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Atazanavir trough plasma concentration monitoring on HAART; NVP Reduced Reyataz trough levels
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Journal of Antimicrobial Chemotherapy Advance Access advance published July 4, 2005
Alan Winston1,2*, Mark Bloch3, Andrew Carr2, Janaki Amin1, Patrick W. G. Mallon1,2,
John Ray2, Debbie Marriott2, David A. Cooper1,2 and Sean Emery1
1National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, 2010,
Australia; 2HIV, Immunology and Infectious Diseases Clinical Services Unit, St. Vincent's Hospital,
Sydney, 2010, Australia; 3Holdsworth House Medical Practice, Sydney, 2010, Australia
Received 5 April 2005; returned 9 May 2005; revised 13 May 2005; accepted 5 June 2005
ABSTRACT
Objectives: Atazanavir is a recently approved HIV protease inhibitor (PI). As with other PIs, careful attention to potential pharmacokinetic drug interactions in clinical practice is necessary. The aim of this study was to assess the clinical associations with plasma atazanavir concentrations in HIV-positive individuals.
Methods: Individuals established on an atazanavir-containing regimen, completed an interviewer administered questionnaire recording atazanavir dosing characteristics, concomitant medication use and adherence. After completion, plasma atazanavir concentrations were measured.
Results: Of 100 individuals, mean trough plasma atazanavir concentrations (mg/L) were 282 (95% CI 95–468, n = 19) and 774 (95% CI 646–902, n = 81) in those on non- and ritonavir-boosted atazanavir regimens, respectively. Eighty-five individuals had HIV RNA <50 copies/mL.
Seven individuals had atazanavir plasma concentrations below the assay limit of detection (<50 mg/L), all of whom had undetectable plasma HIV RNA.
In a multivariate analysis, nevirapine use was associated with significantly lower trough atazanavir concentrations (P = 0.011) and lopinavir/ritonavir use with higher trough atazanavir concentrations (P = 0.032).
Dosing characteristics (including food taken), concomitant medications (including drugs used for dyspepsia) and HIV RNA were not significantly associated with trough atazanavir concentrations.
Conclusions: In this cohort, despite the wide inter-individual variability of atazanavir trough concentrations, no significant association with dosing characteristics, concomitant medication (with the exception of nevirapine and lopinavir/ritonavir) or virological response was observed. Further work is needed to assess the optimal dosing regimen when using atazanavir with nevirapine.
Of interest, no difference in atazanavir plasma concentrations was significantly associated with the use of tenofovir (mean plasma atazanavir level 881 versus 625 mg/L, P = 0.268). Individuals on tenofovir were significantly more likely to be on concomitant ritonavir therapy (P = 0.040, c2).
Didanosine therapy, or timing of didanosine therapy in relation to atazanavir dosing time, were not associated with significant changes in atazanavir plasma levels (P = 0.347 and 0.272, respectively).
Results
Patient selection
A total of 171 individuals were commenced on an atazanavircontaining
HAART regimen at the Department of Immunology, St. Vincent's Hospital, Sydney and Holdsworth House Medical Practice, Sydney during February 2003–June 2004. Of these individuals, 31 stopped taking atazanavir or were lost-to-follow-up. Of the remaining individuals, 100 (71%) successfully completed the
study. There were no differences in detectable versus undetectable HIV RNA (<50 copies/mL) in those completing and not completing the study (72% versus 85% undetectable, P = 0.162, c2). Prior to atazanavir therapy, these 100 individuals were either PI-naive or switching PI therapy due to intolerance or toxicity.
Patient characteristics and atazanavir dosage characteristics Atazanavir dosage is shown in Figure 1. Eighty-one patients were receiving ritonavir-boosted atazanavir regimens and 19 patients were on non-boosted regimens. Seventy-six of the 100 individuals were on recommended dosing regimens, either ATV-400 once daily or ATV/RTV-300/100 once daily.5
Patient characteristics and dosing characteristics are shown in Table 1. Of the 100 individuals, 85 had an HIV RNA below detectable limits (<50 copies/mL). Mean trough plasma atazanavir concentration was 282 mg/L (95% CI 95–468 mg/L) for individuals on nonboosted regimens and 774 mg/L (95% CI 646–902 mg/L) for those on boosted atazanavir. Seven individuals had trough concentrations below detectable limits (<50 mg/L), all of whom had undetectable plasma HIV RNA. Of the 93 patients with atazanavir concentrations >50 mg/L, 85 (91%) had undetectable plasma HIV RNA.
Concomitant HAART and other medications are also shown in Table 1. Ninety-one of the 100 individuals reported taking at least one concomitant medication on the previous day, and 37 individuals reported taking medication listed as contraindicated with atazanavir.
Associations with atazanavir plasma concentrations and patient/dosing characteristics
Associations between patient and dosing characteristics and trough atazanavir plasma concentrations are shown in Table 2. No patient characteristic was significantly associated with atazanavir plasma concentrations.
The following atazanavir dosing characteristics were not associated with trough atazanavir concentrations: once- versus twice daily dosing, dose with or without food, dose with or without a 20 g fat meal, beverage atazanavir dose taken with, any missed doses in past 3 days and result of adherence questionnaire.
The use of recommended versus non-recommended dosing was not significantly associated with changes in atazanavir plasma concentrations overall; and for individuals on ritonavir-boosted atazanavir regimens, no significant changes in plasma concentrations were observed when using a non-recommended dosage.
However, for individuals on non-boosted atazanavir regimens, non-recommended dosing schedules were significantly associated with higher plasma atazanavir concentrations (overall P value =0.002). This was the case for all dosing schedules observed within the cohort, apart from atazanavir 200 mg once daily (P = 0.226, 0.026, 0.015 and 0.009 for atazanavir 200 mg once daily, atazanavir 200 mg twice daily, atazanavir 300 mg once daily and atazanavir
300 mg twice daily, respectively).
Associations with atazanavir plasma concentrations and concomitant antiretroviral medication
In a multivariate analysis (Table 3), higher trough atazanavir plasma concentrations were only significantly associated with the use of lopinavir/ritonavir (mean plasma atazanavir level 1457 versus 604 mg/L, P = 0.032) and ritonavir (mean plasma atazanavir level 774 versus 282 mg/L, P < 0.001) and lower trough atazanavir plasma concentrations were only significantly associated with nevirapine use (mean plasma atazanavir level 350 versus 726 mg/L, P = 0.011).
Of interest, no difference in atazanavir plasma concentrations was significantly associated with the use of tenofovir (mean plasma atazanavir level 881 versus 625 mg/L, P = 0.268). Individuals on tenofovir were significantly more likely to be on concomitant ritonavir therapy (P = 0.040, c2).
Didanosine therapy, or timing of didanosine therapy in relation to atazanavir dosing time, were not associated with significant changes in atazanavir plasma levels (P = 0.347 and 0.272,
respectively).
Associations between atazanavir plasma concentrations and non-antiretroviral concomitant medications
No significant associations were observed between atazanavir plasma concentrations and the use of concomitant medications, or any specific group of concomitant medications including drugs used for dyspepsia and other contraindicated medications (P > 0.15 for all comparisons).
Of note, 12 individuals reported taking drugs used for dyspepsia. This comprised two individuals taking antacids (Gaviscon liquid and Rennie tablets), five individuals taking H2-receptor antagonists (three ranitidine, one famotidine and one nizatidine) and five individuals taking proton-pump-inhibitors (two esomeprazole, two omeprazole and one pantoprazole). Two of the 12 individuals took these agents at the same time as atazanavir, whereas the other 10 took these agents separately. No significant associations were observed for any specific group of drugs used for dyspepsia (P = 0.532, 0.249 and 0.176 for antacids, H2-receptor antagonists and proton-pump-inhibitors, respectively) or for the timing of these medications (P = 0.946).
Factors associated with undetectable trough atazanavir plasma concentrations (<50 mg/L)
Seven individuals had undetectable trough plasma atazanavir concentrations (<50 mg/L), all of whom also had undetectable HIV RNA (<50 copies/mL). Individuals on boosted atazanavir containing regimens were less likely to have undetectable trough atazanavir concentrations (two of the seven patients were on boosted regimens, P < 0.001, c2). Individuals on non-boosted regimens who were receiving non-recommended atazanavir dosing schedules (n = 10) were less likely to have undetectable plasmaconcentrations (P = 0.006, c2).
Although nevirapine use was significantly associated with lower plasma atazanavir concentrations, it was not associated with undetectable plasma levels (P = 0.847). Eleven of the 12 individuals on nevirapine were on boosted atazanavir regimens that may have reduced the likelihood of undetectable plasma atazanavir concentrations.
Factors associated with undetectable HIV RNA (<50 copies/mL)
Fifteen individuals had detectable HIV RNA. Trough plasma atazanavir concentration, atazanavir dose, atazanavir frequency, atazanavir taken with or without food, atazanavir taken with or without a 20 g fat meal, beverage taken with atazanavir, adherence question result, or the concomitant use of ritonavir, nevirapine, contraindicated medications and drugs used for dyspepsia were not associated with undetectable viral load (P > 0.30 for all comparisons).
Discussion
These results demonstrate that trough plasma atazanavir concentrations are significantly increased with the use of ritonavir and lopinavir/ritonavir and significantly decreased with the use of nevirapine. Dosing characteristics, including foods taken with atazanavir, other antiretroviral medication and other concomitant medication including drugs used for dyspepsia do not significantly affect atazanavir plasma concentrations. In addition, dose adjustment in boosted atazanavir regimens has no effect on plasma concentrations. Mean trough atazanavir levels observed are similar to those previously reported (282 versus 273 mg/L for non-boosted regimens and 774 versus 862 mg/L for boosted regimens6).
In this study, there were no associations between the use of efavirenz or tenofovir and reduced atazanavir plasma concentrations. This contrasts with other published results reporting reduced atazanavir concentrations in patients using these agents.9,12 All subjects on efavirenz and tenofovir were also on ritonavirboosted atazanavir regimens, in keeping with current prescribing recommendations, which may explain the lack of an observed interaction.
Recent reports have described a 79% and 28% reduction in atazanavir Ctrough in healthy volunteers treated with ATV/RTV- 300/100 once daily and omeprazole 40 mg11 or famotidine 40 mg,10 respectively. No significant changes in atazanavir exposure associated with drugs used for dyspepsia were observed in our cohort. Of those taking drugs used for dyspepsia, 10 of the 12 individuals took these agents at least 10 h apart from atazanavir and both individuals receiving omeprazole reported taking a lower dose of 20 mg daily. Omeprazole 20 mg daily is associated with less gastric acid suppression than 40 mg daily.17 Famotidine intake temporally separated from atazanavir intake is associated with less impact on atazanavir plasma concentrations.10 These differences in dosing characteristics in this cohort may not lead to a reduction in plasma atazanavir exposure; however, data from formal pharmacokinetic studies are unavailable. Of interest, individuals on nevirapine had significantly lower plasma atazanavir concentrations, while trough atazanavir concentrations were not significantly altered by concomitant efavirenz use. All individuals on efavirenz were on ritonavir-boosted atazanavir regimens and all but one individual on nevirapine were on boosted regimens. Further work is needed to assess the optimal
dosage of atazanavir when prescribed with nevirapine; whether ATV/RTV-300/100 once daily or a higher dose is optimal. Significantly higher atazanavir plasma concentrations were observed in individuals on lopinavir/ritonavir/atazanavir regimens compared with individuals on ritonavir-boosted atazanavir regimens alone. All individuals on lopinavir/ritonavir were on (Kaletra ) three capsules twice daily. The higher dosage of ritonavir (100 mg twice daily) associated with lopinavir/ritonavir therapy, and the resultant greater CYP3A4 inhibition, may explain this finding.
The seven individuals with undetectable plasma atazanavir concentrations in our cohort all had fully suppressed plasma HIV RNA. The estimated IC90 of atazanavir in treatment-naive individuals is 8–12 mg/L and in PI-experienced individuals it is 25 mg/L.18 Although these individuals have plasma atazanavir concentrations below the limit of our assay's detection, they may have plasma concentrations that remain above the threshold required to maintain virological suppression.
Twenty-four per cent of subjects were receiving nonrecommended dosing schedules of atazanavir. For individuals on boosted atazanavir regimens, these schedules were not associated with any significant changes in trough plasma atazanavir concentrations. The increase in atazanavir exposure when boosted
with ritonavir may be greater than any small change in exposure associated with atazanavir dosing changes.
Individuals on non-boosted atazanavir regimens, receiving non-recommended dosing schedules, did have significantly higher trough atazanavir plasma concentrations. These individuals may represent a pre-selected group in whom physicians have individually altered dose in response to a previous atazanavir plasma concentration that was interpreted as suboptimal. No potential clinical advantage of this dose modification is clear as no association between atazanavir concentrations and HIV RNA virological response was observed in this cohort, and ritonavir-boosted atazanavir regimens were associated with significantly higher plasma trough concentrations.
As a cross-sectional analysis, this study was not designed to determine cause-and-effect relationships and there are several limitations. As such, associations demonstrated should be interpreted in the context of the unmeasured bias inherent in these types of studies. These associations need further crossover trails to confirm these findings. As this study only included individuals currently taking atazanavir, data on subjects who had ceased atazanavir due to intolerance or virological failure were not included and therefore subject recruitment was selective. In addition, intra-patient variability in PI plasma exposure has previously been observed and recent guidelines suggest assessing plasma PI concentrations at two discrete time points.19 We cannot assess intra-patient variability in this study as plasma concentrations were measured at one time point only. This may explain the undetectable levels in some subjects as no confirmatory level was available. No weights were assessed that may also be associated with plasma exposure. Plasma drug exposure may differ between ethnic groups. Our cohort consists of a predominantly Caucasian population and further work is needed prior to applying these results to other populations.
Inherent variability in the plasma concentration of the HIV PIs has been demonstrated among all the available PIs20 that may be reduced but not eliminated with the use of ritonavir boosting.21
This inherent variability is only of clinical significance if it is associated with toxicity in the higher range or a lack of virological response in the lower range. In this cohort, we have found no associations with trough atazanavir exposure and virological response, despite observing substantial variability in atazanavir levels. Recently, a therapeutic range for atazanavir Ctrough has been described with a greater virological response observed in individuals with atazanavir Ctrough >150 mg/L22 (86% versus 44% HIV RNA <50 copies/mL in individuals with atazanavir Ctrough above and below 150 mg/L, respectively). This therapeutic range was defined in a group of highly treatment-experienced patients (63% of individuals previously exposed to PI therapy) all treated with boosted atazanavir regimens. This differs from our cohort and may explain the absence of this association in our group.
In summary, in this cohort of individuals on atazanavircontaining HAART regimens, trough plasma levels of atazanavir are significantly decreased with the use of nevirapine and not significantly altered by atazanavir dosing characteristics or the concomitant use of regularly prescribed and non-prescribed medication. Inherent variability is observed with atazanavir trough plasma levels, as with the other PIs, but is not associated with virological outcome. These data do not support dose modification of atazanavir based on plasma concentrations alone. However, therapeutic drug monitoring (TDM) may be a useful tool when newly licensed PIs are approved and become available in clinical practice and formal pharmacokinetic studies are unavailable. TDM may observe drug interactions such as the observation with nevirapine in this cohort.
Ongoing attention for potential interactions with the widespread use of atazanavir is warranted, but from these data no unforeseen interactions are observed with commonly used medications or food/beverage restrictions in clinical practice.
Methods
Study design
All individuals established on atazanavir-containing antiretroviral regimens for >28 days, attending for routine clinic visits at HIVImmunology- Infectious-Diseases Clinical Services Unit, St. Vincent's Hospital, Sydney and Holdsworth House Medical Practice, Sydney, between June 2004–August 2004, were invited to participate in this study, including patients in whom a previous plasma atazanavir concentration was available. Participants completed an intervieweradministered questionnaire and had a plasma atazanavir concentration assessed prior to their usual atazanavir dosing time. Approval was granted from the local Human Ethics Committee prior to commencing the study and all patients provided written informed consent. After completion of the study, plasma atazanavir concentration results were provided to each patient's regular treating physician.
Study questionnaire
Interviews were conducted by four investigators who were all trained to ask study questions and complete the study questionnaires uniformly. The study questionnaire comprised four sections addressing medications taken on the previous day, atazanavir dosing details, medications missed on the previous 3 days and medication adherence assessment.
Investigators documented all medications taken over a 24 h period prior to the interview and specifically prompted every patient for the following categories of medication: antiretroviral therapy, other prescribed medication, concomitant ‘over the counter' medication, medications used for dyspepsia, supplementary medication, vitamins, mineral and herbal therapies, food supplements and recreational drugs. For all medications the dose, frequency and timing were recorded. Recorded information included dose of atazanavir (mg), time taken and beverage or food consumed 2 h prior to, and 1 h after, atazanavir dose on the previous day.
Patients were specifically questioned about missed medication over the past 3 days. Individuals then scored their adherence to prescribed medication over the past 28 days based on a score from 0–10, where 0 equals no medication taken, 5 represents 50% of prescribed medication taken and 10 represents every dose of prescribed medication taken.13
Atazanavir plasma concentration
Atazanavir plasma concentrations were measured after completion of the study interview and were performed using a validated HPLC assay, by the Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney. This laboratory participates in an international external quality assurance programme run from the Netherlands.14 The assay cut-off for the lower limit of detection of plasma atazanavir concentration was 50 mg/L, and the coefficients of variation were 4.4% and 3.9% for low (150 mg/L) and high (8000 mg/L) control samples, respectively.
For individuals unable to attend the study visit prior to the usual atazanavir dosing time, atazanavir plasma concentrations were also assessed during the study visit. For all individuals, 24 h trough plasma atazanavir concentrations were calculated using standard pharmacokinetic formulae.15 Previously reported half-lives of 8.6 and 6.4 h for ATV/RTV-300/100 once daily12 and ATV-400 once daily,16 respectively, were used. In brief, drug elimination was calculated using a first-order process where drug concentration over time is presumed to be log-linear.
Statistical analysis
All assessed atazanavir concentrations were log10 transformed. Predictors of log10 trough atazanavir plasma concentrations were determined using linear regression modelling. The potential predictors assessed in univariate analysis were baseline CD4+ cells/mm3, HIV RNA viral load (log10 copies/mL), gender, time on atazanavir (days), atazanavir dosing characteristics (frequency, recommended versus not recommended dose, with or without food, with or without a 20 g fat meal, beverage), adherence questionnaire result, any missed doses in the past 3 days, other antiretroviral medication and other concomitant medication.
For the purpose of the analysis, fat content of food taken with atazanavir was assessed using Foodworks Professional Edition version 3.00.338 and the results stratified above and below 20 g of fat. Adherence questionnaire results were categorized above and below 9.5 and beverage was stratified for beverages with a pH below 4 (fruit juice, carbonated drinks and alcohol) and a pH above 4 (water, tea, coffee and milk containing drinks).
Associations between atazanavir dosing characteristics were categorized for individuals on ritonavir-boosted atazanavir-containing regimens and non-ritonavir-boosted regimens. For all categorized results, P values for interactions were assessed and quoted where significant to <0.05.
Concomitant medications were grouped according to drug class. Drug class groups were analysed individually where 5% or more of individuals were currently receiving an agent from one class. Multivariate analyses were performed on parameters in univariate models with P values <0.05, using a stepwise-forward method. c2 analysis was used for stratified analyses to aid in interpretation of significant predictors for the multivariate models. All Pvalues are two-tailed with values <0.05 regarded as statistically significant. Data were analysed using STATA statistical software.
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