Chemical formula: C₁₂H₉F₃N₂O₂ Molecular mass: 270.207 g/mol PubChem compound: 54684141
Teriflunomide is an immunomodulatory agent with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), which functionally connects with the respiratory chain. As a consequence of the inhibition, teriflunomide generally reduces the proliferation of rapidly dividing cells that depend on de novo synthesis of pyrimidine to expand. The exact mechanism by which teriflunomide exerts its therapeutic effect in MS is not fully understood, but this is mediated by a reduced number of lymphocytes.
Effects on immune cell numbers in the blood: In the placebo-controlled studies, teriflunomide 14 mg once a day led to a mild mean reduction in lymphocyte count, of less than 0.3 × 109/l, which occurred over the first 3 months of treatment and levels were maintained until the end of the treatment.
In a placebo-controlled thorough QT study performed in healthy subjects, teriflunomide at mean steady-state concentrations did not show any potential for prolonging the QTcF interval compared with placebo: the largest time matched mean difference between teriflunomide and placebo was 3.45 ms with the upper bound of the 90% CI being 6.45 ms.
In the placebo-controlled studies, mean decreases in serum uric acid at a range of 20 to 30% were observed in patients treated with teriflunomide compared to placebo. Mean decrease in serum phosphorus was around 10% in the teriflunomide group compared to placebo. These effects are considered to be related to increase in renal tubular excretion and not related to changes in glomerular functions.
Median time to reach maximum plasma concentrations occurs between 1 to 4 hours post-dose following repeated oral administration of teriflunomide, with high bioavailability (approximately 100%).
Food does not have a clinically relevant effect on teriflunomide pharmacokinetics.
From the mean predicted pharmacokinetic parameters calculated from the population pharmacokinetic (PopPK) analysis using data from healthy volunteers and MS patients, there is a slow approach to steady- state concentration (i.e. approximately 100 days (3.5 months) to attain 95% of steady-state concentrations) and the estimated AUC accumulation ratio is approximately 34-fold.
Teriflunomide is extensively bound to plasma protein (>99%), probably albumin and is mainly distributed in plasma. The volume of distribution is 11 l after a single intravenous (IV) administration. However, this is most likely an underestimation since extensive organ distribution was observed in rats.
Teriflunomide is moderately metabolised and is the only component detected in plasma. The primary biotransformation pathway for teriflunomide is hydrolysis with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.
Teriflunomide is excreted in the gastrointestinal tract mainly through the bile as unchanged active substance and most likely by direct secretion. Teriflunomide is a substrate of the efflux transporter BCRP, which could be involved in direct secretion. Over 21 days, 60.1% of the administered dose is excreted via faeces (37.5%) and urine (22.6%). After the rapid elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in faeces). Based on individual prediction of pharmacokinetic parameters using the PopPK model of teriflunomide in healthy volunteers and MS patients, median t1/2z was approximately 19 days after repeated doses of 14 mg. After a single intravenous administration, the total body clearance of teriflunomide is 30.5 ml/h.
The elimination of teriflunomide from the circulation can be accelerated by administration of cholestyramine or activated charcoal, presumably by interrupting the reabsorption processes at the intestinal level. Teriflunomide concentrations measured during an 11-day procedure to accelerate teriflunomide elimination with either 8 g cholestyramine three times a day, 4 g cholestyramine three times a day or 50 g activated charcoal twice a day following cessation of teriflunomide treatment have shown that these regimens were effective in accelerating teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations, with cholestyramine being faster than charcoal. Following discontinuation of teriflunomide and the administration of cholestyramine 8 g three times a day, the plasma concentration of teriflunomide is reduced 52% at the end of day 1, 91% at the end of day 3, 99.2% at the end of day 7, and 99.9% at the completion of day 11. The choice between the 3 elimination procedures should depend on the patient’s tolerability. If cholestyramine 8 g three times a day is not well-tolerated, cholestyramine 4 g three times a day can be used. Alternatively, activated charcoal may also be used (the 11 days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly).
Systemic exposure increases in a dose proportional manner after oral administration teriflunomide from 7 to 14 mg.
Several sources of intrinsic variability were identified in healthy subjects and MS patients based on the PopPK analysis: age, body weight, gender, race, and albumin and bilirubin levels. Nevertheless, their impact remains limited (≤31%).
Mild and moderate hepatic impairment had no impact on the pharmacokinetic of teriflunomide. Therefore no dose adjustment is anticipated in mild and moderate hepatic-impaired patients. However, teriflunomide is contraindicated in patients with severe hepatic impairment.
Severe renal impairment had no impact on the pharmacokinetic of teriflunomide. Therefore no dose adjustment is anticipated in mild, moderate and severe renal-impaired patients.
In paediatric patients with body weight >40 kg treated with 14 mg once daily, steady state exposures were in the range observed in adult patients treated with the same dosing regimen.
In paediatric patients with body weight ≤40 kg treatment with 7 mg once daily (based on limited clinical data and simulations) led to steady state exposures in the range observed in adult patients treated with 14 mg once daily.
Observed steady state trough concentrations were highly variable between individuals, as observed for adult MS patients.
Repeated oral administration of teriflunomide to mice, rats and dogs for up to 3, 6, and 12 months, respectively, revealed that the major targets of toxicity were the bone marrow, lymphoid organs, oral cavity/gastro intestinal tract, reproductive organs, and pancreas. Evidence of an oxidative effect on red blood cells was also observed. Anaemia, decreased platelet counts and effects on the immune system, including leukopenia, lymphopenia and secondary infections, were related to the effects on the bone marrow and/or lymphoid organs. The majority of effects reflect the basic mode of action of the compound (inhibition of dividing cells). Animals are more sensitive to the pharmacology, and therefore toxicity, of teriflunomide than humans. As a result, toxicity in animals was found at exposures equivalent or below human therapeutic levels.
Teriflunomide was not mutagenic in vitro or clastogenic in vivo. Clastogenicity observed in vitro was considered to be an indirect effect related to nucleotide pool imbalance resulting from the pharmacology of DHO-DH inhibition. The minor metabolite TFMA (4-trifluoromethylaniline) caused mutagenicity and clastogenicity in vitro but not in vivo.
No evidence of carcinogenicity was observed in rats and mice.
Fertility was unaffected in rats despite adverse effects of teriflunomide on male reproductive organs, including reduced sperm count. There were no external malformations in the offspring of male rats administered teriflunomide prior to mating with untreated female rats. Teriflunomide was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic range. Adverse effects on the offspring were also seen when teriflunomide was administered to pregnant rats during gestation and lactation. The risk of male-mediated embryo-foetal toxicity through teriflunomide treatment is considered low. The estimated female plasma exposure via the semen of a treated patient is expected to be 100 times lower than the plasma exposure after 14 mg of oral teriflunomide.
Juvenile rats receiving oral teriflunomide for 7 weeks from weaning through sexual maturity revealed no adverse effects on growth, physical or neurological development, learning and memory, locomotor activity, sexual development, or fertility. Adverse effects comprised anaemia, reduction of lymphoid responsiveness, dose-dependently diminished T cell dependent antibody response and greatly decreased IgM and IgG concentrations, which generally coincided with observations in repeat-dose toxicity studies in adult rats. However, the increase in B cells observed in juvenile rats was not observed in adult rats. The significance of this difference is unknown, but complete reversibility was demonstrated as for most of the other findings. Due to the high sensitivity of animals to teriflunomide, juvenile rats were exposed to lower levels than those in children and adolescents at the maximum recommended human dose (MRHD).
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