Revision Year: 2016 Publisher: RIEMSER Pharma GmbH, An der Wiek 7, 17493 Greifswald – Insel Riems, Germany, phone: +49 30 338427-0, fax: +49 3 83 51 308, e-mail: info@RIEMSER.com
Pharmacotherapeutic group: Drug for the treatment of tuberculosis
ATC code: J04AK03
Terizidone is a Schiff base consisting of 2 D-cycloserine molecules and 1 molecule of terephthalaldehyde. Terizidone is hydrolyzed in vivo and D-cycloserine is released.
The mechanism of action of cycloserine is based on the breakdown of the bacterial cell wall synthesis through inhibition of the alanine-racemase and D-alanyl-D-alanine-synthetase. This is competitive inhibition.
TERIZIDON is a bacteriostatic chemotherapeutic agent for oral application. Terizidone is generally effective against Mycobacterium tuberculosis. Although several in-vitro-studies allow us to suspect the susceptibility of further species of bacteria against terizidone, insufficient data and experience are available on the efficacy of terizidone in the treatment of these infections. The application of terizidone should therefore be limited to the therapy of pulmonary and extrapulmonary tuberculosis, caused by Mycobacterium tuberculosis.
Based on the structural similarity (terizidone is a prodrug of the active substance cycloserine), it can be assumed that the resistance mechanism as described for cycloserine also applies for terizidone.
With regard to the resistance against D-cycloserine, a reduced cellular permeability and mutations in the genes encoding for D-alanine-racemase and D-alanyl-D-alanine-synthetase have been described.
A complete parallel resistance to cycloserine exists. There are no resistance commonalities between terizidone or cycloserine and other antituberculotics.
The prevalence of the obtained resistance to individual species can vary locally and over time. Therefore, local information on the resistance situation, in particular for the adequate treatment of severe infections is required.
The aim should always be to make the selection of the combination partners for the treatment of tuberculosis dependent on a susceptibility test. Terizidone should only be applied if the susceptibility of the pathogens has been verified. The same applies for the respective combination partners. If an empirical start to therapy using terizidone is absolutely necessary, a susceptibility test should be carried out parallel to the start of the treatment. If a susceptibility test is not possible (for example because of no pathogen isolation) and if, based on the local resistance situation, the efficacy of terizidone is placed in question, consultation should be held on the therapy with experts.
Generally susceptible species:
Aerobic gram-positive microorganisms:
Mycobacterium tuberculosis
Species with natural resistance:
Mycobacterium bovis ssp. Bacillus Calmette-Guèrin (BCG)*
* Resistance test against cycloserine
In an in-vitro study with Mycobacterium-tuberculosis-isolates from patients in Germany with variable resistance patterns (3 strains with isoniazide monoresistance, 1 strain with rifampicin monoresistance, 31 strains with isoniazide and rifampicin resistance [multi-drug resistance, of these 2 of the Beijing genotype and 5 of the Latin American genotype]), all strains tested against terizidone proved susceptible. The minimum inhibition concentration on LöwensteinJensen medium was <20 µg/ml.
A study of 261 isolates in 2002 resulted in a resistance rate against cycloserine of 0.8%.
A study with 212 Mycobacterium-tuberculosis-strains with multi-drug resistance from Germany (2003-May 2005) displayed a resistance rate against cycloserine of 2.4%
In another study, 184 multi-drug resistance strains which had been isolated in Germany between 2004 and 2006 were tested for their resistance patterns. Of these isolates, 9 (= 5%) proved resistant against cycloserine.
The Schiff base terizidone is a prodrug, which hydrolyzes after oral intake into cycloserine.
Terizidone is reabsorbed quickly and almost completely from the gastrointestinal tract after oral application. In healthy test people, a maximum serum level of 1.78-6.44 µg cycloserine/ml was achieved within 0.5-5 h (median 1.5 h) after a one-off oral administration of 250 mg TERIZIDON. After repeated administration of 250 mg TERIZIDON three times per day, the maximum cycloserine concentrations fluctuated between 12.7 and 6.2 µg cycloserine/ml (average serum concentration 9 µg cycloserine/ml) during one day.
It is probable that terizidone already hydrolyzes in the gastrointestinal tract, but also in the body, and releases D-cycloserine and terephthalaldehyde. The pharmacokinetics of cycloserine are influenced to a minimal extent by orange juice and antacids, whereas very fatty foods delay adsorption. It can be expected that this also applies to terizidone.
Terizidone (prodrug) hydrolyzes to D-cycloserine. The distribution volume of cycloserine after a single administration of 500 mg terizidone lay at 112.6 L. Cycloserine is widely distributed in tissue and fluids, including cerebrospinal fluid and breast milk. Cycloserine passes through the placenta, whereby the foetal blood concentrations reach that of the mother’s. The cycloserine concentrations in breast milk are stated as being 6-19 µg/ml. The concentration ratio between breast milk and plasma is 0.67–0.75. Cycloserine is not bound to serum proteins.
No specific studies have been undertaken on the metabolization of terizidone. It is probable that terizidone already hydrolyzes in the gastrointestinal tract, but also in the body, and releases D-cycloserine and terephthalaldehyde. Terephthalaldehyde has not been proven to be antibacterially effective in vivo. Approx. 35% of the cycloserine is converted into as yet unspecified metabolites.
The elimination of terizidone is a first-order process. In healthy test people, cycloserine was eliminated after repeated administration of 250 mg TERIZIDON three times per day with a half-life period of 16 hours. Approx. 30% of the daily terizidone dose was excreted in the form of cycloserine in the urine. The renal clearance was approx. 20 ml/min. It is known that cycloserine is mainly eliminated renally via glomerular filtration. Minor amounts of cycloserine are eliminated via the faeces.
The excretion of terizidone takes place more slowly than in younger patients.
The half-life period of terizidone is extended.
Terizidone or cycloserine are haemodialyzable and peritoneal dialyzable. Not enough studies are available indicating that TERIZIDON remains clinically effective in case of continuous forms of dialysis (continuous peritoneal dialysis; CAPD).
From the studies carried out on chronic toxicity, there are no indications which might lead to a suspicion of possible unknown side effects occurring in patients.
With reference to the genotoxicity, terizidone was negative in a bacterial test (Ames test) and in an in-vitro chromosome aberration test on human lymphocytes.
No information is available on the carcinogenic potential of terizidone.
In animal experimentation, terizidone was neither teratogenic nor embryotoxic.
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