Therapeutic Drug Monitoring of Indinavir in HIV-Infected Patients Undergoing HAART

Langmann, Peter; Zilly, Michael; Weißbrich, Benedikt; Desch, Steffen; Väth, T; Klinker, Hartwig

doi:10.1007/s15010-001-1111-0

Cited by 24 publications

(16 citation statements)

References 12 publications

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“…However, the chemical properties of UC781 are similar to those of EFV and NVP, all of which have similar hydrophobicity indices (logP), ionization, etc. While EFV has pronounced serum protein binding (2,34,37,52), which could impact microbicidal activity, NVP and UC781 do not (14,46). Furthermore, NVP has no microbicidal activity, whereas both EFV and UC781 do.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1

Hossain

Parniak

2006

J Virol

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The nonnucleoside reverse transcriptase inhibitor (NNRTI) UC781 is under development as a microbicide to prevent sexual transmission of the human immunodeficiency virus type 1 (HIV-1). However, NNRTIresistant HIV-1 is increasingly prevalent in the infected population, and one of the concerns for NNRTI-based microbicides is that they will be ineffective against drug-resistant virus and may in fact selectively transmit NNRTI-resistant virus. We evaluated the microbicidal activity of UC781 against UC781-resistant (UCR), efavirenz-resistant (EFVR), and nevirapine-resistant (NVPR) strains in a variety of microbicide-relevant tests, including inactivation of cell-free virus, inhibition of cell-to-cell HIV-1 transmission, and the ability of UC781 pretreatment to protect cells from subsequent infection in the absence of exogenous drug. UC781 was 10-to 100-fold less effective against NNRTI-resistant HIV-1 compared to wild-type (wt) virus in each of these tests, with UC781 microbicidal activity against the various virus strains being wt > NVPR > UCR > EFVR. Breakthrough experiments using UC781-pretreated cells and mixtures of wt and NNRTI-resistant HIV-1 showed that UC781-pretreatment selected for NNRTI-resistant HIV-1. However, the efficacy of UC781 was dose dependent, and 25 M UC781 provided essentially equivalent microbicidal activity against NNRTI-resistant and wt virus. The amount of UC781 in topical microbicide formulations under current development is approximately 100-fold greater than this concentration, so transmission of NNRTI-resistant virus may not be an issue at these microbicide formulation levels of UC781. Nonetheless, the reduced microbicidal activity of UC781 against NNRTI-resistant HIV-1 suggests that additional antiviral agents should be included in NNRTIbased microbicide formulations.

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Section: Discussionmentioning

confidence: 99%

In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1

Hossain

Parniak

2006

J Virol

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“…The concentrations of efavirenz required to elicit its effects on lipogenesis are within the range of those observed in plasma from patients receiving therapeutic doses of this antiretroviral agent (63,64). Thus, it is possible that the effects of efavirenz on the 3T3-F442A and 3T3-L1 cell lines and on human preadipocytes observed in vitro may also occur in vivo.…”

Section: Effects Of Efavirenz On Preadipocytes and Adipocytesmentioning

confidence: 97%

“…during Adipocyte Differentiation-To evaluate the effects of efavirenz on preadipocyte differentiation, 3T3-F442A were grown until confluence and then cultured for various periods of time in the absence or in the presence of the drug, with a concentration range that is comparable with that observed in the plasma of treated patients (63,64).…”

Section: Efavirenz Preferentially Inhibits Triglyceride Accumulationmentioning

confidence: 99%

In Vitro Suppression of the Lipogenic Pathway by the Nonnucleoside Reverse Transcriptase Inhibitor Efavirenz in 3T3 and Human Preadipocytes or Adipocytes

Hadri

Glorian

Monsempes

et al. 2004

Journal of Biological Chemistry

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A serious metabolic syndrome combining insulin-resistance, dyslipidemia, central adiposity, and peripheral lipoatrophy has arisen in HIV-infected patients receiving highly active antiretroviral therapy. The aim of this work was to examine the effects of the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz on adipocyte differentiation and metabolism. When induced to differentiate in the presence of efavirenz (5-50 M), 3T3-F442A preadipocytes failed to accumulate cytoplasmic triacylglycerol droplets. This phenomenon was rapidly reversible and was also readily detectable in the 3T3-L1 preadipose cell line and in primary cultures of human preadipocytes. When applied to mature 3T3-

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“…Twenty-four patients were antiretroviral naive (24.7%). A total of 1145 plasma concentrations were available during the defined study period, yielding a median of 11 plasma concentrations per patient (IQR, [8][9][10][11][12][13][14]. Nevirapine and efavirenz were used by 84 and 6 patients, respectively.…”

Section: Patients and Plasma Concentrationsmentioning

confidence: 99%

“…Variations in plasma concentrations could, therefore, have far-reaching clinical consequences. For several PIs and NNRTIs, minimal plasma concentrations have been estimated that should be targeted to maintain adequate viral suppression (2)(3)(4)(7)(8)(9)(10)(11)(12). Therefore, patients not reaching and maintaining these target trough plasma concentrations risk suboptimal treatment and the development of drug-resistant HIV strains.…”

mentioning

confidence: 99%

Subtherapeutic Antiretroviral Plasma Concentrations in Routine Clinical Outpatient HIV Care

Maat¹,

Huitema²,

Mulder³

et al. 2003

Therapeutic Drug Monitoring

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Summary:The objective of this study was to evaluate plasma concentrations of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) within several dosing schemes in a cohort of HIV-infected patients in routine clinical practice and to find possible explanations for subtherapeutic plasma concentrations. Patients were included if a PI or NNRTI was part of their antiretroviral regimen, at least one plasma concentration was obtained, and a complete medication overview from community pharmacy records was available. The study period was from January 1998 to September 2001. Each plasma concentration was related to median plasma concentrations of a pharmacokinetic reference curve, yielding a concentration ratio (CR). A cutoff CR was defined for each antiretroviral drug per specific regimen, discriminating between Նtherapeutic and subtherapeutic concentrations. For the patients with subtherapeutic concentrations, it was sorted out whether drug interactions, adverse events and self-reported symptoms, or nonadherence could be the cause of the lower than expected plasma concentration. Ninety-seven HIV-infected patients fulfilled the criteria. During the defined period, 1145 plasma concentrations were available (median, 11; interquartile range, 8-14). Three hundred fourteen (27.4%) plasma concentrations were classified subtherapeutic. Drug interactions (2; 0.6%), adverse events and self-reported symptoms (67; 21.3%), and nonadherence (14; 4.5%) could only partly explain the subtherapeutic drug levels. Consequently, a large number of the subtherapeutic plasma concentrations (73.6%) remained inexplicable. A high number of subtherapeutic plasma concentrations were observed. No clear causes were found; thus, corrective measures will be difficult to employ. Therefore, therapeutic drug monitoring (TDM) must maintain its crucial place in routine clinical care to be able to identify patients who need extra attention so that therapeutic plasma concentrations are achieved.

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Therapeutic Drug Monitoring of Indinavir in HIV-Infected Patients Undergoing HAART

Cited by 24 publications

References 12 publications

In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1

In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1

In Vitro Suppression of the Lipogenic Pathway by the Nonnucleoside Reverse Transcriptase Inhibitor Efavirenz in 3T3 and Human Preadipocytes or Adipocytes

Subtherapeutic Antiretroviral Plasma Concentrations in Routine Clinical Outpatient HIV Care

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