Longitudinal PKPD biomarkers correlate with treatment outcome in drug sensitive pulmonary tuberculosis; a population pharmacokinetic-pharmacodynamic analysis

Frank Kloprogge; Henry C. Mwandumba; Mercy Kamdolozi; Gertrude Banda; Doris Shani; Elizabeth L. Corbett; Nadia Kontogianni; Steve Ward; Saye H. Khoo; Geraint R. Davies; Derek James Sloan

doi:10.1093/ofid/ofaa218

Longitudinal PKPD biomarkers correlate with treatment outcome in drug sensitive pulmonary tuberculosis; a population pharmacokinetic-pharmacodynamic analysis

Frank Kloprogge, Henry C. Mwandumba, Mercy Kamdolozi, Gertrude Banda, Doris Shani, Elizabeth L. Corbett, Nadia Kontogianni, Steve Ward, Saye H. Khoo, Geraint R. Davies, Derek James Sloan

Research output: Contribution to journal › Article › peer-review

Abstract

Background. This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions.

Methods. Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing.

Results. Higher isoniazid exposure correlated with increased bacillary killing in sputum (P < .01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC)_0-24 (P < .01). Serial sputum colony counting negativity at month 2 (P < .05), isoniazid C_MAX (P < .05), isoniazid C_MAX/minimum inhibitory concentration ([MIC] P < .01), and isoniazid AUC_0-24/MIC (P < .01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (P < .05) and earlier progression to biphasic bacillary decline (P < .01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (P < .05).

Conclusions. Patterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as C_MAX/MIC and AUC_0-24/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings.

Original language	English
Article number	ofaa218
Number of pages	11
Journal	Open Forum Infectious Diseases
Volume	7
Issue number	7
Early online date	6 Jun 2020
DOIs	https://doi.org/10.1093/ofid/ofaa218
Publication status	Published - Jul 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Outcome
Pharmacokinetics
Pharmacodynamics
Standard treatment
Tuberculosis

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10.1093/ofid/ofaa218Licence: CC BY

Kloprogge-2020-Longitudinal-PKPD-biomarkers-OFID-ofaa218-CC
Copyright © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.DOI: 10.1093/ofid/ofaa218
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Kloprogge, F., Mwandumba, H. C., Kamdolozi, M., Banda, G., Shani, D., Corbett, E. L., Kontogianni, N., Ward, S., Khoo, S. H., Davies, G. R., & Sloan, D. J. (2020). Longitudinal PKPD biomarkers correlate with treatment outcome in drug sensitive pulmonary tuberculosis; a population pharmacokinetic-pharmacodynamic analysis. Open Forum Infectious Diseases, 7(7), Article ofaa218. https://doi.org/10.1093/ofid/ofaa218

@article{128b962a7c3a47159b3c6b542badc76e,

title = "Longitudinal PKPD biomarkers correlate with treatment outcome in drug sensitive pulmonary tuberculosis; a population pharmacokinetic-pharmacodynamic analysis",

abstract = "Background. This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions. Methods. Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing. Results. Higher isoniazid exposure correlated with increased bacillary killing in sputum (P < .01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC)0-24 (P < .01). Serial sputum colony counting negativity at month 2 (P < .05), isoniazid CMAX (P < .05), isoniazid CMAX/minimum inhibitory concentration ([MIC] P < .01), and isoniazid AUC0-24/MIC (P < .01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (P < .05) and earlier progression to biphasic bacillary decline (P < .01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (P < .05). Conclusions. Patterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as CMAX/MIC and AUC0-24/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings.",

keywords = "Outcome, Pharmacokinetics, Pharmacodynamics, Standard treatment, Tuberculosis",

author = "Frank Kloprogge and Mwandumba, \{Henry C.\} and Mercy Kamdolozi and Gertrude Banda and Doris Shani and Corbett, \{Elizabeth L.\} and Nadia Kontogianni and Steve Ward and Khoo, \{Saye H.\} and Davies, \{Geraint R.\} and Sloan, \{Derek James\}",

note = "Funding: Wellcome Trust Clinical PhD Fellowship awarded to D.S. (086757/Z/08/A). Funding for the minimum inhibitory concentration assays was provided by a grant from the British Society for Antimicrobial Chemotherapy (GA2015\_036P). F.K. has conducted the research as part of his Medical Research Council fellowship (MR/P014534/1).",

year = "2020",

month = jul,

doi = "10.1093/ofid/ofaa218",

language = "English",

volume = "7",

journal = "Open Forum Infectious Diseases",

issn = "2328-8957",

publisher = "Oxford University Press",

number = "7",

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Kloprogge, F, Mwandumba, HC, Kamdolozi, M, Banda, G, Shani, D, Corbett, EL, Kontogianni, N, Ward, S, Khoo, SH, Davies, GR & Sloan, DJ 2020, 'Longitudinal PKPD biomarkers correlate with treatment outcome in drug sensitive pulmonary tuberculosis; a population pharmacokinetic-pharmacodynamic analysis', Open Forum Infectious Diseases, vol. 7, no. 7, ofaa218. https://doi.org/10.1093/ofid/ofaa218

TY - JOUR

T1 - Longitudinal PKPD biomarkers correlate with treatment outcome in drug sensitive pulmonary tuberculosis; a population pharmacokinetic-pharmacodynamic analysis

AU - Kloprogge, Frank

AU - Mwandumba, Henry C.

AU - Kamdolozi, Mercy

AU - Banda, Gertrude

AU - Shani, Doris

AU - Corbett, Elizabeth L.

AU - Kontogianni, Nadia

AU - Ward, Steve

AU - Khoo, Saye H.

AU - Davies, Geraint R.

AU - Sloan, Derek James

N1 - Funding: Wellcome Trust Clinical PhD Fellowship awarded to D.S. (086757/Z/08/A). Funding for the minimum inhibitory concentration assays was provided by a grant from the British Society for Antimicrobial Chemotherapy (GA2015_036P). F.K. has conducted the research as part of his Medical Research Council fellowship (MR/P014534/1).

PY - 2020/7

Y1 - 2020/7

N2 - Background. This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions. Methods. Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing. Results. Higher isoniazid exposure correlated with increased bacillary killing in sputum (P < .01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC)0-24 (P < .01). Serial sputum colony counting negativity at month 2 (P < .05), isoniazid CMAX (P < .05), isoniazid CMAX/minimum inhibitory concentration ([MIC] P < .01), and isoniazid AUC0-24/MIC (P < .01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (P < .05) and earlier progression to biphasic bacillary decline (P < .01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (P < .05). Conclusions. Patterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as CMAX/MIC and AUC0-24/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings.

AB - Background. This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions. Methods. Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing. Results. Higher isoniazid exposure correlated with increased bacillary killing in sputum (P < .01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC)0-24 (P < .01). Serial sputum colony counting negativity at month 2 (P < .05), isoniazid CMAX (P < .05), isoniazid CMAX/minimum inhibitory concentration ([MIC] P < .01), and isoniazid AUC0-24/MIC (P < .01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (P < .05) and earlier progression to biphasic bacillary decline (P < .01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (P < .05). Conclusions. Patterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as CMAX/MIC and AUC0-24/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings.

KW - Outcome

KW - Pharmacokinetics

KW - Pharmacodynamics

KW - Standard treatment

KW - Tuberculosis

UR - https://www.scopus.com/pages/publications/85090776471

U2 - 10.1093/ofid/ofaa218

DO - 10.1093/ofid/ofaa218

M3 - Article

SN - 2328-8957

VL - 7

JO - Open Forum Infectious Diseases

JF - Open Forum Infectious Diseases

IS - 7

M1 - ofaa218

ER -

Longitudinal PKPD biomarkers correlate with treatment outcome in drug sensitive pulmonary tuberculosis; a population pharmacokinetic-pharmacodynamic analysis

Abstract

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Keywords

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