Pharmacokinetics of First-Line Antituberculosis Drugs Using WHO Revised Dosage in Children With Tuberculosis With and Without HIV Coinfection

Kwara, Awewura; Enimil, Anthony; Gillani, Fizza S.; Yang, Hongmei; Sarfo, Anima; Dompreh, Albert; Ortsin, Antoinette; Osei-Tutu, Lawrence; Owusu, Sandra Kwarteng; Wiesner, Lubbe; Norman, Jennifer; Kurpewski, Jaclynn; Peloquin, Charles A.; Ansong, Daniel; Antwi, Sampson

doi:10.1093/jpids/piv035

Cited by 36 publications

(35 citation statements)

References 24 publications

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“…Pharmacokinetic (PK) sampling was performed at or after 4 weeks of anti-TB treatment as previously described (36). At the time of sampling, none of the HIV-coinfected patients were on antiretroviral therapy.…”

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection

Antwi

Yang

Enimil

et al. 2017

Antimicrob Agents Chemother

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Although human immunodeficiency virus (HIV) coinfection is the most important risk factor for a poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide, and ethambutol 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 and pharmacokinetic parameters calculated using noncompartmental analysis. The area under the concentration-time curve from 0 to 8 h (AUC 0 -8 ), maximum concentration (C max ), and apparent oral clearance divided by bioavailability (CL/F) for each drug were compared between children with and without HIV coinfection. Of 113 participants, 59 (52.2%) had HIV coinfection. The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age Z scores (P Ͻ 0.05). Rifampin, pyrazinamide, and ethambutol median body weight-normalized CL/F values were significantly higher, whereas the plasma AUC 0 -8 values were lower, in the coinfected children than in those with TB alone. In the multivariate analysis, drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC 0 -8 for rifampin, pyrazinamide, and ethambutol. Isoniazid pharmacokinetics were not different by HIV coinfection status. HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children. Whether TB/HIV-coinfected children need higher dosages of rifampin, pyrazinamide, and ethambutol requires further investigation. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.)

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Section: Methodsmentioning

confidence: 99%

“…Drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods as we previously described (36). The observed C max and time to C max (T max ) were determined by inspection of the serum concentration-time graphs for each drug.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection

Antwi

Yang

Enimil

et al. 2017

Antimicrob Agents Chemother

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“…Drug concentrations were determined at the pharmacology laboratory at the University of Cape Town using validated liquid chromatography-mass spectrometry methods. The methods were validated over the concentration ranges of 0.0977 to 26.0 g/ml for isoniazid, 0.117 to 30.0 g/ml for rifampin, 0.200 to 80.0 g/ml for pyrazinamide, and 0.0844 to 5.46 g/ml for ethambutol (20). All samples that were below the level of quantification (BLQ) were set to half of the lower limit of quantification (LLOQ).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines

Bekker

Schaaf

Draper

et al. 2016

Antimicrob Agents Chemother

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cThere are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (C max ) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 g/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 g/ ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC 0 -8 ) were 12.1, 24.7, 239.4, and 5.1 g · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed in C max (geometric mean ratio

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“…TB remains a major cause of childhood mortality in areas where TB is endemic [78,79]. Treatment of childhood TB is particularly challenging because dosing recommendations have been largely derived from schedules employed for adults with a relative lack of supportive data on pharmacokinetics (PK), efficacy, and safety of the anti-TB agents in pediatric patients [80,81].…”

Section: Pediatric Patientsmentioning

confidence: 99%

“…Previously, recommended dosages for the first-line anti-TB drugs in children, expressed in milligram per kilogram body weight, were the same as for adults. However, several studies reported lowplasma concentrations of the first-line anti-TB drugs due to underdosing in children [79]. Consequently, in 2010, WHO recommended increased pediatric dosages for isoniazid (7-15 mg/kg), rifampicin (10-20 mg/kg), pyrazinamide (30-40 mg/kg), and ethambutol (15-25 mg/kg), which are higher than the adult recommended dosages (4-6, 8-12, 20-30, and 15-20 mg/kg, respectively) [2].…”

Section: Pediatric Patientsmentioning

confidence: 99%

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring

Verbeeck

Günther²,

Kibuule

et al. 2016

Eur J Clin Pharmacol

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Pharmacokinetics of First-Line Antituberculosis Drugs Using WHO Revised Dosage in Children With Tuberculosis With and Without HIV Coinfection

Abstract: The revised dosages appeared to be adequate for isoniazid and pyrazinamide, but not for rifampin or ethambutol in this population. Higher dosages of rifampin and ethambutol than currently recommended may be required in most children.

Cited by 36 publications

References 24 publications

Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection

Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection

Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring

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