Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials

The rifamycin antibacterials, rifampicin (rifampin), rifabutin and rifapent ine, are uniquely potent in the treatment of patients with tuberculosis and chronic staphylococcal infections. Absorption is variably affected by food: the maximal concentration of rifam picin is decreased by food. whereas rifapentine absorption is increased in the presence of food. The rifamycins are well-known inducers of enzyme syst ems involved in the metabolism of many drugs, most notably those metabolise d by cytochrome P450 (CYP) 3A. The relative potency of the rifamycins as CY P3A inducers is rifampin > rifapentine > rifabutin; rifabutin is also a CYP 3A substrate. The antituberculosis activity of rifampicin is decreased by a modest dose r eduction from 600 to 450mg. This somewhat surprising finding may be due to the binding of rifampicin to serum proteins, limiting free, active concentr ations of the drug. However, increasing the administration interval (after the first 2 to 8 weeks of therapy) has little effect on the sterilising act ivity of rifampicin, suggesting that relatively brief exposures to a critic al concentration of rifampicin are sufficient to kill intermittently metabo lising 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 combin ed 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.