JAC Advance Access originally published online on August 17, 2007
Journal of Antimicrobial Chemotherapy 2007 60(4):897-900; doi:10.1093/jac/dkm298
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Therapeutic drug monitoring of the HIV protease inhibitor atazanavir in clinical practice
1 Department of Clinical Pharmacy, Radboud University Medical Centre Nijmegen, The Netherlands 2 Nijmegen University Centre for Infectious Diseases (NUCI), Radboud University Medical Center Nijmegen, The Netherlands 3 Department of Internal Medicine, Erasmus Medical Centre Rotterdam, The Netherlands 4 Department of Infectious Diseases, Leiden University Medical Centre, The Netherlands 5 Department of Medical Microbiology, Radboud University Medical Centre Nijmegen, The Netherlands 6 Department of General Internal Medicine, Radboud University Medical Centre, The Netherlands 7 HIV Monitoring Foundation, Amsterdam, The Netherlands
* Correspondence address. Department of Clinical Pharmacy, 864 Radboud UMC Nijmegen, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands. Tel: +31-24-3616405; Fax: +31-24-3668755; E-mail: d.burger{at}akf.umcn.nl
Received 6 May 2007; returned 6 July 2007; revised 9 July 2007; accepted 13 July 2007
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Abstract |
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Background: Therapeutic drug monitoring (TDM) is being applied for a number of antiretroviral agents. Little is known about the use of TDM for atazanavir.
Methods: This is a retrospective cohort analysis on the use of TDM of atazanavir at three clinical sites in The Netherlands. Patients were divided into three groups: (i) all patients with evaluable data of plasma atazanavir concentrations and its relationship with hyperbilirubinaemia; (ii) patients who started atazanavir without documented evidence of protease inhibitor (PI) mutations; (iii) patients who started atazanavir with documented evidence of PI mutations. The genotypic inhibitory quotient (GIQ) was calculated by dividing the mean atazanavir plasma trough concentration by the number of PI mutations.
Results: A total of 108 patients were included; 70 (65.8%) were using atazanavir/ritonavir (300/100 mg once daily). No significant relationship was observed between atazanavir plasma trough concentration and antiviral response in patients starting atazanavir without PI mutations (group 2; n = 82). In contrast, a significant relationship was observed between atazanavir GIQ and treatment response in patients starting atazanavir while having PI mutations (group 3; n = 26). The cut-off value for GIQ most predictive of virological failure was 0.23 mg/L/mutation: patients (n = 8) with a GIQ equal to or below this value had 50% virological failure whereas patients (n = 18) with a GIQ above 0.23 mg/L/mutation had only 11% virological failure (
2: P = 0.030). Atazanavir plasma trough concentrations were significantly related with the occurrence of increased total bilirubin concentrations.
Conclusions: TDM of atazanavir might be beneficial for patients with documented PI resistance or patients with hyperbilirubinaemia.
Keywords: pharmacokinetics , resistance , hyperbilirubinaemia
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Introduction |
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The pharmacokinetics of the HIV protease inhibitor (PI) atazanavir are described by gastric acid- and food-dependent absorption, moderate protein binding (86%) and extensive hepatic metabolism through cytochrome P450-3A isoenzyme. As with other HIV PIs, inter-patient variability in atazanavir pharmacokinetics can be relatively large. A consequence of this can be that patients on atazanavir (with or without ritonavir) have either plasma concentrations that are too low (leading to virological failure) or too high (leading to undesired effects, in particular hyperbilirubinaemia). International guidelines now recommend therapeutic drug monitoring (TDM) in selected cases where inadequate drug exposure can be expected (i.e. children, pregnancy, drug–drug interactions, organ dysfunction, etc.1). The objective of this study was to describe our experience with TDM of atazanavir during the first 2 years since this agent was introduced in the market.
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Methods |
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Patients
This was a retrospective, observational cohort study. Data from all adult HIV-1-infected patients who were treated with atazanavir at three different clinical sites in The Netherlands were collected. Demographics, clinical and laboratory data were retrieved from the national observational database of HIV-infected patients.
Patients were divided into three categories: group 1 consisted of all patients and was used to evaluate the possible relationship between atazanavir plasma concentration and undesired effects or adverse events. Atazanavir-induced adverse effects were defined as grade III/IV hyperbilirubinaemia [total bilirubin concentration >53 µmol/L (
3.1 mg/dL)]. Group 2 consisted of all patients who started atazanavir treatment without documented evidence of protease mutations. Group 3 consisted of patients in which at least one genotypic resistance test was conducted that showed protease mutations associated with reduced antiviral activity of atazanavir according to the most recent update of the IAS-USA list (L10I/F/V/C, G16E, K20R/M/I/T/V, L24I, V32I, L33I/F/V, E34Q, M36I/L/V, M46I/L, G48V, I50L, F53L/Y, I54L/V/M/T/A, D60E, I62V, I64/L/M/V, A71V/I/T/L, G73C/S/T/A, V82A/F/T/I, I84V, I85V, N88S, L90M and I93L/M).
Atazanavir plasma concentrations and genotypic inhibitory quotient (GIQ)
Atazanavir plasma trough concentrations (taken 24 ± 4 h post-dose) were determined using a modification of a validated HPLC method with UV detection as published previously.2 The GIQ (units: mg/L/mutation) was calculated by dividing the mean atazanavir plasma trough concentration by the number of PI mutations as listed above.
Cut-off points for possible relationships between atazanavir plasma concentrations or GIQ with treatment response were determined using receiver operating curve (ROC) analysis. Cross-tabulations of patients having a value below or above the cut-off point were tested using Fisher's exact test.
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Results |
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Patients
A total of 108 patients were included (group 1; see patient flow chart in Figure 1). Demographic data of these patients at baseline are listed in Table 1. Median follow-up was 19 months with an interquartile range (IQR) of 16–29 months. The median atazanavir plasma concentration was 0.64 mg/L (IQR: 0.24–0.91). As expected, median atazanavir plasma trough concentrations were higher in patients using ritonavir-boosted atazanavir than in patients using unboosted atazanavir: 0.74 (IQR: 0.49–1.04 mg/L) versus 0.23 mg/L (IQR: 0.09–0.41 mg/L). Most patients had one (62%) or two (23%) plasma samples analysed for atazanavir during follow-up. The median intra-patient variability in atazanavir plasma concentrations was 52.9%.
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Antiviral response
Overall, 96 patients (91%) showed an antiviral response whereas the remaining 10 patients had a viral load >50 copies/mL at the end of follow-up. Antiviral response was significantly greater in patients from group 2 (no documented PI mutations) than in patients from group 3 (with documented PI mutations): 76/80 (95%) versus 20/26 (77%) (Fisher's exact test: P = 0.013; Figure 1).
All 48 patients with an undetectable viral load at start of atazanavir treatment continued to have the same during follow-up. Finally, the 58 patients who initiated atazanavir treatment while having a detectable viral load consisted of 26 patients with at least one PI mutation (antiviral response: 77%, see above) and 32 patients without documented PI mutations (antiviral response: 88%); see Figure 1.
No significant relationship was observed between atazanavir plasma trough concentration and antiviral response in patients starting atazanavir without documented PI mutations (group 2): area under the ROC curve was 0.655 with a 95% confidence interval (CI) of 0.423–0.888; P = 0.208. In contrast, a significant relationship was observed between atazanavir GIQ and treatment response in patients starting atazanavir while having PI mutations (group 3). The area under the ROC curve was 0.783 (95% CI: 0.577–0.990; P = 0.039). The ROC-defined cut-off value for GIQ most predictive of virological failure was 0.23 mg/L/mutation: patients (n = 8) with a GIQ equal to or below this value had 50% virological failure whereas patients (n = 18) with a GIQ above 0.23 mg/L/mutation had only 11% virological failure (Fisher's exact test: P = 0.030).
All subjects had a total serum bilirubin <10 µmol/L at baseline. The median maximum total bilirubin concentration during follow-up was 46 µmol/L with 45 subjects (42%) meeting the criteria for grade III/IV toxicity for serum bilirubin concentration. Atazanavir plasma trough concentrations were significantly related to the occurrence of increased total bilirubin concentrations. The area under the ROC curve was significantly different from 0.5: 0.672 (95% CI: 0.569–0.776; P = 0.002). The cut-off point for atazanavir trough concentration being most predictive of hyperbilirubinaemia appeared to be 0.76 mg/L: there were 66 patients with a mean atazanavir trough concentration equal to or below 0.76 mg/L of whom 20 (30%) developed grade III/IV hyperbilirubinaemia, versus 42 patients with a mean atazanavir plasma trough concentration >0.76 mg/L, of whom 25 (60%) developed grade III/IV hyperbilirubinaemia (Fisher's exact test: P = 0.003).
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Discussion |
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In this study, we were not able to find a relationship between atazanavir plasma trough concentrations and antiviral response when patients started an atazanavir-containing regimen without documented evidence of PI mutations. In contrast, a significant relationship could be observed between atazanavir GIQ and antiviral response in patients with at least one PI mutation. Finally, atazanavir plasma trough concentrations were significantly related to elevated serum total bilirubin concentrations.
There is an extensive evidence that plasma trough concentrations of HIV PIs correlate with antiviral response. The fact that in this analysis we were not able to find such a relationship in patients without PI mutations suggests that, with currently applied dosing regimens of atazanavir, exposure to the drug is at the maximum plateau of the concentration–activity curve. Other explanations are small sample size or selection bias of patients. The very few virological failures in this cohort (4 of 80 patients without PI mutations) must be explained by other factors, such as (temporal) non-adherence or undocumented presence of resistant virus.
There is also an increasing amount of data that the use of the inhibitory quotient may improve treatment outcome in patients harbouring resistant virus.3 Our data suggest that, in such a situation, the GIQ may be an important tool to improve the likelihood of achieving virological success. It must be noted that we have not adjusted the analysis for adherence data or activity score for the regimen as a whole because this information was not available to us.
Finally, our data confirm the relationship between atazanavir exposure and the increase in total bilirubin concentration. Although our ROC analysis describes a cut-off value for the atazanavir trough concentration of 0.76 mg/L above which the risk for grade III/IV hyperbilirubinaemia significantly increases, this may also occur at lower atazanavir trough concentrations. Polymorphism in UGT1A, the enzyme responsible for glucuronidation of bilirubin and the substrate of atazanavir-mediated inhibition, may explain the relatively weak correlation between atazanavir plasma concentrations and hyperbilirubinaemia.
Our study is not the first one evaluating plasma atazanavir trough concentrations and antiviral response or adverse events. There are, however, a number of features that make our study distinct from other reports.4–10 First, with the exception of two other studies,7,8 all other reported studies included far fewer patients than we did. Second, most studies had only a follow-up period of 12–24 weeks while the median duration of follow-up in our study was 19 months. Third, three studies report only on data of unboosted atazanavir4,8,10 whereas another study reports only on that of boosted atazanavir.6
With respect to a target value for atazanavir GIQ, our data are most comparable to those from Pellegrin et al.6 In that study, 71 PI-experienced but atazanavir-naive patients in virological failure while on HAART were followed for 48 weeks. GIQ analysis was performed only for the 12 week response; the cut-off value they presented was 220 ng/mL/mutation (= 0.22 mg/L/mutation) which is almost exactly equal to the cut-off value of 0.23 mg/L/mutation that we found in our study despite minor differences in the PI mutation list used for calculation of the GIQ.
In conclusion, this retrospective TDM cohort analysis showed no cut-off value for atazanavir in patients without documented evidence of PI mutations. In contrast, TDM of atazanavir may be warranted in patients with multiple PI mutations to optimize virological response rates. Finally, as grade III/IV elevations in serum bilirubin correlate with supra-therapeutic exposure to atazanavir, dose reduction of atazanavir in selected cases where jaundice is considered undesirable by the patient, under guidance of TDM, may improve adherence to atazanavir.
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This study was funded by the Radboud University Nijmegen Medical Center.
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None to declare.
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Acknowledgements |
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We would like to thank the following persons who helped collect clinical and laboratory data: Minny Meeuwissen, Marja Bendik and Willemien Dorama. The technicians of the laboratory of the Department of Clinical Pharmacy are thanked for their help with analysing the TDM samples of atazanavir.
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1 Working Group of the Office of AIDS Research Advisory Council (OARAC). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, version 10 October 2006. www.aidsinfo.nih.gov/guidelines/adultaidsinfo.nih.gov/guidelines/adult (28 July 2007, date last accessed).
2 Droste JAH, Verweij-van Wissen CPWGM, Burger DM. Simultaneous determination of the HIV drugs indinavir, amprenavir, saquinavir, ritonavir, lopinavir, nelfinavir, the nelfinavir hydroxymetabolite M8, and nevirapine in human plasma by reversed-phase high-performance liquid chromatography. Ther Drug Monit (2003) 25:393–9.[CrossRef][Web of Science][Medline]
3 Hoefnagel JG, Koopmans PP, Burger DM, et al. Role of the inhibitory quotient in HIV therapy. Antivir Ther (2005) 10:879–92.[Web of Science][Medline]
4 Gianotti N, Seminari E, Guffanti M, et al. Evaluation of atazanavir Ctrough, atazanavir genotypic inhibitory quotient, and baseline HIV genotype as predictors of a 24-week virological response in highly drug-experienced, HIV-infected patients treated with unboosted atazanavir. New Microbiol (2005) 28:119–25.[Medline]
5 Smith DE, Jeganathan S, Ray J. Atazanavir plasma concentrations vary significantly between patients and correlate with increased serum bilirubin concentrations. HIV Clin Trials (2006) 7:34–8.[CrossRef][Web of Science][Medline]
6 Pellegrin I, Breilh D, Ragnaud JM, et al. Virological responses to atazanavir-ritonavir-based regimens: resistance-substitutions score and pharmacokinetic parameters (Reyaphar study). Antivir Ther (2006) 11:421–9.[Web of Science][Medline]
7 Ray JE, Marriott D, Bloch MT, et al. Therapeutic drug monitoring of atazanavir: surveillance of pharmacotherapy in the clinic. Br J Clin Pharmacol (2005) 60:291–9.[CrossRef][Web of Science][Medline]
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Rodriguez NS, Barreiro P, Rendon A, et al. Plasma levels of atazanavir and the risk of hyperbilirubinaemia are predicted by the 3435C
T polymorphism at the multidrug resistance gene 1. Clin Infect Dis (2006) 42:291–5.[CrossRef][Web of Science][Medline]
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Winston A, Bloch M, Carr A, et al. Atazanavir trough plasma concentration monitoring in a cohort of HIV-1-positive individuals receiving highly active antiretroviral therapy. J Antimicrob Chemother (2005) 56:380–7.
10 Barrios A, Rendon AL, Gallego O, et al. Predictors of virological response to atazanavir in protease inhibitor-experienced patients. HIV Clin Trials (2004) 5:201–5.[CrossRef][Web of Science][Medline]
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