Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients

Marzolini, Catia; Telenti, Amalio; Décosterd, Laurent A.; Greub, Gilbert; Biollaz, J.; Buclin, Thierry

doi:10.1097/00002030-200101050-00011

Cited by 757 publications

(498 citation statements)

References 8 publications

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“…Due to impracticalities in obtaining brain tissue from patients, some groups have used concentrations in cerebrospinal fluid (CSF) as a surrogate for brain concentrations. The majority of pharmacokinetic (PK) studies have focused on describing efavirenz plasma concentrations and elucidating genetic factors that contribute to the variability in efavirenz PK or genetic associations to predict patients at risk of developing CNS toxicity (1,7,8). However, a few small studies investigated efavirenz PK in both plasma and CSF.…”

mentioning

confidence: 99%

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

Curley

Rajoli

Moss

et al. 2017

Antimicrob Agents Chemother

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Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to suppress viral replication, but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate the efavirenz distribution in the cerebrospinal fluid (CSF) and the brain by using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. The efavirenz CNS distribution was calculated using a permeability-limited model on a virtual cohort of 100 patients receiving efavirenz (600 mg once daily). Simulation data were then compared with human data from the literature and with rodent data. Wistar rats were administered efavirenz (10 mg kg of body weight Ϫ1 ) once daily over 5 weeks. Plasma and brain tissue were collected for analysis via liquid chromatography-tandem mass spectrometry (LC-MS/ MS). The median maximum concentrations of drug (C max ) were predicted to be 3,184 ng ml Ϫ1 (interquartile range [IQR], 2,219 to 4,851 ng ml Ϫ1 ), 49.9 ng ml Ϫ1 (IQR, 36.6 to 69.7 ng ml Ϫ1 ), and 50,343 ng ml Ϫ1 (IQR, 38,351 to 65,799 ng ml Ϫ1 ) in plasma, CSF, and brain tissue, respectively, giving a tissue-to-plasma ratio of 15.8. Following 5 weeks of oral dosing of efavirenz (10 mg kg Ϫ1 ), the median plasma and brain tissue concentrations in rats were 69.7 ng ml Ϫ1 (IQR, 44.9 to 130.6 ng ml Ϫ1 ) and 702.9 ng ml Ϫ1 (IQR, 475.5 to 1,018.0 ng ml Ϫ1 ), respectively, and the median tissue-to-plasma ratio was 9.5 (IQR, 7.0 to 10.9). Although it is useful, measurement of CSF concentrations may give an underestimation of the penetration of antiretrovirals into the brain. The limitations associated with obtaining tissue biopsy specimens and paired plasma and CSF samples from patients make PBPK modeling an attractive tool for probing drug distribution.

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confidence: 99%

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

Curley

Rajoli

Moss

et al. 2017

Antimicrob Agents Chemother

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“…[12] Many studies have looked at the effect of the EFV drug level on the frequency of side-effects. Marzolini et al [10] reported a 24% increase in CNS side-effects if the plasma level was >4 000 ng/mL. However, other researchers have found no correlation between adverse effects and plasma concentrations.…”

Section: Discussionmentioning

confidence: 96%

“…[7] CNS symptoms are the most frequently reported side-effects in HIVpositive patients on EFV, and include dizziness, headache, confusion, stupor, impaired concentration, agitation, amnesia, depersonalisation, hallucinations, insomnia and strange dreams. [6,[8][9][10][11][12][13][14] The frequency of CNS side-effects is estimated to be 20 -40%. [10] The majority of patients who develop CNS and psychiatric adverse effects do so in the first 6 weeks of treatment, [11] with most symptoms resolving by 6 -10 weeks after treatment initiation.…”

Section: Discussionmentioning

confidence: 99%

“…[6,[8][9][10][11][12][13][14] The frequency of CNS side-effects is estimated to be 20 -40%. [10] The majority of patients who develop CNS and psychiatric adverse effects do so in the first 6 weeks of treatment, [11] with most symptoms resolving by 6 -10 weeks after treatment initiation. [6] One article documented neurocerebellar side-effects -self-reported dizziness, ataxia, insomnia, bad dreams and hallucinations, without objective assessment of ataxia -in patients using EFV, occurring most frequently in the first month after initiating EFV and declining with time.…”

Section: Discussionmentioning

confidence: 99%

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Efavirenz as a cause of ataxia in children

2015

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“…Marzolini and co-workers proposed a 1000-4000 g/L plasma range at mid-dosing interval as a suitable target for EFV drug levels [2]. When EFV levels reach toxic levels (>4000 g/L) a higher incidence of side-effects occurs such as insomnia, dizziness, abnormal dreams and loss of concentration [2,3], while subtherapeutic levels (<1000 g/L) can lead to treatment failure due to viral resistance [4,5].…”

Section: Introductionmentioning

confidence: 99%

Determination of salivary efavirenz by liquid chromatography coupled with tandem mass spectrometry

Theron

Cromarty

Rheeders

et al. 2010

Journal of Chromatography B

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a b s t r a c tA novel and robust screening method for the determination of the non-nucleoside reverse transcriptase inhibitor, efavirenz (EFV), in human saliva has been developed and validated based on high performance liquid chromatography tandem mass spectrometry (LC-MS/MS). Sample preparation of the saliva involved solid-phase extraction (SPE) on C18 cartridges. The analytes were separated by high performance liquid chromatography (Phenomenex Kinetex C18, 150 mm × 3 mm internal diameter, 2.6 m particle size) and detected with tandem mass spectrometry in electrospray positive ionization mode with multiple reaction monitoring. Gradient elution with increasing methanol (MeOH) concentration was used to elute the analytes, at a flow-rate of 0.4 mL/min. The total run time was 8.4 min and the retention times for the internal standard (reserpine) was 5.4 min and for EFV was 6.5 min. The calibration curves showed linearity (r 2 , 0.989-0.992) over the concentration range of 3.125-100 g/L. Mean intra-and inter-assay relative standard deviation, accuracy, mean extraction recovery, limit of detection (LOD) and limit of quantification (LOQ) were 0.46-9.43%, 80-120%, 60% (±7.95), 1.84 and 6.11 g/L respectively. The working range was defined as 6.25-100 g/L. This novel LC-MS/MS assay is suitable for reliable detection of low EFV concentrations in saliva and can be used as a screening tool for monitoring EFV compliance.

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Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients

Abstract: Treatment failure and CNS side-effects are associated with low and high efavirenz plasma levels, respectively. The important inter-individual variability in efavirenz levels strongly argues for dose adjustment on the basis of therapeutic drug monitoring to optimize treatment.

Cited by 757 publications

References 8 publications

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

Efavirenz as a cause of ataxia in children

Determination of salivary efavirenz by liquid chromatography coupled with tandem mass spectrometry

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