Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study

Durant, J.; Clevenbergh, Philippe; Garraffo, R.; Halfon, Philippe; Icard, S; Giudice, P. Del; Montagne, N; Schapiro, Jonathan; Dellamonica, P.

doi:10.1097/00002030-200007070-00005

Cited by 210 publications

(131 citation statements)

References 15 publications

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“…4 Because body composition and metabolic pathways are rapidly evolving during the transition from infancy through puberty, learning the disposition of NFV in pediatric patients across different age groups and developmental stages is necessary to produce optimal dosing guidelines, limit toxicity, and enhance the sustainability of an effective NFV-containing antiretroviral regimen. In addition, suboptimal dosing may facilitate the selection of mutations associated with drug resistance to a specific agent 10 and cross-resistance with other therapies in a treatment group. 11 Complicated antiviral regimens, large pill burdens, and frequent dosing may cause adherence to diminish over time.…”

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confidence: 99%

Nelfinavir Pharmacokinetics in Stable Human Immunodeficiency Virus-Positive Children: Pediatric AIDS Clinical Trials Group Protocol 377

et al. 2003

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ABSTRACT. Objective. Pharmacokinetic data obtained from children who have human immunodeficiency virus (HIV) infection are essential for the safe and effective use of antiretroviral agents in pediatric populations. The objective of this study was to assess the impact of body weight on the pharmacokinetic disposition of nelfinavir (NFV) in the absence and presence of nevirapine (NVP) and compare the pharmacokinetic profiles of twice-daily (BID) and three-times-daily (TID) NFV regimens.Methods. This was an intensive pharmacokinetic substudy nested in a phase II, multicenter, randomized, open-label trial. Forty-five HIV-infected children receiving NFV 30 mg/kg TID and 6 HIV-infected children receiving NFV 55 mg/kg BID were enrolled in this study and assigned to 1 of 4 stavudine-containing regimens, 3 containing NFV and 2 containing NVP. Area under the plasma concentration-time curves from 0 to 8 hours (AUC 0 -8 hours ) and from 0 to 12 hours (AUC 0 -12 hours ) for the TID and BID regimens, respectively, were determined. For comparative purposes, the AUC 0 -24 hours was also calculated for each regimen.Results. NFV exposure in the absence of NVP was decreased in children who were <25 kg compared with those who were >25 kg (a 2.6-fold difference in median AUC 0 -8 hours ). NFV pharmacokinetics in the presence of NVP did not differ between the <25 kg and >25 kg groups. The AUC 0 -24 hours for children who were <30 kg and on NFV BID was comparable to the AUC 0 -24 hours for children who were >25 kg and on NFV TID but was 2.7-fold greater than AUC 0 -24 hours for children who were <25 kg and on NFV TID.Conclusions. NFV in the absence of NVP resulted in less than half the drug exposure in children who were <25 kg compared with children who were >25 kg. NFV dosed at 55 mg/kg BID in children who are <30 kg provides comparable exposure to that measured in children who are >25 kg and receiving NFV 30 mg/kg TID. Pediatrics 2003;112:e220 -e227. URL: http://www. pediatrics.org/cgi/content/full/112/3/e220; pharmacokinetics, nelfinavir, children, HIV, protease inhibitor, nevirapine.

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confidence: 99%

Nelfinavir Pharmacokinetics in Stable Human Immunodeficiency Virus-Positive Children: Pediatric AIDS Clinical Trials Group Protocol 377

et al. 2003

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“…the clearance (CL) and the volume of distribution (V), according to the population analysis were respectively for CL : 32.1 L/h (standard error (SE): 5.7%) and 34% (SE: 52.4%); for V: 58.5 L (SE: 13.5%) and 227% (SE: 31%). 8 Nine of the 12 patients with nephrolithiasis were fully adherent (data missing for the 3 others) as compared to 214 of 270 patients without nephrolithiasis. In the univariate analysis, only estimated C res , C max , AUC and CR as well as plasma HIV RNA and age remained associated with a higher rate of nephrolithiasis, according to the best cut-off when categorised (Table II).…”

Section: Resultsmentioning

confidence: 99%

“…Many studies in HIV-infected patients have previously focused on a relationship between concentration and effect, in terms of virological response (8)(9)(10)(11), whereas toxicity was a secondary outcome. When adverse events have become a major problem in treated HIV-infected patients, data found in the literature show insufficient evidence to recommend a general therapeutic range, probably because only few databases have both appropriate pharmacokinetics and toxicity data available, like in the ANRS CO8 APROCO-COPILOTE cohort.…”

Section: Introductionmentioning

confidence: 99%

Indinavir Trough Concentration as a Determinant of Early Nephrolithiasis in HIV-1-Infected Adults

Collin

Chêne²,

Retout³

et al. 2007

Therapeutic Drug Monitoring

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Indinavir plasma levels are associated with antiretroviral efficacy however few data is available regarding toxicity. We assessed the relationship between indinavir pharmacokinetic (PK) characteristics and severe nephrolithiasis as well as other severe or serious adverse reactions (SAR). Patients included in the ANRS CO8 APROCO-COPILOTE cohort and receiving indinavir 800 mg thrice daily as first line protease inhibitor, were eligible for this study. To be included in the analysis, their plasma sample at month 1 (M1) had to be available (n=282) to estimate, using population PK modelling, indinavir PK characteristics, i.e. maximum (C max ) and trough plasma (C res ) concentrations, area under the curve (AUC) and observed/predicted concentrations ratio (CR). A Cox model was used to estimate the independent effect of C max , C res , AUC and CR on the hazard of severe nephrolithiasis and SAR. At M1, median C max was 6 205 ng/mL, C res : 631 ng/mL, AUC: 24 242 ng.h/mL and CR: 0.6. After a median follow-up of 12 months, 11% of patients (30/282) had experienced at least one SAR among which 12 were nephrolithiasis.In the multivariate analyses, early high indinavir C res (i.e. ≥ 1000 ng/mL at M1) was associated with a higher rate of severe nephrolithiasis (HR=6.7; 95% confidence interval=1.8-25.2; p<0.01) and was also associated with a higher rate of all SAR but only when nephrolithiasis were included among those cases. Prospective and early indinavir C res determination should be recommended in the patient's care management and dosage adjustments.

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“…C trough s of PIs have been associated with virologic suppression in several clinical studies (1,5,6,9,15), as have AUCs in other studies (1,14). Enhancement of indinavir C trough s by the addition of ritonavir to the antiretroviral drug regimen could theoretically enhance virologic suppression.…”

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confidence: 97%

“…Suboptimal drug exposure in patients receiving combination antiretroviral therapy has been increasingly recognized as an important contributor to virologic failure, particularly with drugs in the protease inhibitor (PI) class (1,2,5,6,15,19). Subinhibitory concentrations of drugs may be a consequence of poor adherence to the drug regimen, but they may also occur due to the wide variabilities in metabolism and the levels in plasma seen with many of the PIs.…”

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confidence: 99%

Virtual Inhibitory Quotient Predicts Response to Ritonavir Boosting of Indinavir-Based Therapy in Human Immunodeficiency Virus-Infected Patients With Ongoing Viremia

&NA;

2002

Infectious Diseases in Clinical Practice

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Depending on the degree of underlying resistance present, optimization of the pharmacokinetics of protease inhibitors may result in improved virologic suppression. Thirty-seven human immunodeficiency virus (HIV)-infected subjects who had chronic detectable viremia and who were receiving 800 mg of indinavir three times a day (TID) were switched to 400 mg of indinavir BID with 400 mg of ritonavir two times a day (BID) for 48 weeks. Full pharmacokinetic evaluations were obtained for 12 subjects before the switch and 3 weeks after the switch. Combination therapy increased the indinavir predose concentrations in plasma by 6.47-fold, increased the minimum concentration in serum by 3.41-fold, and reduced the maximum concentration in serum by 57% without significantly changing the area under the plasma concentration-time curve at 24 h. At week 3, 58% (21 of 36) of the subjects for whom postbaseline measurements were available achieved a viral load in plasma of <50 copies/ml or a reduction from the baseline load of >0.5 log 10 copies/ml. Of these subjects, 82% (14 of 17) whose viruses had three or fewer protease inhibitor mutations and 88% (14 of 16) whose viruses had an indinavir virtual phenotypic susceptibility test of more than sixfold less than that for the baseline isolate were considered virologic responders. The indinavir virtual inhibitory quotient, which is a function of baseline indinavir phenotypic resistance (estimated by virtual phenotype) and the indinavir predose concentration in plasma achieved with indinavir-ritonavir combination therapy, was the best predictor of a viral load reduction. Sixteen subjects discontinued the study by week 48 due to adverse events, predominantly related to hyperlipidemia. Pharmacokinetic intensification of indinavir-based therapy with ritonavir reduced the viral loads in subjects but added toxicity. The virtual inhibitory quotient, which incorporates both baseline viral resistance and the level of drug exposure in plasma, was superior to either baseline resistance or drug exposure alone in predicting the virologic response.

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Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study

Cited by 210 publications

References 15 publications

Nelfinavir Pharmacokinetics in Stable Human Immunodeficiency Virus-Positive Children: Pediatric AIDS Clinical Trials Group Protocol 377

Nelfinavir Pharmacokinetics in Stable Human Immunodeficiency Virus-Positive Children: Pediatric AIDS Clinical Trials Group Protocol 377

Indinavir Trough Concentration as a Determinant of Early Nephrolithiasis in HIV-1-Infected Adults

Virtual Inhibitory Quotient Predicts Response to Ritonavir Boosting of Indinavir-Based Therapy in Human Immunodeficiency Virus-Infected Patients With Ongoing Viremia

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