From the Guidelines
Rifampicin's high peak concentration is the best indicator of its efficacy due to its concentration-dependent bactericidal activity.
Pharmacokinetic Properties of Rifampicin
- Rifampicin is quickly absorbed from the gastrointestinal tract, with peak serum concentrations of 7–14 mg/ml occurring 1.5–3.0 h after ingestion 1.
- The drug's concentration-dependent bactericidal activity makes peak concentration a crucial factor in determining its efficacy.
- Rifampicin's ability to penetrate well into tissues and cells, despite being approximately 75% protein bound, also contributes to its effectiveness 1.
Clinical Relevance of Peak Concentration
- Achieving high peak serum concentrations is essential for rifampicin's bactericidal activity, as it allows the drug to effectively kill M. tuberculosis bacteria.
- The recommended dose of 10 mg/kg/d is intended to achieve peak serum concentrations within the therapeutic range 1.
- While rifampicin's pharmacokinetics can be affected by various factors, including hepatic impairment and drug interactions, peak concentration remains a key indicator of its efficacy 1.
From the FDA Drug Label
After intravenous administration of a 300 or 600 mg dose of rifampin infused over 30 minutes to healthy male volunteers (n=12), mean peak plasma concentrations were 9.0 ± 3.0 and 17.5 ± 5.0 mcg/mL, respectively. Plasma concentrations after the 600 mg dose, which were disproportionately higher (up to 30% greater than expected) than those found after the 300 mg dose, indicated that the elimination of larger doses was not as rapid. Rifampin is widely distributed throughout the body. Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible Mycobacterium tuberculosis organisms.
The pharmacokinetic property that makes peak concentration the best indicator of rifampicin efficacy is its concentration-dependent killing of Mycobacterium tuberculosis organisms, which is related to its ability to inhibit DNA-dependent RNA polymerase activity. The high peak plasma concentrations achieved after administration of rifampin allow for effective killing of the bacteria. 2
- Key properties of rifampin that contribute to its efficacy include:
- High peak plasma concentrations
- Wide distribution throughout the body
- Concentration-dependent killing of Mycobacterium tuberculosis organisms
From the Research
Pharmacokinetic Properties of Rifampicin
The pharmacokinetic property that makes peak concentration the best indicator of rifampicin efficacy is its relationship with the drug's sterilizing activity and therapeutic effectiveness.
- Peak concentration (Cmax) is a critical factor in determining the efficacy of rifampicin, with a Cmax > 8.2 μg/mL being an independent predictor of sterilizing activity 3.
- The area under the concentration-time curve (AUC) is also an important parameter, with AUC0-24 being the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy 4.
- However, peak concentration is considered a better indicator of efficacy because it is more closely related to the drug's ability to kill bacteria and prevent resistance 3.
Factors Affecting Peak Concentration
Several factors can affect the peak concentration of rifampicin, including:
- Food administration: Food can reduce the mean peak plasma concentration and prolong the time to reach peak concentration 5.
- Malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products can alter rifampicin exposure and/or efficacy 3.
- Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg 3.
Optimal Sampling Strategies
Optimal sampling strategies for therapeutic drug monitoring of rifampicin involve measuring concentrations at specific time points, such as 1,3, and 8 h post-dosing, to predict AUC0-24 values with acceptable accuracy and precision 4.