What are the pharmacokinetics of Isoniazid (INH)?

From the Guidelines

Isoniazid (INH) is rapidly absorbed from the gastrointestinal tract, reaching peak plasma concentrations within 1-2 hours after oral administration, with a standard adult dose of 5 mg/kg daily (maximum 300 mg) or 15 mg/kg three times weekly (maximum 900 mg per dose) 1.

Pharmacokinetics of Isoniazid

The pharmacokinetics of INH are characterized by rapid absorption, widespread distribution, and hepatic metabolism.

• INH is absorbed from the gastrointestinal tract, reaching peak plasma concentrations within 1-2 hours after oral administration.
• It distributes widely throughout the body, including the cerebrospinal fluid, and has excellent penetration into all body tissues and fluids.
• The drug undergoes acetylation in the liver primarily by N-acetyltransferase 2 (NAT2), with genetic polymorphisms creating fast and slow acetylator phenotypes.
• Fast acetylators metabolize the drug more quickly (half-life of 0.5-1.5 hours) compared to slow acetylators (half-life of 2-5 hours), which can affect dosing requirements and toxicity risk.
• Approximately 75-95% of a dose is excreted in the urine within 24 hours, primarily as metabolites.

Factors Affecting Pharmacokinetics

Several factors can affect the pharmacokinetics of INH, including:

• Age: Isoniazid's metabolism can be affected by age, with slower clearance in elderly patients and neonates.
• Renal impairment: Dosing adjustments are necessary in patients with severe renal impairment (creatinine clearance <30 mL/min).
• Liver disease: Dosing adjustments are necessary in patients with end-stage liver disease.

Clinical Implications

Understanding the pharmacokinetics of INH is essential for optimizing tuberculosis treatment while minimizing adverse effects like peripheral neuropathy and hepatotoxicity.

• The standard adult dose is 5 mg/kg daily (maximum 300 mg) or 15 mg/kg three times weekly (maximum 900 mg per dose) 1.
• Monitoring of liver function tests (LFTs) is necessary in patients cotreated with isoniazid and hepatotoxic drugs like methotrexate and leflunomide 1.
• Vitamin B6 (300 mg/week) is recommended to reduce neurotoxicity 1.

From the FDA Drug Label

Within 1 to 2 hours after oral administration, isoniazid produces peak blood levels which decline to 50 percent or less within 6 hours. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs, and excreta (saliva, sputum, and feces) The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. From 50 to 70 percent of a dose of isoniazid is excreted in the urine within 24 hours. Isoniazid is metabolized primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined Approximately 50 percent of Blacks and Caucasians are "slow inacti- vators", and the rest are "rapid inactivators"; the majority of Eskimos and Orientals are" rapid inactivators. "

The pharmacokinetics of Isoniazid (INH) are characterized by:

• Peak blood levels within 1 to 2 hours after oral administration
• Decline to 50 percent or less within 6 hours
• Distribution into all body fluids and tissues
• Excretion of 50 to 70 percent of the dose in the urine within 24 hours
• Metabolism primarily by acetylation and dehydrazination, with a genetically determined rate of acetylation 2 Key points include:
• Genetic variation in the rate of acetylation, with approximately 50 percent of Blacks and Caucasians being "slow inactivators" and the rest being "rapid inactivators"
• Variation in blood levels due to the rate of acetylation, which may lead to an increase in toxic reactions in slow inactivators

From the Research

Pharmacokinetics of Isoniazid (INH)

• Isoniazid (INH) is a crucial drug in the prevention and treatment of tuberculosis (TB), but its pharmacokinetics (PK) vary significantly among patients receiving standard dosages 3.
• A two-compartment model with first-order absorption and elimination is commonly used to describe INH PK 3.
• Significant covariates affecting INH PK include NAT2 genotype, body size, and age 3, 4.
• The median clearance (CL) value in fast metabolizers is 2.55-fold higher than in slow metabolizers 3.
• Infants and children have higher CL per weight values than adults with the same metabolic phenotype, and CL value increases with postnatal age 3.
• Patients on concomitant efavirenz-based antiretroviral therapy have higher population predicted clearances of acetyl-isoniazid and isonicotinic acid compared to those who are HIV treatment naïve 4.
• Sex and CD4 cell count also affect the bioavailability of INH 4.

Metabolism and Toxicity

• INH is metabolized to several compounds, including hydrazine (HZ), isonicotinic acid (INA), and acetyl-isoniazid (AcINH) 5, 6.
• The formation and elimination of AcINH are genetically controlled and influence the risk of peripheral neurotoxicity and hepatotoxicity 6.
• Slow acetylation increases the risk of INH-induced toxicity, while fast acetylation may lead to lower treatment success rates 7, 6.
• Hepatotoxicity is related to HZ and its metabolites, which can generate free radicals 6.
• The mechanism of INH neurotoxicity is not fully understood but may involve HZ and other metabolites 6.

Dosing and Bioavailability

• The daily dose of INH should be increased by 200-600 mg in fast metabolizers compared to slow metabolizers 3.
• Pediatric patients require a higher dose per kilogram than adults to achieve effective treatment 3.
• Isoniazid-solid lipid nanoparticles (SLNs) can improve bioavailability and reduce hepatotoxicity by bypassing first-pass metabolism and releasing INH slowly 5.
• A physiologically based pharmacokinetic (PBPK) model can be used to simulate INH PK and guide individualized dosing regimens 7.