The Development of an Age-Appropriate Fixed Dose Combination for Tuberculosis Using Physiologically-Based Pharmacokinetic Modeling (PBBM) and Risk Assessment
<b>Background/Objectives:</b> The combination of isoniazid (INH) and rifampicin (RIF) is indicated for the treatment maintenance phase of tuberculosis (TB) in adults and children. In Brazil, there is no current reference listed drug for this indication in children. Farmanguinhos has unde...
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| author | Xavier J. H. Pepin Juliana Johansson Soares Medeiros Livia Deris Prado Sandra Suarez Sharp |
| author_facet | Xavier J. H. Pepin Juliana Johansson Soares Medeiros Livia Deris Prado Sandra Suarez Sharp |
| author_sort | Xavier J. H. Pepin |
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| description | <b>Background/Objectives:</b> The combination of isoniazid (INH) and rifampicin (RIF) is indicated for the treatment maintenance phase of tuberculosis (TB) in adults and children. In Brazil, there is no current reference listed drug for this indication in children. Farmanguinhos has undertaken the development of an age-appropriate dispersible tablet to be taken with water for all age groups from birth to adolescence. The primary objective of this work was to develop and validate a physiologically-based biopharmaceutics model (PBBM) in GastroPlus<sup>TM</sup>, to link the product’s in vitro performance to the observed pharmacokinetic (PK) data in adults and children. <b>Methods</b>: The PBBM was developed based on measured or predicted physico-chemical and biopharmaceutical properties of INH and RIF. The metabolic clearance was specified mechanistically in the gut and liver for both parent drugs and acetyl-isoniazid. The model incorporated formulation related measurements such as dosage form disintegration and dissolution as inputs and was validated using extensive literature as well as in house clinical data. <b>Results</b>: The model was used to predict the exposure in children across the targeted dosing regimen for each age group using the new age-appropriate formulation. Probabilistic models of efficacy and safety versus exposure, combined with real world data on children, were utilized to assess drug efficacy and safety in the target populations. <b>Conclusions</b>: The model predictions (systemic exposure) along with clinical data from the literature linking systemic exposure to clinical outcomes confirmed that the proposed dispersible pediatric tablet and dosing regimen are anticipated to be as safe and as effective as adult formulations at similar doses. |
| format | Article |
| id | doaj-art-6d5b27a54bb84a61a2657e75c9748992 |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj-art-6d5b27a54bb84a61a2657e75c97489922024-12-27T14:46:36ZengMDPI AGPharmaceutics1999-49232024-12-011612158710.3390/pharmaceutics16121587The Development of an Age-Appropriate Fixed Dose Combination for Tuberculosis Using Physiologically-Based Pharmacokinetic Modeling (PBBM) and Risk AssessmentXavier J. H. Pepin0Juliana Johansson Soares Medeiros1Livia Deris Prado2Sandra Suarez Sharp3Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA 93534-7059, USATechnological Development Coordination, Instituto de Tecnologia em Fármacos (Farmanguinhos)/Fiocruz, Av. Cmte. Guaranys, 447-Jacarepaguá, Rio de Janeiro 22775-903, BrazilTechnological Development Coordination, Instituto de Tecnologia em Fármacos (Farmanguinhos)/Fiocruz, Av. Cmte. Guaranys, 447-Jacarepaguá, Rio de Janeiro 22775-903, BrazilSimulations Plus, Inc., 42505 10th Street West, Lancaster, CA 93534-7059, USA<b>Background/Objectives:</b> The combination of isoniazid (INH) and rifampicin (RIF) is indicated for the treatment maintenance phase of tuberculosis (TB) in adults and children. In Brazil, there is no current reference listed drug for this indication in children. Farmanguinhos has undertaken the development of an age-appropriate dispersible tablet to be taken with water for all age groups from birth to adolescence. The primary objective of this work was to develop and validate a physiologically-based biopharmaceutics model (PBBM) in GastroPlus<sup>TM</sup>, to link the product’s in vitro performance to the observed pharmacokinetic (PK) data in adults and children. <b>Methods</b>: The PBBM was developed based on measured or predicted physico-chemical and biopharmaceutical properties of INH and RIF. The metabolic clearance was specified mechanistically in the gut and liver for both parent drugs and acetyl-isoniazid. The model incorporated formulation related measurements such as dosage form disintegration and dissolution as inputs and was validated using extensive literature as well as in house clinical data. <b>Results</b>: The model was used to predict the exposure in children across the targeted dosing regimen for each age group using the new age-appropriate formulation. Probabilistic models of efficacy and safety versus exposure, combined with real world data on children, were utilized to assess drug efficacy and safety in the target populations. <b>Conclusions</b>: The model predictions (systemic exposure) along with clinical data from the literature linking systemic exposure to clinical outcomes confirmed that the proposed dispersible pediatric tablet and dosing regimen are anticipated to be as safe and as effective as adult formulations at similar doses.https://www.mdpi.com/1999-4923/16/12/1587tuberculosisformulationpediatricsPBBMsafetyefficacy |
| spellingShingle | Xavier J. H. Pepin Juliana Johansson Soares Medeiros Livia Deris Prado Sandra Suarez Sharp The Development of an Age-Appropriate Fixed Dose Combination for Tuberculosis Using Physiologically-Based Pharmacokinetic Modeling (PBBM) and Risk Assessment Pharmaceutics tuberculosis formulation pediatrics PBBM safety efficacy |
| title | The Development of an Age-Appropriate Fixed Dose Combination for Tuberculosis Using Physiologically-Based Pharmacokinetic Modeling (PBBM) and Risk Assessment |
| title_full | The Development of an Age-Appropriate Fixed Dose Combination for Tuberculosis Using Physiologically-Based Pharmacokinetic Modeling (PBBM) and Risk Assessment |
| title_fullStr | The Development of an Age-Appropriate Fixed Dose Combination for Tuberculosis Using Physiologically-Based Pharmacokinetic Modeling (PBBM) and Risk Assessment |
| title_full_unstemmed | The Development of an Age-Appropriate Fixed Dose Combination for Tuberculosis Using Physiologically-Based Pharmacokinetic Modeling (PBBM) and Risk Assessment |
| title_short | The Development of an Age-Appropriate Fixed Dose Combination for Tuberculosis Using Physiologically-Based Pharmacokinetic Modeling (PBBM) and Risk Assessment |
| title_sort | development of an age appropriate fixed dose combination for tuberculosis using physiologically based pharmacokinetic modeling pbbm and risk assessment |
| topic | tuberculosis formulation pediatrics PBBM safety efficacy |
| url | https://www.mdpi.com/1999-4923/16/12/1587 |
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