Efavirenz Concentrations and Probability of HIV Replication in Children

Homkham, Nontiya; Cressey, Tim R.; Bouazza, Naïm; Chanta, Chulapong; Aurpibul, Linda; Narkbunnam, Thition; Krikajornkitti, Sawitree; Kamonpakorn, Nareerat; Lallemant, Marc; Ingsrisawang, Lily; Salvadori, Nicolas; Tréluyer, Jean Marc; Urien, Saı̈k; Jourdain, Gonzague

doi:10.1097/inf.0000000000000854

Cited by 7 publications

(13 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A Thai study of 188 school-age children following FDA-approved weight band dosing correlated EFV concentrations and probability of HIV replication and reported that odds of viral load >400 copies/ml increased by 2.1 (odds ratio: 2.1, 95% CI: 1.4–3.0; p=0.03) for each 0.5 mg/L decrease in EFV C24. [15] Similarly, Ren et. al.…”

Section: Discussionmentioning

confidence: 97%

CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3–36 months with HIV infection

Bolton‐Moore

Capparelli

Samson

et al. 2017

Aids

View full text Add to dashboard Cite

Objectives To determine safety, efficacy and genotypic-specific dose requirements of EFV in children aged 3 – < 36 months of age with HIV infection with or without TB co-infection. Design IMPAACT P1070 was a 24 week prospective cohort trial of EFV (as open capsules) plus two nucleoside reverse transcriptase inhibitors in children with HIV infection 3–<36 months without tuberculosis (Cohort 1). Methods CYP2B6 G516T genotype was determined and intensive PK’s were performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35–180 mcg*hr/mL. PK and CYP2B6 G516T genotype data were used to model EFV exposures based on FDA-approved doses. Results Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow up; 38 516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT versus 516GG/GT (median 490 vs 107 p =0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, PK modeling predicted that 83% of participants met the AUC target (31/38 516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce sub-therapeutic AUCs in almost one third of participants with 516GG/GT and excessive AUCs in >50% with 516TT genotypes. Conclusion CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to out-perform other dosing approaches.

show abstract

Section: Discussionmentioning

confidence: 97%

CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3–36 months with HIV infection

Bolton‐Moore

Capparelli

Samson

et al. 2017

Aids

View full text Add to dashboard Cite

show abstract

“…Efavirenz plasma concentration data were predicted using a previously published population pharmacokinetic (PK) model generated from the same study population . Efavirenz plasma concentrations were described using a 1‐compartment model with delayed absorption via 2 transit compartments.…”

Section: Methodsmentioning

confidence: 99%

“…C av = dose/(dosing interval × CL i ), where CL i is the individual efavirenz clearance (L/h). The individual efavirenz clearances were estimated using our previously published population PK model described above …”

Section: Methodsmentioning

confidence: 99%

“…Efavirenz plasma concentration data were predicted using a previously published population pharmacokinetic (PK) model generated from the same study population. 15 Efavirenz plasma concentrations were described using a 1-compartment model with delayed absorption via 2 transit compartments. Also, a mixture model was used for efavirenz clearance (CL/F), that is, children were separated into 2 groups as either "fast" (95% of children) or "slow" metabolizers.…”

Section: Population Pharmacokinetic-pharmacodynamic Analysismentioning

confidence: 99%

“…The individual efavirenz clearances were estimated using our previously published population PK model described above. 15 Total cholesterol concentrations over time were estimated using the following equation similarly to Friedewald et al 14 : total cholesterol = a × HDL + b × LDL + c × triglycerides, where a, b, and c are the parameter coefficients for HDL, LDL, and triglycerides, respectively, and these parameters were estimated.…”

Section: Population Pharmacokinetic-pharmacodynamic Analysismentioning

confidence: 99%

See 2 more Smart Citations

A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz‐Based Regimens

Homkham

Cressey

Ingsrisawang

et al. 2016

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

Efavirenz use is associated with changes in cholesterol concentrations, but it is unclear whether this effect is related to drug concentrations. Using efavirenz and cholesterol plasma concentrations measured in 87 antiretroviral-naive children in Thailand, we assessed indirect response models to describe the evolution of high- and low-density lipoprotein (HDL, LDL) cholesterol concentrations in relation to efavirenz plasma concentrations over time where efavirenz was assumed to either stimulate cholesterol production or inhibit its elimination. Simulations of cholesterol evolution for children with different average efavirenz concentrations (Cav ) according to their assumed status of "fast" or "slow" metabolizers of efavirenz were performed. At treatment initiation, children's median (interquartile range, IQR) age was 8 years (5 to 10), body mass index z-score 0.01 (-1.05 to 1.44), HDL 31 mg/dL (24 to 44), and LDL 83 mg/dL (69 to 100). Median (IQR) efavirenz Cav was 1.7 mg/L (1.3 to 2.1) during the period of observation. The best model describing the evolution of HDL and LDL cholesterol concentrations over time assumed that efavirenz inhibited their elimination. HDL concentrations increase over 5 years, whereas LDL concentrations increased only during the first 4 months and then returned to baseline levels afterward. Simulations predicted that, after 3 years, HDL would increase to 63 mg/dL in "fast" metabolizers and 97 mg/dL in "slow" metabolizers of efavirenz. The population pharmacokinetic-pharmacodynamic (PK-PD) model shows that favorable HDL cholesterol changes can be expected in children with current efavirenz dosing guidelines over 5 years of treatment.

show abstract

Evaluation of the estimation and classification performance of NONMEM when applying mixture model for drug clearance

Hui

Lam

2021

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

Maximum likelihood estimation of parameters involving mixture model is known to have significant and specific patterns of errors. Population pharmacokinetic (PopPK) modeling using NONMEM is no exception. A few relevant studies on estimation and classification performance were done, but a comprehensive study was not yet available. The current study aims to evaluate performance and likelihood ratio test (LRT)-based true covariate detection rate when fitting a bimodal mixture of drug clearance (CL) in NONMEM. A large number of PopPK datasets with various settings were simulated and then estimated. The estimates were compared to the simulated values and summarized. The separation between the CL distributions of the two subpopulations is systematically overestimated. The major factor associated with the performance is the change in the minimum objective function value after removing the mixture component (dOFV). Other significant factors include estimated disparity index (DI), estimated mixing proportion, and number of subjects in the dataset. Small dOFV and large estimated DI are associated with the worst performance. Omitting a true mixture resulted in reduced true covariate detection rates. It is recommended that on top of routinely generated standard errors and model diagnostics, dOFV, and other factors when necessary, should be taken into account for the evaluation of performance when fitting mixture model using NONMEM. In addition, when fitting mixture model for CL is intended, the mixture component should be introduced prior to LRTbased covariate model development for CL. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Estimation of a bimodal drug clearance (CL) distribution with mixture model in NONMEM using likelihood maximization algorithms is subject to biases related to the disparity.

show abstract

Efavirenz Concentrations and Probability of HIV Replication in Children

Cited by 7 publications

References 7 publications

CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3–36 months with HIV infection

CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3–36 months with HIV infection

A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz‐Based Regimens

Evaluation of the estimation and classification performance of NONMEM when applying mixture model for drug clearance

Contact Info

Product

Resources

About