cine and has the following structure:
CH3-CH-CONHCH2-COOH
SH
Tiopronin has the empirical formula C5H9NO3S and a molecular weight of 163.20. In this drug product tioproninexists as a dl racemic mixture.
Tiopronin is a white crystalline powder, which is freely soluble in water.
Each THIOLA EC tablet contains 100 or 300 mg of tiopronin. The inactive ingredients in THIOLA EC tabletsinclude lactose monohydrate, hydroxypropyl cellulose, hydroxypropyl cellulose (low substitute), magnesiumstearate, hydroxypropyl methylcellulose E5, methacrylic acid: ethyl acrylate copolymer (Eudragit E 100), talc,
triethyl citrate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The goal of therapy is to reduce urinary cystine concentration below its solubility limit. Tiopronin is an activereducing agent which undergoes thiol-disulfide exchange with cystine to form a mixed disulfide of tiopronincysteine.
From this reaction, a water-soluble mixed disulfide is formed and the amount of sparingly solublecystine is reduced.
12.2 Pharmacodynamics
The decrement in urinary cystine produced by tiopronin is generally proportional to the dose. A reduction inurinary cystine of 250-350 mg/day at tiopronin dosage of 1 g/day, and a decline of approximately 500 mg/dayat a dosage of 2 g/day, might be expected. Tiopronin has a rapid onset and offset of action, showing a fall in
cystine excretion on the first day of administration and a rise on the first day of drug withdrawal.
12.3 Pharmacokinetics
Absorption
THIOLA EC Tablets
When THIOLA IR and THIOLA EC single doses were given to fasted healthy subjects (n = 39) in a crossoverstudy, the median time to peak plasma levels (Tmax) were 1 (range: 0.5 to 2.1) and 3 (range: 1.0 to 6.0) hours,respectively. The peak exposure (Cmax) and total exposure (AUC0-t) of tiopronin from THIOLA EC tablets were
decreased by 22% and 7% respectively compared to THIOLA IR tablets.
Food Effects
Administration of the THIOLA EC tablet with food decreases Cmax of tiopronin by 13% and AUC0-t by 25%compared to THIOLA EC administered in a fasted state. Since the drug is dosed to effect, the study resultssupport administration of THIOLA EC tablets with or without food; administer at the same time each day with aroutine pattern with regard to meals.
Elimination
Excretion
When tiopronin is given orally, up to 48% of dose appears in urine during the first 4 hours and up to 78% by72 hours.
Drug Interactions
Alcohol
An in vitro dissolution study was conducted to eva luate the impact of alcohol (5, 10, 20, and 40%) on the dosedumping of THIOLA EC tablets. The study results showed that the addition of alcohol to the dissolution mediaincreases the dissolution rate of THIOLA EC tablets in the acidic media of 0.1N HCl [see Drug Interactions (7.1)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis
Long-term carcinogenicity studies in animals have not been performed.
Mutagenesis
Tiopronin was not genotoxic in the chromosomal aberration, sister chromatid exchange, and in vivomicronucleus assays.
Impairment of Fertility
High doses of tiopronin in experimental animals have been shown to interfere with maintenance of pregnancyand viability of the fetus. In 2 published male fertility studies in rats, tiopronin at 20 mg/kg/day intramuscular(IM) for 60 days induced reductions in testis, epididymis, vas deferens, and accessory sex glands weights and
in the count and motility of cauda epi |
