Tags

Type your tag names separated by a space and hit enter

Pharmacokinetics and pharmacodynamics of intensive anti-tuberculosis treatment of tuberculous meningitis.

Abstract

The most effective anti-tuberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomised controlled trial comparing standard treatment with a regimen intensified by rifampin 15mg/kg and levofloxacin for the first 60 days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic/pharmacodynamic study in 237 trial participants to define exposure-response relationships that might explain the trial results and improve future therapy. Rifampin 15mg/kg increased plasma and CSF exposures compared to 10mg/kg: day 14 plasma AUC0-24 increased from 48.2h∙mg/L (range 18.2-93.8) to 82.5h∙mg/L (range 8.7-161.0) and CSF AUC0-24 from 3.5h∙mg/L (range 1.2-9.6) to 6.0h∙mg/L (range 0.7-15.1). However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death and linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.

Authors+Show Affiliations

Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. The WorldWide Antimalarial Resistance Network, Oxford, United Kingdom. Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, Vietnam.Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, Vietnam.Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, Vietnam.Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, Vietnam. Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, Vietnam.Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. The WorldWide Antimalarial Resistance Network, Oxford, United Kingdom. Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31956998

Citation

Ding, Junjie, et al. "Pharmacokinetics and Pharmacodynamics of Intensive Anti-tuberculosis Treatment of Tuberculous Meningitis." Clinical Pharmacology and Therapeutics, 2020.
Ding J, Thuong NTT, Van Toi P, et al. Pharmacokinetics and pharmacodynamics of intensive anti-tuberculosis treatment of tuberculous meningitis. Clin Pharmacol Ther. 2020.
Ding, J., Thuong, N. T. T., Van Toi, P., Heemskerk, D., Pouplin, T., Chau, T. T. H., ... Tarning, J. (2020). Pharmacokinetics and pharmacodynamics of intensive anti-tuberculosis treatment of tuberculous meningitis. Clinical Pharmacology and Therapeutics, doi:10.1002/cpt.1783.
Ding J, et al. Pharmacokinetics and Pharmacodynamics of Intensive Anti-tuberculosis Treatment of Tuberculous Meningitis. Clin Pharmacol Ther. 2020 Jan 19; PubMed PMID: 31956998.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics and pharmacodynamics of intensive anti-tuberculosis treatment of tuberculous meningitis. AU - Ding,Junjie, AU - Thuong,Nguyen Thuy Thuong, AU - Van Toi,Pham, AU - Heemskerk,Dorothee, AU - Pouplin,Thomas, AU - Chau,Tran Thi Hong, AU - Mai,Nguyen Thi Hoang, AU - Phu,Nguyen Hoan, AU - Loc,Phan Phu, AU - Chau,Nguyen Van Vinh, AU - Thwaites,Guy, AU - Tarning,Joel, Y1 - 2020/01/19/ PY - 2020/1/21/entrez JF - Clinical pharmacology and therapeutics JO - Clin. Pharmacol. Ther. N2 - The most effective anti-tuberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomised controlled trial comparing standard treatment with a regimen intensified by rifampin 15mg/kg and levofloxacin for the first 60 days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic/pharmacodynamic study in 237 trial participants to define exposure-response relationships that might explain the trial results and improve future therapy. Rifampin 15mg/kg increased plasma and CSF exposures compared to 10mg/kg: day 14 plasma AUC0-24 increased from 48.2h∙mg/L (range 18.2-93.8) to 82.5h∙mg/L (range 8.7-161.0) and CSF AUC0-24 from 3.5h∙mg/L (range 1.2-9.6) to 6.0h∙mg/L (range 0.7-15.1). However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death and linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers. SN - 1532-6535 UR - https://www.unboundmedicine.com/medline/citation/31956998/Pharmacokinetics_and_pharmacodynamics_of_intensive_anti-tuberculosis_treatment_of_tuberculous_meningitis L2 - https://doi.org/10.1002/cpt.1783 DB - PRIME DP - Unbound Medicine ER -