High Prevalence of Subtherapeutic Plasma Concentrations of Efavirenz in Children

Ren, Yuan; Nuttall, James; Egbers, Claire; Eley, Brian; Meyers, Tammy; Smith, Peter J.; Maartens, Gary; McIlleron, Helen

doi:10.1097/qai.0b013e31805c9d52

Cited by 62 publications

(60 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…(i) C min s, C max s, and AUCs were consistent with those of previous studies: 1.64 mg/liter, 3.71 mg/liter, and 65.2 mg/ liter ⅐ h, respectively, in our study compared to 1.18 to 1.45 mg/liter, 4.09 to 5.52 mg/liter, and 60 to 63.6 mg/liter ⅐ h in previous studies (7,16,19) (Table 3).…”

Section: Discussionsupporting

confidence: 81%

“…Theoretically, C min may be more important to provide continuous suppression of viral replication; thus, we considered C min the target pharmacokinetic parameter in our study. In all studies, a high percentage of children fell below the target concentrations (7,16,19,21). Similarly, with the recommended dose of EFV administered to 46 out of 48 children in the present study, 19% of children had C min s of Ͻ1 mg/liter.…”

Section: Discussionmentioning

confidence: 83%

See 1 more Smart Citation

Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

Hirt

Urien

Mathieu

et al. 2009

Antimicrob Agents Chemother

View full text Add to dashboard Cite

We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (C min and C max , respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The threshold C min (and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) had C min s below 1 mg/liter. A significantly higher percentage of children with C min s of >1.1 mg/liter or AUCs of >51 mg/liter ⅐ h than of children with lower values had viral load decreases greater than 2 log 10 copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with C min s between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.The combination of didanosine (ddI), lamivudine (3TC), and efavirenz (EFV) once daily has improved compliance for adults and shown good antiretroviral efficacy (12); moreover, the treatment could be better tolerated in the long term (5, 6, 13). For children, the efficacy and tolerance of this ddI-3TC-EFV combination have not been investigated. The aims of the BURKINAM (ANRS 12103) study, then, were to investigate the pharmacokinetics of EFV, ddI, and 3TC given once daily in children 30 months to 15 years old and to evaluate the efficacy and tolerance of this combination.EFV is metabolized exclusively via CYP2B6 (cytochrome P450 isoenzyme) in the liver (20). Several factors (covariates), such as age (9), duration of treatment (7), or ethnici...

show abstract

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 83%

Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

Hirt

Urien

Mathieu

et al. 2009

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Likewise, previous studies have estimated the relative bioavailability of the oral liquid formulations in children to be 0.47 and 0.62 (48,49). Such low bioavailability may explain the high incidence of subtherapeutic EFV concentrations among children (17)(18)(19) and suggests the need to use oral liquid formulations at doses that are 150% of the capsule doses.…”

Section: Discussionmentioning

confidence: 99%

“…Little information is available about the correlation between EFV PK parameters and pediatric population covariates and the influence of developmental changes that take place during infancy and childhood on CYP2B6 expression and EFV PK (16). Moreover, some clinical studies have reported a high prevalence of subtherapeutic EFV concentrations among children, suggesting a need to develop alternative dosing guidelines for this important population (17)(18)(19). The aims of the current study were to quantify the interindividual and intraindividual variability of EFV PK in HIV-1-infected children; to identify factors that describe this variability, including growth and maturation; and to develop a population pharmacokinetic model that incorporates these covariates in order to guide EFV dosing in children.…”

mentioning

confidence: 99%

Pharmacometric Characterization of Efavirenz Developmental Pharmacokinetics and Pharmacogenetics in HIV-Infected Children

Salem

Fletcher

Brundage

2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The aim of this analysis was to create a pharmacometric model of efavirenz developmental pharmacokinetics and pharmacogenetics in HIV-infected children. The data consisted of 3,172 plasma concentrations from 96 HIV-1-infected children who participated in the Pediatric AIDS Clinical Trials Group 382 (PACTG382) study. Analyses were performed using NONMEM, and the impacts of body weight, age, race, sex, formulation, liver function, and cytochrome P450 2B6 (CYP2B6)-G516T and multidrugresistance transporter gene (MDR1)-C3435T polymorphisms were assessed. A one-compartment model using weight-based allometry on oral clearance and apparent volume of distribution adequately described the data. A sigmoid maximum-effect (E max ) maturation model demonstrated an increase in oral clearance with age to reach 90% of its mature level by the age of 9 months. The liquid formulation bioavailability relative to the capsule was found to increase with age to reach 90% of its mature value by the age of 8 years. The CYP2B6-G516T polymorphism decreased oral clearance, while the MDR1-C3435T polymorphism demonstrated no effect. E favirenz (EFV) is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) that is indicated, in combination with other antiretroviral agents, for treatment of human immunodeficiency virus type 1 (HIV-1) infection (1). EFV is highly bound to plasma proteins, predominantly albumin (2). It is mainly metabolized by cytochrome P450 enzymes to hydroxylated derivatives that are subsequently glucuronidated and renally excreted (2).High interindividual variability (IIV) and intraindividual variability in EFV pharmacokinetics (PK) has been observed in both adults and children (3-5). This variability is of particular concern due to the narrow therapeutic index of EFV (6, 7). Studies have shown that elevated EFV concentrations are associated with an increased risk of central nervous system (CNS) toxicity (8) and elevated liver enzymes (9). In addition, differences in EFV concentrations were found between responders and nonresponders (4), and children with higher intraindividual PK variability, presumably arising from more variable medication-taking behavior, have been reported to have a higher likelihood of viral rebound and a shorter time to their first viral rebound (3).Sources of EFV PK variability have been extensively studied in adults (4,5,(10)(11)(12). Covariates found to account for this variability include the polymorphic nature of cytochrome P450 2B6 (CYP2B6) and other isoforms that are responsible for EFV metabolism (13, 14). In addition, some studies have shown EFV PK to vary across genders and ethnicities (10-12, 15). Little information is available about the correlation between EFV PK parameters and pediatric population covariates and the influence of developmental changes that take place during infancy and childhood on CYP2B6 expression and EFV PK (16). Moreover, some clinical studies have reported a high prevalence of subtherapeutic EFV concentrations among children, suggesting a need to develop altern...

show abstract

“…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]. It is thus important to ensure that EFV plasma levels are within the therapeutic window.…”

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

View full text Add to dashboard Cite

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.

show abstract

High Prevalence of Subtherapeutic Plasma Concentrations of Efavirenz in Children

Cited by 62 publications

References 12 publications

Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

Pharmacometric Characterization of Efavirenz Developmental Pharmacokinetics and Pharmacogenetics in HIV-Infected Children

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

Contact Info

Product

Resources

About