhea in patients with acquired immunodeficiency syndrome (AIDS) may cause malabsorption of medications and failure of antiretroviral therapy (ART). We prospectively evaluated human immunodeficiency virus-1 (HIV-1)-infected patients with and without chronic diarrhea initiating ART in Haiti. We report mean plasma antiretroviral concentrations at 2 and 4 weeks. We measured plasma HIV-1 RNA levels at four points. Fifty-two HIV-1-infected patients (26 matched pairs) were enrolled. No differences in antiretroviral concentrations were detected. At week 24, 18/25 (72%) cases and 16/24 (68%) controls had undetectable plasma HIV-1 RNA levels (P = 0.69). Patients with plasma HIV-1 RNA levels > 50 copies/mL at week 24 had lower early efavirenz concentrations than patients with undetectable HIV-1 RNA (2,621 ng/mL versus 5,278 ng/mL; P = 0.02). Diarrhea at ART initiation does not influence plasma concentrations of the medications evaluated. Virologic outcome at Week 24 does correlate with efavirenz concentrations early in therapy but not with the presence of chronic diarrhea.

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Pharmacokinetic Parameters of Nevirapine and Efavirenz in Relation to Antiretroviral Efficacy

Cited by 65 publications

References 32 publications

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV‐infected Ugandans

AIDS Diarrhea and Antiretroviral Drug Concentrations: A Matched-Pair Cohort Study in Port au Prince, Haiti

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