What are the pharmacokinetics of Pyrazinamide (PZA)?

From the Guidelines

Pyrazinamide is rapidly absorbed from the gastrointestinal tract, reaching peak serum concentrations of 30–50 mg/ml approximately 2 hours after ingestion, with nearly complete absorption and a significant impact on the treatment of tuberculosis. The pharmacokinetics of pyrazinamide is characterized by its absorption, distribution, metabolism, and excretion.

• Absorption: Pyrazinamide is nearly completely absorbed from the gastrointestinal tract, with peak serum concentrations occurring approximately 2 hours after ingestion 1.
• Distribution: The drug distributes widely throughout the body, but specific details on its volume of distribution are not provided in the given evidence.
• Metabolism: Pyrazinamide is metabolized in the liver, but the specific details of its metabolic pathway are not fully described in the provided studies.
• Excretion: Approximately 70% of the drug is excreted in urine, mostly as metabolites, with only a small percentage excreted unchanged, although the exact percentage is not specified in the given evidence 1. The unique ability of pyrazinamide to kill semi-dormant mycobacteria in acidic environments makes it a critical component of first-line tuberculosis treatment regimens, particularly during the initial intensive phase. Recent studies have focused on optimizing treatment regimens for tuberculosis, including the use of pyrazinamide in combination with other drugs to shorten treatment duration, as seen in the recent advances in the treatment of tuberculosis 1. However, the specific pharmacokinetic properties of pyrazinamide, such as its half-life and the need for dose adjustments in patients with renal or hepatic impairment, are not detailed in the provided evidence but are crucial for its effective and safe use in clinical practice.

From the FDA Drug Label

CLINICAL PHARMACOLOGY Pyrazinamide is well absorbed from the GI tract and attains peak plasma concentrations within 2 hours. Plasma concentrations generally range from 30 to 50 mcg/mL with doses of 20 to 25 mg/kg. It is widely distributed in body tissues and fluids including the liver, lungs and cerebrospinal fluid (CSF) The CSF concentration is approximately equal to concurrent steady-state plasma concentrations in patients with inflamed meninges. Pyrazinamide is approximately 10% bound to plasma proteins. The half-life (t1/2) of pyrazinamide is 9 to 10 hours in patients with normal renal and hepatic function. The plasma half-life may be prolonged in patients with impaired renal or hepatic function. Pyrazinamide is hydrolyzed in the liver to its major active metabolite, pyrazinoic acid. Pyrazinoic acid is hydroxylated to the main excretory product, 5-hydroxypyrazinoic acid. Approximately 70% of an oral dose is excreted in the urine, mainly by glomerular filtration within 24 hours.

The pharmacokinetics of pyrazinamide can be described as follows:

• Absorption: Well absorbed from the GI tract, with peak plasma concentrations attained within 2 hours.
• Distribution: Widely distributed in body tissues and fluids, including the liver, lungs, and cerebrospinal fluid (CSF).
• Protein binding: Approximately 10% bound to plasma proteins.
• Half-life: 9 to 10 hours in patients with normal renal and hepatic function, but may be prolonged in patients with impaired renal or hepatic function.
• Metabolism: Hydrolyzed in the liver to its major active metabolite, pyrazinoic acid.
• Excretion: Approximately 70% of an oral dose is excreted in the urine, mainly by glomerular filtration within 24 hours 2.

From the Research

Pharmacokinetics of Pyrazinamide

The pharmacokinetics of pyrazinamide have been studied in various populations, including healthy subjects and patients with tuberculosis.

• Pyrazinamide is rapidly absorbed, with a time to maximum concentration (tmax) of less than or equal to 1 hour 3.
• The drug has a short distribution phase followed by an elimination phase with a half-life (t1/2 beta) of 9.6 hours 3.
• The pharmacokinetic parameters of pyrazinamide and its metabolites have been studied in healthy subjects, showing that the drug is extensively metabolized to pyrazinoic acid, 5-hydroxy-pyrazinamide, 5-hydroxy-pyrazinoic acid, and pyrazinuric acid 3.
• The formation and elimination of these metabolites are influenced by the activity of microsomal deamidase and xanthine oxidase 3.

Factors Affecting Pyrazinamide Pharmacokinetics

Several factors can affect the pharmacokinetics of pyrazinamide, including:

• Dose per kilogram of body weight, which is associated with the concentrations of pyrazinamide and other antituberculosis drugs 4.
• Patient characteristics, such as human immunodeficiency virus infection, which can reduce the concentrations of pyrazinamide and other drugs 4.
• Formulation factors, which can affect the bioavailability of pyrazinamide and other drugs 4.

Pyrazinamide Dosage and Efficacy

The dosage and efficacy of pyrazinamide have been studied in adults and children.

• The maximum concentration (Cmax) of pyrazinamide is similar in children and adults receiving the same mg/kg body weight dosage 5.
• Children can receive the same mg/kg body weight pyrazinamide dosage as adults, suggesting that the same dosage regimen can be used in both populations 5.
• Pyrazinamide is an essential sterilizing drug and, with rifampicin, enables six-month short-course antituberculosis chemotherapy 5.