Lisa C Martial1, Jordy Kerkhoff2, Nilza Martinez3, Mabel Rodríguez3, Rosarito Coronel3, Gladys Molinas3, Myriam Roman4, Roscio Gomez4, Sarita Aguirre5, Erwin Jongedijk6, Justine Huisman6, Daan J Touw6, Domingo Pérez3, Gilberto Chaparro3, Felipe Gonzalez3, Rob E Aarnoutse1, Jan-Willem Alffenaar6, Cecile Magis-Escurra7. 1. Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Pharmacy, Nijmegen, The Netherlands. 2. Radboud University Medical Center-Dekkerswald, Department of Pulmonary Diseases, Groesbeek, The Netherlands. 3. Instituto Nacional de Enfermedades Respiratorias y del Ambiente, Asunción, Paraguay. 4. Instituto Nacional de Enfermedades Respiratorias y del Ambiente, Asunción, Paraguay; Programa Nacional de Lucha contra la Tuberculosis, Asunción, Paraguay. 5. Programa Nacional de Lucha contra la Tuberculosis, Asunción, Paraguay. 6. University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands. 7. Radboud University Medical Center-Dekkerswald, Department of Pulmonary Diseases, Groesbeek, The Netherlands. Electronic address: Cecile.magis-escurra@RadboudUMC.nl.
Abstract
BACKGROUND: Dried blood spot (DBS) sampling for pharmacokinetic (PK) studies and therapeutic drug monitoring have unique advantages over venous sampling. This study aimed to evaluate a DBS method for first-line anti-tuberculosis drugs in children, and DBS sampling to assess PK parameters. METHODS: Paraguayan children were treated according to the revised paediatric dosing scheme of the World Health Organization. A PK curve was performed both with DBS sampling and conventional venous sampling for rifampicin, pyrazinamide and ethambutol. Passing-Bablok regression, Bland-Altman plots and predictive performance evaluation were used to assess agreement between DBS and plasma concentrations. The percentages of patients attaining population PK values for Cmax and AUC0-24h were calculated. RESULTS: After use of a conversion factor, Passing-Bablok regression showed no significant proportional or systematic bias between DBS and plasma concentrations. Bland-Altman plots showed that 95% of the ratios of the DBS predicted:observed plasma concentrations lay between 0.6 and 1.4 for rifampicin, 0.5 and 1.6 for pyrazinamide and -0.4 and 2.8 for ethambutol. DBS measurements showed acceptable predictive performance for rifampicin and pyrazinamide, but not for ethambutol. Assessment of Cmax target attainment was 62.5% for isoniazid, 25% for rifampicin, 100% for pyrazinamide and 75% for ethambutol. CONCLUSION: For rifampicin and pyrazinamide, the DBS method was accurate in predicting plasma concentrations, and was used successfully for PK parameter assessment. However, predicting ethambutol plasma concentrations with DBS measurement was associated with too much imprecision. Despite higher dosing, only 25% of the population reached average target adult rifampicin exposures.
BACKGROUND: Dried blood spot (DBS) sampling for pharmacokinetic (PK) studies and therapeutic drug monitoring have unique advantages over venous sampling. This study aimed to evaluate a DBS method for first-line anti-tuberculosis drugs in children, and DBS sampling to assess PK parameters. METHODS: Paraguayan children were treated according to the revised paediatric dosing scheme of the World Health Organization. A PK curve was performed both with DBS sampling and conventional venous sampling for rifampicin, pyrazinamide and ethambutol. Passing-Bablok regression, Bland-Altman plots and predictive performance evaluation were used to assess agreement between DBS and plasma concentrations. The percentages of patients attaining population PK values for Cmax and AUC0-24h were calculated. RESULTS: After use of a conversion factor, Passing-Bablok regression showed no significant proportional or systematic bias between DBS and plasma concentrations. Bland-Altman plots showed that 95% of the ratios of the DBS predicted:observed plasma concentrations lay between 0.6 and 1.4 for rifampicin, 0.5 and 1.6 for pyrazinamide and -0.4 and 2.8 for ethambutol. DBS measurements showed acceptable predictive performance for rifampicin and pyrazinamide, but not for ethambutol. Assessment of Cmax target attainment was 62.5% for isoniazid, 25% for rifampicin, 100% for pyrazinamide and 75% for ethambutol. CONCLUSION: For rifampicin and pyrazinamide, the DBS method was accurate in predicting plasma concentrations, and was used successfully for PK parameter assessment. However, predicting ethambutol plasma concentrations with DBS measurement was associated with too much imprecision. Despite higher dosing, only 25% of the population reached average target adult rifampicin exposures.
Authors: Hannah Yejin Kim; Kenneth C Byashalira; Scott K Heysell; Anne-Grete Märtson; Stellah G Mpagama; Prakruti Rao; Marieke G G Sturkenboom; Jan-Willem C Alffenaar Journal: Ther Drug Monit Date: 2022-02-01 Impact factor: 3.118