SETTING: The currently recommended dosages of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol in children are extrapolated from adult pharmacokinetic studies, and have not been adequately evaluated in children. OBJECTIVE: To describe the pharmacokinetics of RMP, INH and PZA given thrice weekly in children with tuberculosis (TB), and to relate pharmacokinetics to treatment outcomes. METHODS: Eighty-four human immunodeficiency virus negative children with TB aged 1-12 years in Chennai and Madurai, India, were recruited. Phenotypic INH acetylator status was determined. Nutritional status was assessed using Z scores. During the intensive phase of anti-tuberculosis treatment, a complete pharmacokinetic study was performed after directly observed administration of drugs. At 2 and 6 months, drug levels were measured 2 h post-dose. Drug concentrations were measured using high performance liquid chromatography and pharmacokinetic variables were calculated. Multivariable regression analysis was performed to explore factors impacting drug levels and treatment outcomes. RESULTS AND CONCLUSIONS: Children aged <3 years had significantly lower RMP, INH and PZA concentrations than older children, and 90% of all children had sub-therapeutic RMP Cmax (<8 μg/ml). Age, nutritional status and INH acetylator status influenced drug levels. Peak RMP and INH concentrations were important determinants of treatment outcome. Recommendations for anti-tuberculosis treatment in children should take these factors into consideration.
SETTING: The currently recommended dosages of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol in children are extrapolated from adult pharmacokinetic studies, and have not been adequately evaluated in children. OBJECTIVE: To describe the pharmacokinetics of RMP, INH and PZA given thrice weekly in children with tuberculosis (TB), and to relate pharmacokinetics to treatment outcomes. METHODS: Eighty-four human immunodeficiency virus negative children with TB aged 1-12 years in Chennai and Madurai, India, were recruited. Phenotypic INH acetylator status was determined. Nutritional status was assessed using Z scores. During the intensive phase of anti-tuberculosis treatment, a complete pharmacokinetic study was performed after directly observed administration of drugs. At 2 and 6 months, drug levels were measured 2 h post-dose. Drug concentrations were measured using high performance liquid chromatography and pharmacokinetic variables were calculated. Multivariable regression analysis was performed to explore factors impacting drug levels and treatment outcomes. RESULTS AND CONCLUSIONS:Children aged <3 years had significantly lower RMP, INH and PZA concentrations than older children, and 90% of all children had sub-therapeutic RMP Cmax (<8 μg/ml). Age, nutritional status and INH acetylator status influenced drug levels. Peak RMP and INH concentrations were important determinants of treatment outcome. Recommendations for anti-tuberculosis treatment in children should take these factors into consideration.
Authors: Elizabeth W Tucker; Beatriz Guglieri-Lopez; Alvaro A Ordonez; Brittaney Ritchie; Mariah H Klunk; Richa Sharma; Yong S Chang; Julian Sanchez-Bautista; Sarah Frey; Martin A Lodge; Steven P Rowe; Daniel P Holt; Jogarao V S Gobburu; Charles A Peloquin; William B Mathews; Robert F Dannals; Carlos A Pardo; Sujatha Kannan; Vijay D Ivaturi; Sanjay K Jain Journal: Sci Transl Med Date: 2018-12-05 Impact factor: 17.956
Authors: Museveni Justine; Anita Yeconia; Ingi Nicodemu; Domitila Augustino; Jean Gratz; Estomih Mduma; Scott K Heysell; Sokoine Kivuyo; Sayoki Mfinanga; Charles A Peloquin; Theodore Zagurski; Gibson S Kibiki; Blandina Mmbaga; Eric R Houpt; Tania A Thomas Journal: J Pediatric Infect Dis Soc Date: 2020-02-28 Impact factor: 3.164
Authors: Kendra K Radtke; Kelly E Dooley; Peter J Dodd; Anthony J Garcia-Prats; Lindsay McKenna; Anneke C Hesseling; Radojka M Savic Journal: Lancet Child Adolesc Health Date: 2019-07-16
Authors: Geetha Ramachandran; A K Hemanth Kumar; P K Bhavani; T Kannan; S Ramesh Kumar; N Poorana Gangadevi; V V Banurekha; L Sekar; N Ravichandran; G Mathevan; G N Sanjeeva; Rajeshwar Dayal; Soumya Swaminathan Journal: Antimicrob Agents Chemother Date: 2014-12-08 Impact factor: 5.191