Population Pharmacokinetics and Pharmacodynamics of Efavirenz, Nelfinavir, and Indinavir: Adult AIDS Clinical Trial Group Study 398

Pfister, Marc; Labbé, Line; Hammer, Scott M.; Mellors, John W.; Bennett, Kara; Rosenkranz, Susan L.; Sheiner, Lewis B.

doi:10.1128/aac.47.1.130-137.2003

Cited by 116 publications

(121 citation statements)

References 29 publications

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“…This two-compartment model with first-order absorption and lag-time was similar to the model with transition compartments [28], but slightly different from the one-compartment models used for population analyses of efavirenz [8,27]. However, pharmacokinetic estimates of efavirenz obtained from the present and previous studies using different models were in good agreement.…”

Section: Discussionsupporting

confidence: 71%

“…The estimated average clearance of efavirenz (0.105-0.126 l/h/kg) in the present study was smaller than that previously reported in patients (0.186 l/h/kg) [26], although a recent report based on population analysis presented a value in patients given efavirenz at 600 mg/day almost identical to that found in this study [27]. For volume of distribution at steady state (V ss ), estimates ranging from 3.012 to 4.412 l/kg were consistent with literature [8,27,28]. These data along with previous observations indicate that amprenavir does not substantially alter efavirenz pharmacokinetics.…”

Section: Discussioncontrasting

confidence: 53%

“…Since all currently available PIs are CYP3A4 inhibitors with varying inhibitory and induction activities, significant drug interactions have been reported when efavirenz and PIs are used in combination [4][5][6][7]. It has been reported that ritonavir produced a 21% increase in efavirenz exposure, whereas the hepatic clearance of efavirenz was unaltered by weaker inhibitors, such as indinavir, nelfinavir or saquinavir [8]. However, few data are available on the administration of efavirenz with dual PIs and the pharmacokinetic interactions that result at steady-state.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Forrest

Rosenkranz

et al. 2007

Biopharm & Drug Disp

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The combination of efavirenz with HIV-1 protease inhibitors (PI) results in complex interactions secondary to mixed induction and inhibition of oxidative metabolism. ACTG A5043 was a prospective, open-label, controlled, two-period, multiple-dose study with 55 healthy volunteers. The objective of the present study was to evaluate the potential pharmacokinetic interaction between efavirenz and dual PIs. The subjects received a daily dose of 600 mg efavirenz for 10 days with amprenavir 600 mg twice daily added at day 11 and were randomized to receive nelfinavir, indinavir, ritonavir, saquinavir, or no second PI on days 15-21. Intensive pharmacokinetic studies were conducted on day 14 and 21. Efavirenz plasma concentrations were fit to candidate models using weighted non-linear regression. The disposition of efavirenz was described by a linear two-compartment model with first order absorption following a fitted lag time. Apparent clearance (CL t /F), volume of distribution at steady state (V ss /F), intercompartmental clearance, and the central and peripheral volume of distribution were estimated. The mean CL t /F and V ss /F of efavirenz were 0.126 l/h/kg and 4.412 l/kg, respectively. Both AUC and CL t /F of efavirenz remained unchanged after 7 days of dual PI dosing. The mean V ss /F of efavirenz increased an average of 89% across arms, ranging from 52% (nelfinavir) to 115% (indinavir) relative to efavirenz with amprenavir alone. Increases were also observed in V p /F after the addition of nelfinavir, indinavir, ritonavir and saquinavir by 85%, 170%, 162% and 111%, respectively. In conclusion, concomitant administration of dual PIs is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2B6 substrates in general or oral efavirenz specifically.

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Section: Discussionsupporting

confidence: 71%

Section: Discussioncontrasting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Forrest

Rosenkranz

et al. 2007

Biopharm & Drug Disp

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“…Univariate two-way ANOVA testing for significance in the change in CD4-cell count after 6 months of ART detected no discernible effect of patient ethnicity on immune response to ART. The results of this study do not confirm those of Wegner et al, 26 Pfister et al 27 and Kappelhoff et al, 28 who reported a statistically significant effect of patient ethnicity on ARV drug response. Possible explanations for these findings include a greater degree of genetic similarity between the Mixed-Ancestry and Xhosa populations, as well as the limited sample size of our cohort.…”

Section: Discussioncontrasting

confidence: 99%

A pharmacogenetic study of CD4 recovery in response to HIV antiretroviral therapy in two South African population groups

Gebhardt

et al. 2009

J Hum Genet

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South Africa, like many other Southern African countries, has one of the highest HIV infection rates in the world and many individuals consequently receive antiretroviral therapy (ART). However, knowledge regarding (i) the prevalence of functional single nucleotide polymorphisms (SNPs) in pharmacologically relevant genes, and (ii) variance in pharmacotherapy both within and between different populations and ethnic groups is limited. The aim of this study was to determine whether selected polymorphisms in cytochrome P450 (CYP) genes (CYP2B6 and CYP3A4) and the multidrug-resistance 1 (ABCB1) gene underlie altered antiretroviral (ARV) drug response in two South African populations. DNA samples from 182 HIV-positive individuals of Mixed-Ancestry and Xhosa ethnicity on ART were genotyped for the A-392G SNP in CYP3A4, the G516T and A785G SNPs in CYP2B6, and the T-129C, C1236T, G2677T/A and C3435T SNPs in ABCB1. Univariate two-way analysis of variance (ANOVA) testing revealed no apparent effect of ethnicity on immune recovery (in terms of CD4-cell count) in response to ART. Univariate one-way ANOVA testing revealed a discernible effect of genotype on immune recovery in the cases of the T-129C (P¼0.03) and G2677A (Po0.01) polymorphisms in the ABCB1 gene. This study serves as a basis for better understanding and possible prediction of pharmacogenetic risk profiles and drug response in individuals and ethnic groups in South Africa.

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“…These observations are not surprising if the hypothesis that a higher concentration of the drug correlates with a higher risk for side effects is valid. Nevirapine concentrations are consistently higher among women compared with men [28,29], but studies of efavirenz have shown varying pharmacokinetic profile results [32][33][34]. The risk for nevirapine toxicity is also related to the degree of immunocompromise.…”

Section: Influence Of Sex On Arv-associated Adverse Events In Nonpregmentioning

confidence: 99%

Considerations for the Antiretroviral Management of Women in 2008

Clark

2008

Womens Health (Lond Engl)

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Clinicians should be familiar with sex-specific considerations when managing antiretroviral (ARV) treatment among women. Pregnancy is a critical influence on when to start treatment and what ARVs should be included in a regimen. Sex, pregnancy and hormonal contraceptive therapies can each influence ARV pharmacokinetic profiles. Women may be prone to have higher serum levels with selected ARV treatments, which may improve potency but also increase the risk for toxicities. Several studies have demonstrated that women do have higher frequencies of selected ARV-associated adverse events when compared with men. Although HIV treatment guidelines for nonpregnant women do not differ from men, clinicians should be aware of the high potential for certain ARV-related toxicities and follow suggestions in order to decrease the risk of side effects.The most recent statistics from the US CDC as of March 2008 show that the cumulative total number of women reported to have AIDS in the USA was 189,566 and women accounted for 26% of persons infected with HIV [101]. It has become increasingly clear that women have unique antiretroviral (ARV) management issues and clinicians should be familiar with sex-specific considerations. Women may metabolize selected drugs differently from men, which can result in different ARV pharmacokinetic profiles and the potential for adverse side effects. In addition, women of child-bearing potential have reproductive concerns that include optimal contraception and potential fetal toxicity for selected ARV therapies. When to start ARVsPregnancy status is the first consideration when determining whether to or when to initiate ARVs, since this will affect timing [102,103]. All pregnant women need to initiate ARVs regardless of their CD4 cell count or HIV RNA level. Those who have ARVs initiated only to prevent maternal-fetal transmission can afford to delay starting ARVs until after the first trimester, but others who require medication for their own health can start immediately, regardless of their gestational stage.The decision is more complicated for nonpregnant women. Over the years, the pendulum has swung both ways with regard to early versus late ARV initiation, with CD4 cell count criteria ranging from 500 down to 200 cells/mm 3 for asymptomatic HIV-infected nonpregnant individuals. Experts have carefully weighed possible survival benefits against long-term toxicities demonstrated in cohort studies and randomized clinical trials. The most recent version of the Department of Health and Human Services (DHHS) guidelines from January 2008 recommend initiating ARVs when the CD4 cell count drops to less than 350 cells/mm 3 for both men and nonpregnant women. The consideration for initiating ARVs for nonpregnant individuals with higher CD4 cell counts should take into account the specific patient scenario and comorbidities. Women with HIV-associated nephropathy or those who require treatment for a hepatitis B infection should have HIV treatment initiated, regardless of their CD4 cell count [102].In most c...

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Population Pharmacokinetics and Pharmacodynamics of Efavirenz, Nelfinavir, and Indinavir: Adult AIDS Clinical Trial Group Study 398

Cited by 116 publications

References 29 publications

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

A pharmacogenetic study of CD4 recovery in response to HIV antiretroviral therapy in two South African population groups

Considerations for the Antiretroviral Management of Women in 2008

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