JAC Advance Access originally published online on May 13, 2008
Journal of Antimicrobial Chemotherapy 2008 62(3):579-582; doi:10.1093/jac/dkn204
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Original research |
The steady-state pharmacokinetics of atazanavir/ritonavir in HIV-1-infected adult outpatients is not affected by gender-related co-factors
1 Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Johann Wolfgang Goethe University, Frankfurt, Germany 2 HIVCENTER, Medical HIV Treatment and Research Unit, Johann Wolfgang Goethe University, Frankfurt, Germany 3 Infektiologikum Frankfurt, Frankfurt, Germany
* Corresponding author. Tel: +49-69-63016956; Fax: +49-69-63017636; E-mail: hentig{at}em.uni-frankfurt.de
Received 17 December 2007; returned 26 February 2008; revised 11 April 2008; accepted 15 April 2008
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Abstract |
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Objectives: Pharmacokinetic differences, contributing to drug-related side effects, between men and women have been reported for HIV protease inhibitors. As only limited and inconclusive data on ritonavir-boosted atazanavir are available, we evaluated the respective steady-state pharmacokinetics in 48 male and 26 female HIV-1-infected adults receiving atazanavir/ritonavir 300/100 mg once-daily as part of their antiretroviral therapy.
Methods: Pharmacokinetic profiles (24 h) of atazanavir/ritonavir were assessed and measured by HPLC/tandem mass spectrometry. Geometric mean (GM; ANOVA) of minimum and maximum plasma drug concentrations (Cmin and Cmax), area under the concentration–time curve (AUC) and total clearance (CLtotal) were compared between the sexes and correlated to demographic (age, gender and ethnicity), physiological (weight and body mass index) and clinical (CD4+ cell count, HIV-RNA, co-medication and hepatitis serology) co-factors.
Results: The GM of the atazanavir AUC, Cmax and Cmin of men versus women were 32 643 versus 36 232 ng·h/mL [GM ratio (GMR) = 1.11, P = 0.435], 2802 versus 3211 ng/mL (GMR = 1.15, P = 0.305) and 398 versus 470 ng/mL (GMR = 1.18, P = 0.406), respectively. Although weight (80.6 versus 63.9 kg, P = 0.001) and body weight-adjusted atazanavir dose (3.84 versus 4.60 mg/kg, P = 0.013) were different between the sexes, no significant correlation to atazanavir pharmacokinetics was observed. A linear regression analysis detected significant correlations of atazanavir Cmin with ritonavir AUC (P < 0.001) and the co-administration of methadone oral solution (P = 0.032), and inverse correlations with the time since the first HIV infection diagnosis (P = 0.003) and the number of previous antiretroviral treatments (P = 0.022).
Conclusions: Atazanavir/ritonavir steady-state pharmacokinetics was comparable in men and women, despite gender-related significant differences in atazanavir dose/body weight. The administration of atazanavir/ritonavir is pharmacokinetically safe; 95% of all trough samples were above the recommended plasma concentration of 150 ng/mL.
Keywords: HIV protease inhibitors , antiviral , antiretroviral therapy
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Introduction |
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Previous studies showed differences in HIV progression, and virological and immunological response between men and women,1 and also detected increased risks for women of developing toxicities when given highly active antiretroviral therapy (HAART), e.g. lactic acidosis,2 dyslipidaemia3 or hepatotoxicity.4 As high plasma drug concentrations can be directly related to toxicity, variations in the pharmacokinetic profiles of antiretrovirals are one probable reason for increased toxicity in women.4 Regarding HIV protease inhibitors, gender differences have been observed for saquinavir [area under the concentration–time curve (AUC) 25% higher and minimum plasma concentrations 3-fold higher in women], indinavir [clearance (CL) 30% lower in women] and lopinavir (random concentration 1.67-fold higher in women),5 but inconsistent results have been published for atazanavir: pharmacokinetic data of a small study in patients (n = 15) showed a 2.4-fold higher atazanavir AUC0–24 (combined with saquinavir/ritonavir) in women compared with men,6 whereas the prescription information reports no pharmacokinetic differences for unboosted atazanavir in healthy males compared with young female (18–40 years, n = 29) or elderly female (
65 years, n = 30) volunteers.7 Therefore, we evaluated the pharmacokinetics of atazanavir/ritonavir in 74 adult outpatients regarding gender-related differences and demographic/clinical co-factors potentially altering HIV protease inhibitor pharmacokinetics.
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Patients and methods |
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Patients
Forty-eight men and 26 women, infected with HIV-1, received a second-line therapy with atazanavir/ritonavir 300/100 mg once-daily plus at least two nucleoside/nucleotide reverse transcriptase inhibitors.
Protease inhibitor therapy-experienced patients (n = 48) were selected for the regimen, provided that the genotypic resistance testing asserted sufficient susceptibility of the HIV-1 to the compounds. There were no CD4 cell count or viral load restrictions included in this study. Pharmacokinetic data were assessed from all patients who started with an atazanavir/ritonavir therapy regimen between June 2003 and June 2006.
Patients with hepatic impairment (Child–Pugh classification B or C) and patients receiving co-medication with CYP3A4/5 enzyme inhibitors/inducers as well as antacids were not included in the analyses; the same applied to patients who took antibiotics or antifungals such as azoles, which are frequently used in therapy of opportunistic infections of HIV; an exception was made for co-trimoxazole 960 mg three times a week intake.
This pharmacokinetic study design is observational. No additional intervention was performed, and Ethics approval was not obtained according to the national laws and the previously obtained advice of the responsible institutional Ethics Committee. Patients were individually informed and trained in the therapeutic drug monitoring (TDM) procedure and agreed with the recording of their data.
Pharmacokinetic assessment and assay
After at least 4 weeks on the regimen, patients underwent a standardized pharmacokinetic assessment under steady-state conditions. The schedule of atazanavir/ritonavir intake was documented by the patients for 3 days prior to the pharmacokinetic assessment and all concomitant drug intake had to be documented by patients and physicians. On the day of the study, patients were weighed, body height was measured and body mass index [BMI = weight (kg)/height2 (m2)] was calculated. Fasting trough atazanavir/ritonavir plasma concentrations were obtained immediately before drug intake, followed by a standardized breakfast of 
2500 kJ (25% from fat). Plasma samples were then collected at 1, 2, 4, 6, 9, 12 and 24 h after drug intake.
Atazanavir/ritonavir plasma concentrations were measured by validated HPLC/tandem mass spectrometry methods. The reliable lower limit of quantification was 20 ng/mL and the linearity of the calibration curve for atazanavir/ritonavir was proven up to 20 000 ng/mL.
A standard non-compartmental analysis module was used to calculate the AUC0–24, the elimination half-life (t1/2) and the total clearance (CLtotal). Cmin and Cmax values were read directly from the plasma concentration–time curves of atazanavir/ritonavir within the dosing interval.
The Cmin, Cmax, AUC
, CLtotal and t1/2 of atazanavir and ritonavir were compared between men and women by means of ANOVA. Absence of a significant difference of the atazanavir/ritonavir exposure between groups was suggested when no significant difference (at a 0.05 level) of the geometric mean (GM) ratio, together with a 90% confidence interval (CI), was determined. The sample size calculation for the comparison between groups was based on the detection of a difference of ±25% atazanavir AUC0–24 to either group. A minimum sample size of 25 subjects per group was calculated for a power of 80% and a two-sided significance level of 
= 0.05 for the ANOVA analysis. The correlation analysis (Spearman's 
) was supposed to be significant at a level of significance of P = 0.001 after Bonferroni's correction. Linear regression analysis was performed with the backward deletion of variables at a level of significance of P > 0.05 (SPSS 15.0 for Windows®).
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Results |
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Patients’ disposition
A number of baseline characteristics (Table 1) differed between men and women: statistically significant differences occurred regarding baseline viral load (HIV-RNA log10 3.34 versus 4.33 copies/mL; P = 0.018), the number of previous HAART (5.5 versus 3.1; P = 0.034), weight (80.6 versus 63.9 kg, P = 0.001) and BMI (24.9 versus 20.7 kg/m2, P = 0.020), and accordingly different atazanavir doses per weight (3.84 versus 4.60 mg/kg, P = 0.013). Twenty-three women (88.5%) and 31 men (67.4%) received tenofovir-DF (P = 0.054), and 11 women (42.5%) and 9 men (18.7%) received emtricitabine (P = 0.042) as co-medication. The other parameters did not reveal statistically significant differences. In spite of an apparent number of replicating hepatitis B and C virus infections, all patients were classified as Child–Pugh score A, not presenting clinical or metabolic signs of hepatic impairment.
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Pharmacokinetics
The GMs and 90% CIs of the pharmacokinetic parameters of atazanavir/ritonavir (Figure 1) showed no significant gender differences. The GM (90% CI) of atazanavir Cmin, Cmax, AUC, t1/2 and CLtotal of women compared with men were 470 (339–580) versus 398 (314–457) ng/mL (P = 0.406), 3211 (2613–3792) versus 2802 (2434–3117) ng/mL (P = 0.305), 36 232 (29 608–42 988) versus 32 643 (28 421–36 504) ng·h/mL (P = 0.435), 7.46 (6.45–8.15) versus 8.47 (7.32–9.02) h (P = 0.211) and 138 (111–161) versus 153 (131–169) mL/min (P = 0.572). The GM (90% CI) of ritonavir Cmin, Cmax, AUC, t1/2 and CLtotal in women compared with men were 51 (35–62) versus 48 (38–53) ng/mL (P = 0.745), 1099 (857–1322) versus 870 (731–979) ng/mL (P = 0.076), 9600 (7690–11 499) versus 7922 (6865–8856) ng·h/mL (P = 0.099), 4.63 (4.05–4.96) versus 4.95 (4.31–5.21) h (P = 0.464) and 174 (137–205) versus 211 (181–234) mL/min (P = 0.162), respectively.
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The bivariate correlation analysis detected significant correlations of atazanavir Cmin with ritonavir Cmin (r2 = 0.644, P < 0.001), Cmax (r2 = 0.418, P < 0.001) and AUC (r2 = 0.595, P < 0.001), but not with age, weight, dose/weight, BMI, baseline CD4 cell count or viral load. Correlations were also found for atazanavir Cmax with ritonavir Cmax (r2 = 0.420, P < 0.001) and AUC (r2 = 0.416, P < 0.001) and atazanavir AUC with ritonavir Cmax (r2 = 0.418, P < 0.001) and AUC (r2 = 0.506, P < 0.001), respectively.
A linear regression analysis focused on the correlation between atazanavir Cmin, taken as the most relevant parameter for therapy outcome, and co-variables that previously were either correlated (Spearman's ) to atazanavir plasma concentration or significantly different between the sexes (ANOVA, 
2 tests). The final regression model presented a correlation between the atazanavir Cmin and the ritonavir AUC (P < 0.001), the time since the first HIV infection diagnosis (P = 0.003), the number of previous HAART regimens (P = 0.022) and the co-administration of methadone liquid oral solution (P = 0.032). The 12 patients receiving daily methadone maintenance treatment revealed comparatively low GM (90% CI) of atazanavir Cmin, Cmax and AUC of 315 (197–448) ng/mL, 1714 (1238–2262) ng/mL and 21 987 (15 870–29 327) ng·h/mL, respectively, and a high variability in the GM (90% CI) of atazanavir clearance of 227 (161–298) mL/min. The GM (90% CI) of ritonavir Cmin, Cmax and AUC was within the expected range of 68 (39–97) ng/mL, 906 (553–1322) ng/mL and 9401 (6376–13 094) ng·h/mL, respectively.
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Discussion |
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Unlike lopinavir, amprenavir or saquinavir,8 atazanavir revealed only marginal gender-related pharmacokinetic differences when combined with low-dose ritonavir. Atazanavir/ritonavir pharmacokinetics remained unaffected by demographic parameters, i.e. gender, ethnicity and age, or physiological and clinical parameters, i.e. body weight, AIDS diagnosis, baseline CD4 cell count or viral load, and hepatitis B or C co-infection without signs of hepatic impairment. The only significant associations seen were those between a higher ritonavir AUC and a higher atazanavir Cmin, as can be expected, and those between a longer time since the initial HIV diagnosis or a higher number of previously taken HAART regimens, and a lower atazanavir Cmin. Weight and accordingly weight-adjusted atazanavir dose were not significantly associated with atazanavir pharmacokinetics; both were excluded from the final regression model at levels of significance of P = 0.213 and 0.279 in the pre-last iteration steps.
The comparatively low atazanavir plasma concentrations in 12 patients who concomitantly took methadone maintenance therapy are probably of no clinical relevance, provided that a genotypic resistance testing asserts the susceptibility of the individual HIV-1 virus strains to atazanavir. The recommended lower boundary of the atazanavir plasma Cmin is 150 ng/mL for wild-type HIV-1.9
Altogether, eight samples were below the recommended minimum atazanavir concentration, which corresponds to a proportion of 5.1% of all trough and 24 h plasma samples in this study (n = 156). The proportion of male and female patients on methadone maintenance therapy (Fisher's exact P = 0.197) and a pharmacokinetic subanalysis of patients not receiving methadone maintenance therapy confirmed that methadone intake was not a confounder in the gender analysis. Also, co-administered tenofovir-DF, which previously has been reported to impair plasma concentrations of atazanavir,10 had only marginal impact on the steady-state plasma concentrations of ritonavir-boosted atazanavir.
Summarizing the results of this pharmacokinetic analysis, the combination of atazanavir/ritonavir provides sufficient plasma concentrations in men and women over the entire dosing interval, and neither gender-related physiological and demographic co-variables nor tenofovir co-administration call for the routine assessment of atazanavir plasma concentrations in the absence of relevant protease inhibitor resistance mutations.
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Funding |
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This study was supported by internal funds.
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Transparency declarations |
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None to declare.
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References |
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1 Poundstone KE, Chaisson RE, Moore RD. Differences in HIV disease progression by injection drug use and by sex in the era of highly active antiretroviral therapy. AIDS (2001) 15:1115–23.[CrossRef][Web of Science][Medline]
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6
King JR, Kakuda TN, Paul S, et al. Pharmacokinetics of saquinavir with atazanavir or low-dose ritonavir administered once daily (ASPIRE I) or twice daily (ASPIRE II) in seronegative volunteers. J Clin Pharmacol (2007) 47:201–8.
7 Reyataz Product Information. NDA 21-567/S-012. Princeton, NJ, USA: Bristol Myers Squibb Company. Update 22 March 2007.
8 Umeh O, Currier J. Sex differences in the pharmacokinetics and toxicity of antiretroviral therapy. Expert Opin Drug Metab Toxicol (2006) 2:273–83.[CrossRef][Web of Science][Medline]
9 Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 2006, updated 29 January 2008 wwww.aidsinfo.nih.gov (3 March 2008, date last accessed).
10
Taburet A, Piketty C, Chazallon C, et al. Interactions between atazanavir–ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother (2004) 48:2091–6.
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