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Comparative Pharmacokinetics and Pharmacodynamics of the Rifamycin Antibacterials

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  • Drug Disposition
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Abstract

The rifamycin antibacterials, rifampicin (rifampin), rifabutin and rifapentine, are uniquely potent in the treatment of patients with tuberculosis and chronic staphylococcal infections.

Absorption is variably affected by food; the maximal concentration of rifampicin is decreased by food, whereas rifapentine absorption is increased in the presence of food. The rifamycins are well-known inducers of enzyme systems involved in the metabolism of many drugs, most notably those metabolised by cytochrome P45O (CYP) 3A. The relative potency of the rifamycins as CYP3A inducers is rifampin > rifapentine > rifabutin; rifabutin is also a CYP3A substrate.

The antituberculosis activity of rifampicin is decreased by a modest dose reduction from 600 to 450mg. This somewhat surprising finding may be due to the binding of rifampicin to serum proteins, limiting free, active concentrations of the drug. However, increasing the administration interval (after the first 2 to 8 weeks of therapy) has little effect on the sterilising activity of rifampicin, suggesting that relatively brief exposures to a critical concentration of rifampicin are sufficient to kill intermittently metabolising mycobacterial populations. The high protein binding of rifapentine (97%) may explain the suboptimal efficacy of the currently recommended dose of this drug.

The toxicity of rifampicin is related to dose and administration interval, with increasing rates of presumed hypersensitivity with higher doses combined with administration frequency of once weekly or less. Rifabutin toxicity is related to dose and concomitant use of CYP3A inhibitors.

The rifamycins illustrate the complexity of predicting the pharmacodynamics of treatment of an intracellular pathogen with the capacity for dormancy.

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Acknowledgements

Dr Burman would like to thank the Centers for Disease Control and Prevention (Tuberculosis Trials Consortium) in Atlanta, USA for their support. Dr Gallicano would like to acknowledge the support of the AIDS Program, Committee of the Ontario Ministry of Health and the Canadian HIV Trials Network (CTN 117) and Dr Peloquin would like to acknowledge support from the NIAID (grant AI37845).

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Authors and Affiliations

  1. Department of Public Health, Denver Health and Hospital Authority and the Department of Medicine (Division of Infectious Diseases), University of Colorado Health Sciences Center, Denver, Colorado, USA

    William J. Burman

  2. Clinical Investigational Unit, Ottawa General Hospital, Ottawa, Ontario, Canada

    Keith Gallicano

  3. Infectious Diseases Pharmacokinetics Laboratory, National Jewish Center, Denver, Colorado, USA

    Charles Peloquin

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  1. William J. Burman
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  2. Keith Gallicano
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  3. Charles Peloquin
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Correspondence to William J. Burman.

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Burman, W.J., Gallicano, K. & Peloquin, C. Comparative Pharmacokinetics and Pharmacodynamics of the Rifamycin Antibacterials. Clin Pharmacokinet 40, 327–341 (2001). https://doi.org/10.2165/00003088-200140050-00002

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