{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T12:42:46Z","timestamp":1791636166579,"version":"4.3.4"},"reference-count":35,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,6,13]],"date-time":"2019-06-13T00:00:00Z","timestamp":1560384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G1002586, MR\/N028376\/1 and MC_PC_14111"],"award-info":[{"award-number":["G1002586, MR\/N028376\/1 and MC_PC_14111"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Increasing rifampicin (RIF) dosages could significantly reduce tuberculosis (TB) treatment durations. Understanding the pharmacokinetic-pharmacodynamics (PK\u2013PD) of increasing RIF dosages could inform clinical regimen selection. We used intracellular PD modelling (PDi) to predict clinical outcomes, primarily time to culture conversion, of increasing RIF dosages. PDi modelling utilizes in vitro-derived measurements of intracellular (macrophage) and extracellular Mycobacterium tuberculosis sterilization rates to predict the clinical outcomes of RIF at increasing doses. We evaluated PDi simulations against recent clinical data from a high dose (35 mg\/kg per day) RIF phase II clinical trial. PDi-based simulations closely predicted the observed time-to-patient culture conversion status at eight weeks (hazard ratio: 2.04 (predicted) vs. 2.06 (observed)) for high dose RIF-based treatments. However, PDi modelling was less predictive of culture conversion status at 26 weeks for high-dosage RIF (99% predicted vs. 81% observed). PDi-based simulations indicate that increasing RIF beyond 35 mg\/kg\/day is unlikely to significantly improve culture conversion rates, however, improvements to other clinical outcomes (e.g., relapse rates) cannot be ruled out. This study supports the value of translational PDi-based modelling in predicting culture conversion rates for antitubercular therapies and highlights the potential value of this platform for the improved design of future clinical trials.<\/jats:p>","DOI":"10.3390\/pharmaceutics11060278","type":"journal-article","created":{"date-parts":[[2019,6,13]],"date-time":"2019-06-13T11:15:58Z","timestamp":1560424558000},"page":"278","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Intracellular PD Modelling (PDi) for the Prediction of Clinical Activity of Increased Rifampicin Dosing"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5288-4501","authenticated-orcid":false,"given":"Ghaith","family":"Aljayyoussi","sequence":"first","affiliation":[{"name":"Centre for Drugs &amp; Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Donnellan","sequence":"additional","affiliation":[{"name":"Centre for Drugs &amp; Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Ward","sequence":"additional","affiliation":[{"name":"Centre for Drugs &amp; Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo A.","family":"Biagini","sequence":"additional","affiliation":[{"name":"Centre for Drugs &amp; Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,13]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2017). Global Tuberculosis Report, World Health Organization."},{"key":"ref_2","unstructured":"World Health Organization (2018). United Nations General Assembly on Ending Tuberculosis, World Health Organization."},{"key":"ref_3","unstructured":"(1978). Controlled clinical trial of four short-course regimens of chemotherapy for two durations in the treatment of pulmonary tuberculosis: First report: Third East African\/British Medical Research Councils study. Am. Rev. Respir. Dis., 118, 39\u201348."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"641","DOI":"10.3389\/fmicb.2015.00641","article-title":"High-dose rifampicin kills persisters, shortens treatment duration, and reduces relapse rate in vitro and in vivo","volume":"6","author":"Hu","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1164\/rccm.201407-1264OC","article-title":"A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis","volume":"191","author":"Boeree","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1164\/rccm.201207-1210OC","article-title":"Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model","volume":"187","author":"Aarnoutse","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1164\/rccm.201712-2524OC","article-title":"Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial","volume":"198","author":"Velasquez","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1128\/AAC.47.7.2118-2124.2003","article-title":"Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis","volume":"47","author":"Jayaram","year":"2003","journal-title":"Antimicrob. Agents ChemoTher."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2974","DOI":"10.1128\/AAC.01520-08","article-title":"Population modeling and Monte Carlo simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of rifampin in lungs","volume":"53","author":"Goutelle","year":"2009","journal-title":"Antimicrob. Agents ChemoTher."},{"key":"ref_10","first-page":"71","article-title":"Two three-month treatment regimens for pulmonary tuberculosis","volume":"51","author":"Kreis","year":"1976","journal-title":"Bull. Int. Union Tuberc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1128\/AAC.01474-06","article-title":"Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears","volume":"51","author":"Diacon","year":"2007","journal-title":"Antimicrob. Agents ChemoTher."},{"key":"ref_12","first-page":"3","article-title":"What is the \u2018right\u2019 dose of rifampin?","volume":"7","author":"Peloquin","year":"2003","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e194","DOI":"10.1093\/cid\/cir184","article-title":"Why Do We Use 600 mg of Rifampicin in Tuberculosis Treatment?","volume":"52","author":"Aarnoutse","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S1473-3099(16)30274-2","article-title":"High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: A multi-arm, multi-stage randomised controlled trial","volume":"17","author":"Boeree","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1093\/cid\/ciy026","article-title":"The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis","volume":"67","author":"Aarnoutse","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/s41598-017-00529-6","article-title":"Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration","volume":"7","author":"Aljayyoussi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1097\/FTD.0b013e31825c4ba6","article-title":"Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R","volume":"34","author":"Neely","year":"2012","journal-title":"Ther. Drug Monit."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1128\/AAC.43.6.1329","article-title":"Intrapulmonary concentrations of pyrazinamide","volume":"43","author":"Conte","year":"1999","journal-title":"Antimicrob. Agents ChemoTher."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2358","DOI":"10.1128\/AAC.46.8.2358-2364.2002","article-title":"Effects of gender, AIDS, and acetylator status on intrapulmonary concentrations of isoniazid","volume":"46","author":"Conte","year":"2002","journal-title":"Antimicrob. Agents ChemoTher."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1128\/AAC.00133-06","article-title":"Interpretation of antibiotic concentration ratios measured in epithelial lining fluid","volume":"52","author":"Kiem","year":"2008","journal-title":"Antimicrob. Agents ChemoTher."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2891","DOI":"10.1128\/AAC.45.10.2891-2896.2001","article-title":"Effects of AIDS and gender on steady-state plasma and intrapulmonary ethambutol concentrations","volume":"45","author":"Conte","year":"2001","journal-title":"Antimicrob. Agents ChemoTher."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"395","DOI":"10.2165\/00003088-200443060-00003","article-title":"Effect of sex and AIDS status on the plasma and intrapulmonary pharmacokinetics of rifampicin","volume":"43","author":"Conte","year":"2004","journal-title":"Clin. Pharmacokinet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.tube.2017.05.002","article-title":"Assessment of treatment response by colony forming units, time to culture positivity and the molecular bacterial load assay compared in a mouse tuberculosis model","volume":"105","author":"Dickinson","year":"2017","journal-title":"Tuberculosis (Edinb)"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1128\/AAC.00461-07","article-title":"Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption","volume":"52","author":"Wilkins","year":"2008","journal-title":"Antimicrob. Agents ChemoTher."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4230","DOI":"10.1128\/AAC.00274-11","article-title":"Population pharmacokinetics of ethambutol in South African tuberculosis patients","volume":"55","author":"Jonsson","year":"2011","journal-title":"Antimicrob. Agents ChemoTher."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/j.1365-2125.2011.03940.x","article-title":"Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients","volume":"72","author":"Wilkins","year":"2011","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_27","unstructured":"R Core Team (2017). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1002\/cpt.778","article-title":"A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses","volume":"103","author":"Svensson","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_29","unstructured":"IBM Corp. (IBM SPSS Statistics for Windows, 2016). IBM SPSS Statistics for Windows, Version 24.0, Released 2016."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"van Zyl-Smit, R.N., Binder, A., Meldau, R., Mishra, H., Semple, P.L., Theron, G., Peter, J., Whitelaw, A., Sharma, S.K., and Warren, R. (2011). Comparison of quantitative techniques including Xpert MTB\/RIF to evaluate mycobacterial burden. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028815"},{"key":"ref_31","first-page":"503","article-title":"The cost of antituberculous drug regimens","volume":"120","author":"Fox","year":"1979","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1002\/cpt.1102","article-title":"Forecasting Clinical Dose-Response From Preclinical Studies in Tuberculosis Research: Translational Predictions With Rifampicin","volume":"104","author":"Wicha","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1111\/cts.12472","article-title":"New Paradigm for Translational Modeling to Predict Long-term Tuberculosis Treatment Response","volume":"10","author":"Bartelink","year":"2017","journal-title":"Clin. Transl. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S428","DOI":"10.1093\/clinids\/5.Supplement_3.S428","article-title":"Pharmacokinetics and metabolism of rifampin in humans","volume":"5","author":"Acocella","year":"1983","journal-title":"Rev. Infect. Dis."},{"key":"ref_35","first-page":"751","article-title":"Comparison between regimes of rifampicin-isoniazid administered daily and administered twice a week (initial results of a comparative study conducted in 4 medical services of the Parisian region)","volume":"33","author":"Decroix","year":"1969","journal-title":"Rev. Tuberc. Pneumol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/6\/278\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:58:10Z","timestamp":1760187490000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/6\/278"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,13]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["pharmaceutics11060278"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics11060278","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,13]]}}}