Evaluation of the Adequacy of the 2010 Revised World Health Organization Recommended Dosages of the First-line Antituberculosis Drugs for Children

Yang, Hongmei; Enimil, Anthony; Gillani, Fizza S.; Antwi, Sampson; Dompreh, Albert; Ortsin, Antoinette; Awhireng, Eugene Adu; Owusu, Maxwell; Wiesner, Lubbe; Peloquin, Charles A.; Kwara, Awewura

doi:10.1097/inf.0000000000001687

Cited by 15 publications

(13 citation statements)

References 38 publications

(46 reference statements)

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“…In contrast, one study among children aged Յ10 years treated according to the WHO 2010 revised dosages reported low 2-hour-postdose concentrations (C-2 h) of RIF, EMB, and PZA in 94%, 85%, and 45% of the children, respectively (13), while another among infants who were treated according to the WHO 2010 guidelines reported low RIF C max in all the participants and low EMB C max in 94% of participants (12). In the largest study published to date, we found that a majority of Ghanaian children treated according to the 2014 WHO recommendations achieved C max of INH and PZA on the revised dosages, but 60% of the participants had low RIF or EMB C max (16). In this study, we used the data from our previously published studies (16,17) to develop a model for the population pharmacokinetics of the 4 drugs in children, as well as simulations to predict dosage ranges for each weight band that could achieve desired plasma concentration targets in children.…”

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confidence: 63%

“…In the largest study published to date, we found that a majority of Ghanaian children treated according to the 2014 WHO recommendations achieved C max of INH and PZA on the revised dosages, but 60% of the participants had low RIF or EMB C max (16). In this study, we used the data from our previously published studies (16,17) to develop a model for the population pharmacokinetics of the 4 drugs in children, as well as simulations to predict dosage ranges for each weight band that could achieve desired plasma concentration targets in children.…”

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confidence: 82%

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Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations

Horita

Alsultan

Kwara

et al. 2018

Antimicrob Agents Chemother

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Optimal doses for antituberculosis (anti-TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosage ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods. Nonlinear mixed-effects models were applied to describe the population PK of those drugs using MonolixSuite2016R1 (Lixoft, France). Bayesian estimation was performed, the correlation coefficient, bias, and precision between the observed and predicted areas under the concentration-time curve (AUCs) were calculated, and Bland-Altman plots were analyzed. The population PK of RIF and PZA was described by a one-compartment model and that for INH and EMB by a two-compartment model. Plasma maximum concentration () and AUC targets were based on published results for children from India. The lowest target values for pediatric TB patients were attainable at the WHO-recommended dosage schedule for RIF and INH, except for -acetyltransferase 2 non-slow acetylators (rapid and intermediate acetylators) in the lower-weight bands. However, higher published adult targets were not attainable for RIF and INH. The targets were not achieved for PZA and EMB. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.).

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confidence: 63%

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confidence: 82%

Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations

Horita

Alsultan

Kwara

et al. 2018

Antimicrob Agents Chemother

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“…Almost all studies investigating ethambutol PK reported lower ethambutol AUC (range: −40% to −60%) and lower ethambutol C max (range: −40% to −70%) in children that were HIV infected compared with uninfected children. 144–146 , 148 , 149 One small study ( n = 18) found low ethambutol C max values regardless of HIV status. 151 Nevertheless, ethambutol exposures generally are substantially lower in HIV-infected children compared with uninfected children.…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetics of antiretroviral and tuberculosis drugs in children with HIV/TB co-infection: a systematic review

Jacobs

Svensson

Musiime

et al. 2020

Journal of Antimicrobial Chemotherapy

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Introduction Management of concomitant use of ART and TB drugs is difficult because of the many drug–drug interactions (DDIs) between the medications. This systematic review provides an overview of the current state of knowledge about the pharmacokinetics (PK) of ART and TB treatment in children with HIV/TB co-infection, and identifies knowledge gaps. Methods We searched Embase and PubMed, and systematically searched abstract books of relevant conferences, following PRISMA guidelines. Studies not reporting PK parameters, investigating medicines that are not available any longer or not including children with HIV/TB co-infection were excluded. All studies were assessed for quality. Results In total, 47 studies met the inclusion criteria. No dose adjustments are necessary for efavirenz during concomitant first-line TB treatment use, but intersubject PK variability was high, especially in children <3 years of age. Super-boosted lopinavir/ritonavir (ratio 1:1) resulted in adequate lopinavir trough concentrations during rifampicin co-administration. Double-dosed raltegravir can be given with rifampicin in children >4 weeks old as well as twice-daily dolutegravir (instead of once daily) in children older than 6 years. Exposure to some TB drugs (ethambutol and rifampicin) was reduced in the setting of HIV infection, regardless of ART use. Only limited PK data of second-line TB drugs with ART in children who are HIV infected have been published. Conclusions Whereas integrase inhibitors seem favourable in older children, there are limited options for ART in young children (<3 years) receiving rifampicin-based TB therapy. The PK of TB drugs in HIV-infected children warrants further research.

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“…Precision dosing algorithms, which account for additional patient and/or disease factors that impact exposure (e.g., HIV infection, SLCO1B1 genotype, and NAT2 acetylator status), will likely be needed to achieve WHO targets with current therapeutics. 20,22,[25][26][27] Optimized FDC formulations were explored based on the individualized doses, but drug doses and dose ratios varied by pharmacokinetic model and isoniazid metabolizing capacity. Our work along with others 16,28 suggests that higher anti-tuberculosis doses and new FDC formulations are needed to ensure optimal outcomes.…”

Section: Discussionmentioning

confidence: 99%

Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study

Radtke

Dooley

Dodd

et al. 2019

The Lancet Child & Adolescent Health

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Evaluation of the Adequacy of the 2010 Revised World Health Organization Recommended Dosages of the First-line Antituberculosis Drugs for Children

Abstract: The high frequency of low rifampin and ethambutol Cmax in our study is consistent with emerging pharmacokinetic data in children treated according to the new WHO recommendations. Higher dosages than currently recommended especially for rifampin may be necessary in children.

Cited by 15 publications

References 38 publications

Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations

Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations

Pharmacokinetics of antiretroviral and tuberculosis drugs in children with HIV/TB co-infection: a systematic review

Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study

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