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Mathematical Modeling to Explore Shorter Multi-Drug Therapy for Pulmonary Tuberculosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2013 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Standard treatment for TB usually involves lengthy therapy based on up to four different drugs taken over 6 months. An alternative shorter-duration therapy would mean less need for high patient adherence, and reduced risk of bacterial resistance. Many previous PK/PD models for tuberculosis have focused on short-term drug effects during the initial days of treatment rather than overall therapy outome. In-vitro experiments of TB drug effectiveness often are based on monotherapy, even though standard patient treatment for TB usually involves use of two or more drugs.

This study analyzed relative effectiveness of TB therapy alternatives, evaluating factors such as drug dose and dose patterns, multi-dose therapy, and therapy start time and duration. The simulation results suggest intracellular bacterial growth inhibition and killing is central to therapeutic outcome, while extracellular killing only has secondary effects. Exchange of bacteria between intra- and extracellular compartments creates a bacterial reservoir limiting the effect of drugs which only act extracellularly, such as isoniazid.

Minimal therapy duration appears governed by the net kill rate of intracellular bacteria. High doses of rifampin, such as 2x or 3x of normal dose, may allow 40 to 60 percent shorter therapy duration. Furthermore, the use of different dose patterns, such as alternating high vs. low dose every other day may also reduce overall treatment duration by 35 to 40 percent. The time from initial TB infection to drug therapy start has significant influence on total treatment time. If therapy is initiated at 120 vs. 180 days post-infection, treatment time may be reduced by 60 to 90 days.

Assay of patient TB therapy effect based on extracellular bacterial count, such as sputum smear test, may underestimate remaining intracellular bacteria, which later may lead to renewed acute infection. Complete bacterial clearance may take 60 days or more beyond when extracellular bacteria is fully eliminated.

Place, publisher, year, edition, pages
2013. , 91 p.
Keyword [en]
tuberculosis, TB, multi-drug therapy, rifampin, isoniazid, PK/PD, modeling, immune response, bacterial resistance, high-dose therapy
National Category
Pharmacology and Toxicology
URN: urn:nbn:se:uu:diva-199843OAI: oai:DiVA.org:uu-199843DiVA: diva2:621719
External cooperation
University of California San Francisco (UCSF)
Subject / course
Pharmaceutical Bioinformatics
Educational program
Freestanding course
Available from: 2013-06-11 Created: 2013-05-16 Last updated: 2013-06-11Bibliographically approved

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