Benefit of therapeutic drug monitoring of protease inhibitors in HIV-infected patients depends on PI used in HAART regimen--ANRS 111 trial.
ABSTRACT As a result of high inter-patient variability, and efficacy-concentration and toxicity-concentration relationships, optimization of HIV-protease inhibitor (PI) doses based on plasma concentrations could be beneficial. During a 48-week open prospective non-randomized interventional study of 115 protease inhibitor-naïve patients initiating an indinavir/ritonavir- or lopinavir/ritonavir-, or nelfinavir-containing therapy, protease inhibitor dose was modified when plasma trough concentrations (C(trough)) at weeks 2, 8, 16 and 24 were outside predefined optimal concentration ranges. Failure of the strategy was defined as the proportions of patients with HIV-RNA above 200 copies/mL from weeks 24 to 48 and/or experiencing grades 2, 3 or 4 PI-related adverse events during the study; proportion of patients with last C(trough) measurement outside the concentration range was determined at each visit. Virological failure and/or occurrence of adverse event were observed in 37/94 assessable patients (39%; 95% CI: 29.4-50.0). In the on-treatment analysis, failure of the strategy was noted in 16% of indinavir/r- or lopinavir/r-treated patients (8/51; 95% CI: 7.0-28.6; virological failure: 2; adverse event: 6) but in 44% of nelfinavir-treated patients (11/25; 95% CI: 24.4-65.1; virological failure: 10; adverse event: 1); C(trough) concentrations outside the range were less frequent at the last measurement than at W2 (41% vs. 66%; P < 0.05), with proportions of 35% for indinavir/r- or lopinavir/r-treated patients, but 57% for nelfinavir-treated patients. The proposed strategy of therapeutic drug monitoring may be beneficial to indinavir/r- and lopinavir/r-treated patients, but failed to move concentrations into the predefined range and to produce the expected virological success for nelfinavir-treated patients.
- Thérapie 40(2):111-8. · 0.37 Impact Factor
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ABSTRACT: We evaluated the feasibility and effectiveness of therapeutic drug monitoring (TDM) and adherence support (collectively, AT) vs standard of care (SOC) in patients receiving HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) within a nurse-led clinic. Primary end points were failure to achieve viral load of <50 copies/mL at 24 weeks, viral rebound, or development of treatment limiting toxicity. One hundred twenty-two patients (AT 63 and SOC 59) were followed-up every 12 weeks, for a median of 72 weeks. No difference was observed between arms in risk of reaching a study end point or between groups of patients with abnormal vs "therapeutic" drug concentrations. Interindividual variabilities (coefficient of variation) were the following: efavirenz, 77.5%; nevirapine, 74.5%; lopinavir, 73.4%; nelfinavir, 83.7%; indinavir, 80.8%; saquinavir, 112.4%. Intraindividual variabilities (median coefficient of variation) were the following: NNRTIs, approximately 25%; PIs, 48.4%. Despite persistently abnormal results in 26 of patients in the AT arm (38%), dosage adjustment was only undertaken in 9 patients (35%).A significant proportion of patients had drug concentrations outside the therapeutic range. The Pharmacologic Optimization of PIs and NNRTIs (POPIN) study confirms that TDM trials are complex to interpret and statistically underpowered, with effectiveness better assessed through the clinical utility of a TDM result, whether normal or abnormal. Although TDM of PIs and NNRTIs may be useful in selected patients, routine and unselected use is not supported by current evidence.JAIDS Journal of Acquired Immune Deficiency Syndromes 05/2006; 41(4):461-7. · 4.65 Impact Factor
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ABSTRACT: The protease inhibitor ritonavir is increasingly administered at subtherapeutic doses in highly active antiretroviral treatment, to utilize its potential for drug interactions and to enhance the plasma concentrations of other concomitantly prescribed protease inhibitors. The addition of low doses of ritonavir to nelfinavir was investigated to describe the extent of pharmacokinetic interaction. In this randomized, open-label, one-sequence crossover study, nelfinavir 1250 mg twice a day was dosed for 17 days, followed by 14 days of nelfinavir 1250 mg twice a day plus low doses of ritonavir of either 100 mg or 200 mg orally. Twenty-four healthy volunteers were evaluated for pharmacokinetics of nelfinavir, its metabolite M8, and ritonavir. Plasma concentrations were measured up to 12 hours after morning and evening dosing, respectively, on days 14 and 31. Ritonavir increased the area under the plasma concentration-time curve (AUC) of nelfinavir by 20% (P =.024) and 39% (P =.001) after morning and evening administration, respectively. The AUC of nelfinavir metabolite M8 was increased by 74% and 86% after morning and evening dosing (P <.001 for both). During ritonavir combination therapy a clear although minor drug effect on nelfinavir pharmacokinetics was demonstrated but no dose effect was shown.Clinical Pharmacology & Therapeutics 08/2002; 72(2):123-32. · 6.85 Impact Factor