From the Guidelines
Rifampicin is rapidly absorbed from the gastrointestinal tract, reaching peak plasma concentrations within 2-4 hours after oral administration, with excellent bioavailability and extensive first-pass metabolism in the liver, as described in the context of its pharmacokinetics 1. The pharmacokinetics of Rifampicin involves several key aspects, including:
- Absorption: Rifampicin is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations reached within 2-4 hours after oral administration 1.
- Bioavailability: It has excellent bioavailability, which is approximately 68-93%, and undergoes extensive first-pass metabolism in the liver.
- Distribution: Rifampicin is widely distributed throughout the body, including to the cerebrospinal fluid, and has a high volume of distribution.
- Protein binding: It is moderately protein-bound, ranging from 80-85%.
- Half-life: Rifampicin has a half-life of 2-5 hours, which decreases to 2-3 hours during long-term therapy due to its ability to induce its own metabolism (autoinduction) 1.
- Metabolism: Rifampicin is primarily metabolized in the liver through deacetylation and hydrolysis, forming an active metabolite (25-desacetyl rifampicin).
- Excretion: It is excreted mainly through the biliary system, with 60-65% eliminated in feces and 30-35% in urine.
- Enzyme induction: Rifampicin is a potent inducer of cytochrome P450 enzymes, particularly CYP3A4, CYP2C9, and CYP2C19, which significantly affects the metabolism of many other drugs, often reducing their plasma concentrations and therapeutic effects, as noted in the management of non-tuberculous mycobacterial pulmonary disease 1. The dosage of Rifampicin is as follows:
- Adults (<50 kg): 450 mg once a day (oral or intravenous) 1.
- Adults (50 kg+): 600 mg once a day (oral or intravenous) 1.
- Children: 15 mg/kg (max 450 mg if <50 kg; 600 mg if 50 kg+) once a day (oral or intravenous) 1. It is essential to take Rifampicin 30–60 min before food, or 2 hours after food, to ensure optimal absorption and effectiveness 1.
From the FDA Drug Label
Intravenous Administration 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. Total body clearances after the 300 and 600 mg IV doses were 0.19 ± 0.06 and 0.14 ± 0. 03 L/hr/kg, respectively. Volumes of distribution at steady state were 0.66 ± 0.14 and 0.64 ± 0. 11 L/kg for the 300 and 600 mg IV doses, respectively. Rifampin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampin is about 80% protein bound. Most of the unbound fraction is not ionized and therefore diffuses freely into tissues Rifampin is rapidly eliminated in the bile and undergoes progressive enterohepatic circulation and deacetylation to the primary metabolite, 25-desacetyl-rifampin.
The pharmacokinetics of rifampicin can be described as follows:
- Peak plasma concentrations: 9.0 ± 3.0 and 17.5 ± 5.0 mcg/mL after 300 and 600 mg IV doses, respectively.
- Total body clearances: 0.19 ± 0.06 and 0.14 ± 0.03 L/hr/kg after 300 and 600 mg IV doses, respectively.
- Volumes of distribution: 0.66 ± 0.14 and 0.64 ± 0.11 L/kg after 300 and 600 mg IV doses, respectively.
- Protein binding: about 80% protein bound.
- Elimination: rapidly eliminated in the bile and undergoes progressive enterohepatic circulation and deacetylation to the primary metabolite, 25-desacetyl-rifampin 2.
From the Research
Pharmacokinetics of Rifampicin
The pharmacokinetics of rifampicin is characterized by considerable inter- and intra-individual variability, which can be reduced by administration during fasting 3. Several factors can alter rifampicin exposure and/or efficacy, including:
- Malnutrition
- HIV infection
- Diabetes mellitus
- Dose size
- Pharmacogenetic polymorphisms
- Hepatic cirrhosis
- Substandard medicinal products
Rifampicin Concentration
Rifampicin maximum (peak) concentration (Cmax) > 8.2 μg/mL is an independent predictor of sterilizing activity, and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8 µg/mL 3. A higher rifampicin Cmax is required for severe forms of TB, such as TB meningitis, with Cmax ≥ 22 μg/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC6) ≥ 70 μg·h/mL associated with reduced mortality 3.
Factors Influencing Rifampicin Pharmacokinetics
Several factors can influence rifampicin pharmacokinetics, including:
- Human immunodeficiency virus (HIV) infection, which can reduce rifampicin concentrations by 39% 4
- Formulation factors, which can affect rifampicin bioavailability 4
- Patient characteristics, such as age, weight, and sex, which can influence rifampicin concentrations 4, 5
- Dose size and frequency, which can impact rifampicin exposure and efficacy 3, 5
Bioavailability of Rifampicin
The bioavailability of rifampicin can vary depending on the formulation and manufacturing process, with some fixed-dose combinations (FDCs) showing impaired rifampicin absorption 6. Studies have shown that the bioavailability of rifampicin from FDCs can be comparable to that of separate formulations, but this can vary depending on the specific formulation and population being studied 7.