Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations

L M Verhagen, D López, P W M Hermans, A Warris, R de Groot, J F García, J H de Waard, R E Aarnoutse

Research output: Contribution to journalArticle

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Abstract

OBJECTIVES: The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela.

METHODS: Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined.

RESULTS: 25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01).

CONCLUSION: We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.

Original languageEnglish
Pages (from-to)1449-1456
Number of pages8
JournalTropical Medicine and International Health
Volume17
Issue number12
Early online date24 Oct 2012
DOIs
Publication statusPublished - Dec 2012

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Tuberculosis
Pharmacokinetics
Isoniazid
Pyrazinamide
Pharmaceutical Preparations
Rifampin
Ethambutol
Venezuela
Body Weight
Malnutrition
Guidelines
Pediatrics
Phenotype

Keywords

  • Acetyltransferases
  • Adolescent
  • Age Factors
  • Antitubercular Agents
  • Area Under Curve
  • Biological Availability
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Ethambutol
  • Female
  • Humans
  • Infant
  • Isoniazid
  • Least-Squares Analysis
  • Male
  • Malnutrition
  • Polymorphism, Genetic
  • Practice Guidelines as Topic
  • Pyrazinamide
  • Rifampin
  • Tuberculosis
  • Venezuela
  • World Health Organization
  • Journal Article

Cite this

Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age : supportive evidence for the implementation of revised WHO dosing recommendations. / Verhagen, L M; López, D; Hermans, P W M; Warris, A; de Groot, R; García, J F; de Waard, J H; Aarnoutse, R E.

In: Tropical Medicine and International Health, Vol. 17, No. 12, 12.2012, p. 1449-1456.

Research output: Contribution to journalArticle

Verhagen, L M ; López, D ; Hermans, P W M ; Warris, A ; de Groot, R ; García, J F ; de Waard, J H ; Aarnoutse, R E. / Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age : supportive evidence for the implementation of revised WHO dosing recommendations. In: Tropical Medicine and International Health. 2012 ; Vol. 17, No. 12. pp. 1449-1456.
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AU - Hermans, P W M

AU - Warris, A

AU - de Groot, R

AU - García, J F

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N2 - OBJECTIVES: The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela.METHODS: Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined.RESULTS: 25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01).CONCLUSION: We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.

AB - OBJECTIVES: The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela.METHODS: Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined.RESULTS: 25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01).CONCLUSION: We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.

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KW - Child, Preschool

KW - Dose-Response Relationship, Drug

KW - Ethambutol

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KW - Infant

KW - Isoniazid

KW - Least-Squares Analysis

KW - Male

KW - Malnutrition

KW - Polymorphism, Genetic

KW - Practice Guidelines as Topic

KW - Pyrazinamide

KW - Rifampin

KW - Tuberculosis

KW - Venezuela

KW - World Health Organization

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