Sex differences in pharmacokinetics and toxicity of antiretroviral therapy

Umeh, Obiamiwe C.; Currier, Judith S.

doi:10.1517/17425255.2.2.273

Cited by 48 publications

(31 citation statements)

References 30 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%

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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%

“…The correlation analysis (Spearman's ρ) was set to a significance level of 0.001 level after Bonferroni-correction (SPSS ver. 16.0 for Windows; SPSS, Chicago, IL).…”

Section: Methodsmentioning

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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“…[14][15][16] Furthermore, women have higher rates of stimulant dependence, more severe forms of stimulant addiction and lower rates of treatment than men, [20][21][22][23] which may result in differential levamisole exposure. In addition, sex differences in both the pharmacokinetics of HIV medication 24 and the natural course of HIV disease 25 have been identified.…”

Section: Design and Samplementioning

confidence: 99%

Levamisole-Contaminated Cocaine Use in HIV-Infected and Uninfected Unstably Housed Women

Riley

Kral

Cohen

et al. 2016

Journal of Women's Health

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A growing number of case reports cite serious health complications linked to the cocaine adulterant, levamisole and women are disproportionately affected; however, the clinical effects are not well established. Between April and October of 2010, we conducted a cross-sectional study among 222 homeless and unstably housed women (116 human immunodeficiency virus [HIV]-infected and 106 HIV-uninfected). Immune markers and behavioral factors were compared in separate models by cocaine and levamisole exposure. Overall, 63% of participants were toxicology positive for cocaine/benzoylecgonine, 85% of whom also tested positive for levamisole. Differences in immune markers did not reach levels of significance among HIV-uninfected persons. Compared to HIV-infected persons who were negative for both cocaine and levamisole, the adjusted odds of low white blood cell count were significantly higher among HIV-infected persons positive for both ( p = 0.03), but not for those positive for cocaine only. Neutrophil count and HIV viral load did not differ by cocaine and levamisole status among HIV-infected persons. In a separate model, the adjusted odds of testing positive for levamisole were higher among African American women compared to Caucasian and Asian women ( p = 0.02). In the context of high levamisole prevalence, results suggest that decreased immune function as a result of levamisole exposure occurs mainly in individuals who are already immune compromised (e.g., HIV-positive), and race/ethnicity appears to be an important factor in understanding levamisole exposure among cocaine-using women. While larger and geographically diverse studies are needed to elucidate these initial findings, results suggest that levamisole may be one mechanism of immune dysfunction in HIV-infected cocaine-using women.

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“…The influence of sex on pharmacokinetics is available for one of these newer drugs. The clearance of enfuvirtide is reported to be 20% less among women compared with men, even after adjustment for bodyweight [30,107].…”

Section: Sex Influence On Pharmacokinetic Profilesmentioning

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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Sex differences in pharmacokinetics and toxicity of antiretroviral therapy

Cited by 48 publications

References 30 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

Levamisole-Contaminated Cocaine Use in HIV-Infected and Uninfected Unstably Housed Women

Considerations for the Antiretroviral Management of Women in 2008

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