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Therapeutic Drug Monitoring of Nevirapine Reduces Pharmacokinetic Variability But Does Not Affect Toxicity or Virologic Success in the ATHENA Study
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JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 39(2) 1 June 2005
LETTER TO THE EDITOR
Crommentuyn, Kristel M PhD*; Huitema, Alwin D*; Brinkman, Kees; van der Ende, Marchina E; de Wolf, Frank; Beijnen, Jos H*
*Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands HIV Monitoring Foundation, Amsterdam, The Netherlands Department of Infectious Disease Epidemiology, Imperial College, London, United Kingdom Faculty of Pharmaceutical Sciences, Department of Biomedical Analysis, Division of Drug Toxicology, Utrecht University, Utrecht, The Netherlands
To the Editor:
Therapeutic drug monitoring (TDM) implies individualized dosing of a drug by analysis and interpretation of the plasma drug concentrations. We investigated whether routine TDM of nevirapine in treatment-naive HIV-1-infected patients has an effect on its pharmacokinetics, and thus on the occurrence of toxicity and the virologic response to treatment. Our analysis was performed within the framework of the ATHENA study, a national observational cohort of HIV-infected patients followed in 22 treatment centers in The Netherlands.
Patients were randomized to a TDM group or a control group after informed consent was signed.1 For patients in the TDM group, the drug concentration with an interpretation was reported to the treating physician. For patients in the control group, drug concentrations were measured but not reported.2
Blood was sampled 4 and 12 weeks after the start of treatment and every 12 weeks thereafter. Plasma drug concentrations were determined using a validated high-performance liquid chromatography method.3 Individual nevirapine plasma concentrations were compared with standardized pharmacokinetic curves.4 For each sample, the quotient of the measured drug concentration and the time-adjusted value in the standard pharmacokinetic curve (concentration ratio [CR]) were determined. CR-values of 0.9 and 2, based on data from the literature, were used as target concentrations.5
The primary end points of the study were treatment discontinuation and virologic response (HIV-1 RNA level less than 500 copies/mL), using an intention-to-treat noncompleter equals failure analysis. Differences between the TDM group and the control group were evaluated using the Pearson χ2 test for the nominal parameters and the Student t test for the continuous values. All statistical tests were performed with the Statistical Product and Service Solutions (SPSS) for Windows, version 11.0.1 (SPSS, Chicago, IL).
Forty-five treatment-naive patients starting a nevirapine-containing regimen were included in the study (24 in the TDM group and 21 in the control group). There were no significant differences at baseline between the groups (Table 1).
No significant differences were found in the exposure to nevirapine between the TDM and control group with regard to the mean nevirapine plasma concentration, the CR, or the number of calculated CRs outside the established limits (see Table 1). The variance of the nevirapine concentration was smaller in the TDM group than in the control group (SD = 1.37 mg/L vs. 1.81 mg/L; P = 0.02, F test), however.
After 24 months of follow-up, 21% of the patients in the TDM group versus 19% of the patients in the control group (P = 1.0) discontinued their nevirapine-containing regimen. The median time to discontinuation was 9.4 months (range: 3.3-20.1 months) in the TDM group versus 19.3 months (range: 11.2-21.5 months) in the control group (P = 0.142, Mann-Whitney U test).
No significant differences in treatment success could be observed between the 2 study groups after 6, 12, 18, or 24 months of follow-up (see Table 1).
In this study, routine TDM had no effect on the plasma concentrations of nevirapine, although the pharmacokinetic variability was significantly reduced. Apparently, reporting TDM results to physicians drew their attention and resulted in better patient care to achieve nevirapine target plasma levels. It did not, however, have an effect on the outcome of treatment in this treatment-naive HIV-infected patient group, which may be explained by several factors.
First, nevirapine is a highly effective drug6 and shows only moderate variability in plasma pharmacokinetics, especially in comparison to protease inhibitors.7 Furthermore, the association between nevirapine plasma concentrations and its main toxicities of rash and hepatotoxicity has not been established conclusively.8-11 Therefore, a much larger randomized trial would be needed to demonstrate any significant effect of TDM of nevirapine.
Burger et al2 showed a benefit of TDM for patients in the ATHENA study using the protease inhibitor indinavir or nelfinavir. Because the relations between plasma concentrations of these protease inhibitors and treatment efficacy and toxicity are more pronounced than for nevirapine, this benefit could be shown in a relatively small patient population.
In conclusion, pharmacokinetic variability was reduced, but no effect of routine TDM on treatment outcome was shown in this study. With this finding, we see no argument for routine TDM of nevirapine in treatment-naive patients, although in specific cases of, for example, suspected drug-drug interactions or noncompliance, TDM of nevirapine may still be valid.4
Kristel M. Crommentuyn, PhD*
Alwin D. Huitema*
Kees Brinkman
Marchina E. van der Ende
Frank de Wolf
Jos H. Beijnen*
*Department of Pharmacy and Pharmacology Slotervaart Hospital Amsterdam, The Netherlands Department of Internal Medicine Onze Lieve Vrouwe Gasthuis Amsterdam, The Netherlands Department of Internal Medicine Erasmus University Medical Centre Rotterdam, The Netherlands HIV Monitoring Foundation Amsterdam, The Netherlands Department of Infectious Disease Epidemiology Imperial College London, United Kingdom Faculty of Pharmaceutical Sciences Department of Biomedical Analysis Division of Drug Toxicology Utrecht University Utrecht, The Netherlands
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