Higher Efavirenz Plasma Levels Correlate With Development of Insomnia

Núñez, Marina; Requena, Daniel González de; Gallego, L.; Jiménez-Nácher, Inmaculada; González-Lahoz, Juan; Soriano, Vincent

doi:10.1097/00126334-200112010-00015

Cited by 114 publications

(42 citation statements)

References 5 publications

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“…As surprising as that could be, patients in our study had in general very high plasma concentrations of EFV. Opposite to several authors who have found association between EFV plasma concentration and presence of neuropsychic AE [1,5,[25][26][27][28], we did not highlighted such an association in our study. This could be related to the transverse nature of our study involving under-notification.…”

Section: Plasma Concentrations and Adverse Effectscontrasting

confidence: 99%

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

Constant¹,

Mikal²,

Marcel³

et al. 2017

JPP

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Therapeutic plasma concentrations of EFV (efavirenz) are between 1,000 ng/mL and 4,000 ng/mL. Concentrations below 1000 ng/mL are associated with higher risk of treatment failure, and concentrations above 4,000 ng/mL are associated with toxicity. The aim of the study was to appreciate EFV plasmas concentrations profile and the association between plasma levels and various characteristics in Beninese patients treated by a 600 mg standard daily-dose. Blood samples were collected and EFV plasma levels were measured by liquid chromatography coupled with mass spectrometry detection in HIV-infected patients receiving EFV in combination with other antiretroviral drugs for at least 14 days. Adverse effects occurring during treatment were collected through a questionnaire. An over-exposure to EFV among Beninese HIV patients were observed, with 46.4% of patients presenting EFV concentration above 4,000 ng/mL, although adverse effects were tolerated indicating that antiretroviral treatment is safe. The measurement of plasma concentration at the steady-state could contribute to early detection of treatment failure and adapt treatment in subjects presenting serious adverse effects within context of therapeutic drug monitoring.

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Section: Plasma Concentrations and Adverse Effectscontrasting

confidence: 99%

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

Constant¹,

Mikal²,

Marcel³

et al. 2017

JPP

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“…To assess results of comparisons between regimens, we calculated the percentage of children with (i) EFV middose concentrations (C 12 h ) below 1 mg/liter and (ii) EFV middose concentrations above 4 mg/liter. These thresholds have been shown to be associated with EFV virological efficacy (7,8,11,20,29) or EFV toxicity (20,30) in HIV-infected adults. The individual pharmacokinetic parameters from all participants were used to simulate the 2016 FDA dosing guidelines without regard to CYP2B6 genotype and to simulate the protocol P1070 dose of EFV according to the CYP2B6 genotype (Table 1).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Efavirenz at a High Dose of 25 Milligrams per Kilogram per Day in Children 2 to 3 Years Old

Pressiat

Amorissani‐Folquet

Yonaba

et al. 2017

Antimicrob Agents Chemother

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The MONOD ANRS 12206 trial was designated to assess simplification of a successful lopinavir (LPV)-based antiretroviral treatment in HIV-infected children younger than 3 years of age using efavirenz (EFV; 25 mg/kg of body weight/day) to preserve the class of protease inhibitors for children in that age group. In this substudy, EFV concentrations were measured to check the consistency of an EFV dose of 25 mg/kg and to compare it with the 2016 FDA recommended dose. Fifty-two children underwent blood sampling for pharmacokinetic study at 6 months and 12 months after switching to EFV. We applied a Bayesian approach to derive EFV pharmacokinetic parameters using the nonlinear mixed-effect modeling (NONMEM) program. The proportion of midinterval concentrations 12 h after drug intake (C 12 h ) corresponding to the EFV therapeutic pharmacokinetic thresholds (1 to 4 mg/liter) was assessed according to different dose regimens (25 mg/kg in the MONOD study versus the 2016 FDA recommended dose). With both the 25 mg/kg/day dose and the 2016 FDA recommended EFV dose, simulations showed that the majority of C 12 h values were within the therapeutic range (62.6% versus 62.8%). However, there were more children underexposed with the 2016 FDA recommended dose (11.6% versus 1.2%). Conversely, there were more concentrations above the threshold of toxicity with the 25 mg/kg dose (36.2% versus 25.6%), with C 12 h values of up to 15 mg/liter. Only 1 of 52 children was switched back to LPV because of persistent sleeping disorders, but his C 12 h value was within therapeutic ranges. A high EFV dose of 25 mg/kg per day in children under 3 years old achieved satisfactory therapeutic effective levels. However, the 2016 FDA recommended EFV dose appeared to provide more acceptable safe therapeutic profiles. (This study has been registered at ClinicalTrials.gov under identifier NCT01127204.)

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“…Although its safety profile is considered satisfactory, central nervous system (CNS) side effects are commonly reported.The CNS side effects range from headaches and dizziness to insomnia, hallucinations, acute mania and psychosis [2]. The exact mechanism responsible for CNS toxicity associated with efavirenz remains unknown [2,3], but high plasma concentrations have been reported to be a predictor of early neuropsychological disturbances in patients initiating an efavirenz containing antiretroviral regimen [2,[4][5][6]. Significant interindividual variability in efavirenz plasma concentrations in adults and children has been observed [2,3,7,8].…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic markers of CYP2B6 associated with efavirenz plasma concentrations in HIV‐1 infected Thai adults

Sukasem

Cressey

Prapaithong

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Interindividual variability in efavirenz plasma concentrations is associated with CYP2B6 genetic polymorphisms.• Twenty‐nine different alleles of the CYP2B6 gene are listed. CYP2B6*6, *9, *16, *26, *27 and *28 carriers are reported to be associated with slower efavirenz oral clearance.• The allelic variant 516G>T is associated with diminished activity of CYP2B6 and high efavirenz plasma concentrations are associated with an increase risk of neuropsychological toxicity.WHAT THIS STUDY ADDS• This study identified three SNPs in the CYP2B6 gene which could potentially act as additional independent predictors of efavirenz plasma concentrations beyond that provided by the CYP2B6 c.516G>T polymorphism.• The GAC‐CYP2B6 haplotype (G516T/A785G/C21563T) is associated with higher plasma efavirenz concentrations in HIV‐infected Thai adults.• The CYP2B6 g.18492 T>C polymorphism was significantly associated with lower efavirenz concentrations than those with the homozygous wild‐type.AimsTo investigate the frequency of CYP2B6 polymorphisms and the influence of haplotype structure on plasma efavirenz concentrations in Thai adults with HIV‐1 infection.MethodsGenotyping of nine single nucleotide polymorphisms (SNPs, c.64C>T, c.499C>G, c.516G>T, c.785A>G, c.1375A>G, c.1459C>T, g.3003T>C, g.18492C>T and g.21563C>T) of CYP2B6 were performed using real‐time PCR‐based allelic discrimination on blood samples from 52 HIV‐infected adults who had received an efavirenz‐based regimen. Plasma efavirenz concentrations were measured by high performance liquid chromatography.ResultsThe minor allele frequencies for c.64C>T, c.516G>T, c.785A>G, g.3003C>T, g.18492T>C and g.21563C>T were 0.087, 0.365, 0.413, 0.308 and 0.356, respectively. However, no variant alleles were identified for three SNPs (c.499 C>G, c.1375 A>G and c.1459 C>T). Efavirenz plasma concentrations were significantly associated with c.516G>T (P= 0.0095), c.785A>G (P= 0.0017), g.21563C>T (P= 0.0036) and g.18492C>T (P= 0.0011). The composite CYP2B6 of three SNPs (c.516G ≥ T, c.785A ≥ G and g.21563C ≥ T) genotypes were significantly associated with higher efavirenz concentrations.ConclusionsOur data indicate that the GAC‐CYP2B6 haplotype is associated with higher plasma efavirenz concentrations in HIV‐infected Thai adults.

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Higher Efavirenz Plasma Levels Correlate With Development of Insomnia

Cited by 114 publications

References 5 publications

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

Pharmacokinetics of Efavirenz at a High Dose of 25 Milligrams per Kilogram per Day in Children 2 to 3 Years Old

Pharmacogenetic markers of CYP2B6 associated with efavirenz plasma concentrations in HIV‐1 infected Thai adults

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