AFARIS PAED 75/50 Tablet Ref.[115239] Active ingredients: Isoniazid Rifampicin

Source: Health Products Regulatory Authority (ZA)  Revision Year: 2024  Publisher: Macleods Pharmaceuticals SA (Pty) Ltd., Ground Floor, Block 1, Bassonia Estate Office Park (East), 1 Cussonia Drive, Bassonia Rock Ext 12, Alberton, Gauteng

Pharmacodynamic properties

A 20.2.3 Tuberculostatic
Antimicrobial medicine

Rifampicin and isoniazid are bactericidal antituberculosis medicines which both act against tuberculosis. Isoniazid is bactericidal for rapidly dividing micro-organisms and bacteriostatic for resting bacilli.

Rifampicin

Rifampicin inhibits the growth of Mycobacterium tuberculosis. Rifampicin binds to the β subunit of DNA-dependent RNA polymerase (rpoB) to form a stable medicine-enzyme complex. Rifampicin binding suppresses chain formation in RNA synthesis.

Isoniazid

Isoniazid is bactericidal and the mechanism of action is by entering the bacilli through passive diffusion. Isoniazid then inhibits the biosynthesis of mycolic acids which are essential components of the cell wall of Mycobacterium tuberculosis, leading to bacterial cell death.

Pharmacokinetic properties

Rifampicin

Absorption

Rifampicin is readily absorbed from the gastrointestinal tract with an oral bioavailability of 68% for a 150 mg dose; Cmax of 2,1 μg/mL and tmax of 1,5 – 2,0 hours. Absorption of rifampicin is reduced by about 30% when ingested with food.

Distribution

Rifampicin is widely distributed throughout the body and has good penetration into many tissues, but levels in CNS reach only approximately 5% of those in plasma. Rifampicin is about 85% protein bound.

Metabolism

Rifampicin is metabolised by microsomal β-esterases and cholinesterases that remove the acetyl group at position 25, resulting in 25-O-desacetyl rifampicin. Rifampicin is also metabolised by hydrolysis to 3-formyl rifampicin. A major pathway for rifampicin elimination is CYP3A. Due to autoinduction, rifampicin reduces its own area under concentration-time curve (AUC) with repeated administration.

Elimination

The half-life of rifampicin ranges from 2 – 5 hours. Rifampicin and its metabolites are excreted by bile and eliminated via faeces, with urine elimination accounting for one–third and less of metabolites.

Isoniazid

Absorption

Isoniazid is readily absorbed from the gastrointestinal tract with an oral bioavailability of 100% for a 300 mg dose; Cmax of 3,4 – 7,4 μg/ml for rapid acetylators and Cmax of 5,2 – 9 μg/ml for slow acetylators; tmax of 1,1 ± 0,5 hours for rapid acetylators and 1,1 ± 0,6 hours for slow acetylators. Absorption of isoniazid is decreased by food and antacids.

Distribution

The ratio of isoniazid in the epithelial lining fluid to that in plasma is 1–2 and for CSF is 0,9. Approximately 10% of isoniazid is protein bound.

Metabolism

Isoniazid is metabolised by hepatic arylamine N-acetyltransferase type 2 (NAT2). Isoniazid is N-acetylated to N-acetylisoniazid in reactions that uses acetyl-coA. Acetylisoniazid is excreted by the kidney; acetylisoniazid can also be converted to acetylhydrazine and then to hepatoxic metabolites by CYP2E1. Alternatively, acetylhydrazine may be further acetylated by NAT2 to diacetylhydrazine, which is non-toxic. Isoniazid clearance in patients is classified as one of two phenotypic groups: “slow” acetylators and “fast” acetylators. Rapid acetylators will remove acetylhydrazine while slower acetylators or induction of CYP2E1 will lead to more toxic metabolites.

Elimination

The half-life of isoniazid ranges from 1,1 ± 0,1 hours for rapid acetylators and 3,1 ± 1,1 for slow acetylators. From 75 – 95% of a dose of isoniazid is excreted in the urine within 24 hours, mostly as acetylisoniazid and isonicotinic acid.

© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.