Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model.

Abstract

RATIONALE:

The dosage of 10 mg/kg/d rifampin, as currently used in the treatment of tuberculosis (TB), is not an optimal dose. Shortening of treatment duration might be achievable using an increased rifampin dose.

OBJECTIVES:

Determination of optimal rifampin dosage in mice, resulting in maximum therapeutic effect and without adverse effects. Assessment of associated pharmacokinetic parameters and pharmacokinetic/pharmacodynamic indices.

METHODS:

A murine TB infection using a Beijing genotype Mycobacterium tuberculosis strain was established by intratracheal bacterial instillation followed by proper inhalation, while keeping mice in a vertical position. We assessed dose-dependent activity of rifampin in single-drug treatment during 3 weeks. The maximum tolerated dosage, pharmacokinetic parameters, and pharmacokinetic/pharmacodynamic index were determined. Therapeutic efficacy of a range of rifampin (R) dosages added to a regimen of isoniazid (H) and pyrazinamide (Z) was assessed.

MEASUREMENTS AND MAIN RESULTS:

Maximum tolerated dosage of rifampin in the murine TB was 160 mg/kg/d. Pharmacokinetic measurement in HR(10)Z and HR(160)Z therapy regimens showed for rifampin a C(max) of 16.2 and 157.3 mg/L, an AUC(0-24h) of 132 and 1,782 h·mg/L, and AUC(0-24h)/minimum inhibitory concentration ratios of 528 and 7129, respectively. A clear dose-effect correlation was observed for rifampin after 3-week single-drug treatment. Administration of HR(80)Z allowed 9-week treatment duration to be effective without relapse of infection.

CONCLUSIONS:

Our findings indicate that the currently used rifampin dosage in the therapy of TB is too low. In our murine TB model a rifampin dosage of 80 mg/kg/d enabled a significant reduction in therapy duration without adverse effects.

• Authors: Jurriaan E M de Steenwinkel, Rob E Aarnoutse, Gerjo J de Knegt, Marian T ten Kate, Marga Teulen, Henri A Verbrugh, Martin J Boeree, Dick van Soolingen, Irma A J M Bakker-Woudenberg
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 187 Issue 10 Pg. 1127-34 (May 15 2013) ISSN: 1535-4970 [Electronic] United States
• PMID: 23525933 (Publication Type: Journal Article)

Chemical References

• Antibiotics, Antitubercular
• Rifampin

Topics

• Animals
• Antibiotics, Antitubercular (pharmacokinetics, pharmacology)
• Area Under Curve
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Maximum Tolerated Dose
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Rifampin (pharmacokinetics, pharmacology)
• Treatment Outcome
• Tuberculosis (drug therapy)