Actions of Leflunomid-Mepha 20mg in details
Leflunomid-Mepha 20mg is a prodrug that is rapidly and almost completely metabolized following oral administration to its pharmacologically active metabolite, A77 1726. This metabolite is responsible for essentially all of the drug's activity in-vivo. The mechanism of action of Leflunomid-Mepha 20mg has not been fully determined, but appears to primarily involve regulation of autoimmune lymphocytes. It has been suggested that Leflunomid-Mepha 20mg exerts its immunomodulating effects by preventing the expansion of activated autoimmune lymphocytes via interferences with cell cycle progression. In-vitro data indicates that Leflunomid-Mepha 20mg interferes with cell cycle progression by inhibiting dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine ribonucleotide uridine monophosphate (rUMP)synthesis) and has antiproliferative activity. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that Leflunomid-Mepha 20mg inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of Leflunomid-Mepha 20mg is cytostatic rather than cytotoxic. Other effects that result from reduced rUMP levels include interference with adhesion of activated lymphocytes to the synovial vascular endothelial cells, and increased synthesis of immunosuppressive cytokines such as transforming growth factor-β (TGF-β). Leflunomid-Mepha 20mg is also a tyrosine kinase inhibitor. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells.
How should I take Leflunomid-Mepha 20mg?
Take Leflunomid-Mepha 20mg exactly as prescribed by your doctor. Before you start treatment with Leflunomid-Mepha 20mg, your doctor may perform tests to make sure you do not have tuberculosis or other infections.
Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.
Your blood pressure will need to be checked often.
Leflunomid-Mepha 20mg can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your treatment may be stopped for a short time based on the results of these tests.
After you stop taking Leflunomid-Mepha 20mg, you may need to be treated with other medicines to help your body eliminate Leflunomid-Mepha 20mg quickly. If you do not undergo this drug elimination procedure, Leflunomid-Mepha 20mg could stay in your body for up to 2 years. Follow your doctor's instructions.
You will also need to go through this drug elimination procedure if you plan to become pregnant after you stop taking Leflunomid-Mepha 20mg.
Arthritis is often treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.
Store at room temperature away from moisture, heat, and light.
Leflunomid-Mepha 20mg administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Before you start taking Leflunomid-Mepha 20mg, you may need a skin test to make sure you do not have tuberculosis.
Your doctor may occasionally change your dose to make sure you get the best results.
Leflunomid-Mepha 20mg can lower blood cells that help your body fight infections. This can make it easier for you to get sick from being around others who are ill. To be sure your blood cells do not get too low, your blood will need to be tested often. Your liver function may also need to be tested. Visit your doctor regularly.
After you stop taking Leflunomid-Mepha 20mg, you may need to be treated with other medications to help your body eliminate Leflunomid-Mepha 20mg quickly. Without receiving this drug elimination procedure, Leflunomid-Mepha 20mg could stay in your body for up to 2 years. Follow your doctor's instructions.
Rheumatoid arthritis is often treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.
Store at room temperature away from moisture, heat, and light.
Leflunomid-Mepha 20mg pharmacology
Mechanism Of Action
Leflunomid-Mepha 20mg is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.
Pharmacokinetics
Following oral administration, Leflunomid-Mepha 20mg is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of Leflunomid-Mepha 20mg's in vivo activity. Plasma concentrations of the parent drug, Leflunomid-Mepha 20mg, have been occasionally seen at very low concentrations. Studies of the pharmacokinetics of Leflunomid-Mepha 20mg have primarily examined the plasma concentrations of the active metabolite, teriflunomide.
Absorption
Following oral administration, peak teriflunomide concentrations occurred between 6 - 12 hours after dosing. Due to the very long half-life of teriflunomide (18-19 days), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state teriflunomide concentrations. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require about two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that plasma teriflunomide concentrations are dose proportional.
Effect of Food
Co-administration of Leflunomid-Mepha 20mg tablets with a high fat meal did not have a significant impact on teriflunomide plasma concentrations.
Distribution
Teriflunomide is extensively bound to plasma protein ( > 99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration.
Elimination
Teriflunomide, the active metabolite of Leflunomid-Mepha 20mg, has a median half-life of 18-19 days in healthy volunteers. The elimination of teriflunomide can be accelerated by administration of cholestyramine or activated charcoal. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations of less than 0.02 mg/L, due to individual variation in drug clearance. After a single IV administration of the metabolite (teriflunomide), the total body clearance of teriflunomide was 30.5 mL/h.
Metabolism
In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19 and 3A4 are involved in Leflunomid-Mepha 20mg metabolism. In vivo, Leflunomid-Mepha 20mg is metabolized to one primary (teriflunomide) and many minor metabolites. In vitro, teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase enzymes. The parent compound is rarely detectable in plasma.
Excretion
Teriflunomide, the active metabolite of Leflunomid-Mepha 20mg, is eliminated by direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces).
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide is not dialyzable.
Specific Populations
Gender. Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of teriflunomide.
Smoking. A population based pharmacokinetic analysis of the clinical trial data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.
Drug Interaction Studies
Drug interaction studies have been conducted with both Leflunomid-Mepha 20mg (Leflunomid-Mepha 20mg) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.
The Potential Effect of Other Drugs on Leflunomid-Mepha 20mg
- Potent CYP and transporter inducers:
Following concomitant administration of a single dose of Leflunomid-Mepha 20mg to subjects receiving multiple doses of rifampin, teriflunomide peak concentrations were increased (~40%) over those seen when Leflunomid-Mepha 20mg was given alone
- An in vivo interaction study with Leflunomid-Mepha 20mg and cimetidine (non-specific weak CYP inhibitor) has demonstrated a lack of a significant impact on teriflunomide exposure.
The Potential Effect of Leflunomid-Mepha 20mg on Other Drugs
- CYP2C8 Substrates
There was an increase in mean repaglinide Cmax and AUC (1.7-and 2.4-fold, respectively), following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The magnitude of interaction could be higher at the recommended repaglinide dose.
- CYP1A2 Substrates
Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo.
- OAT3 Substrates
There was an increase in mean cefaclor Cmax and AUC (1.43-and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter 3 (OAT3) in vivo.
- BCRP and OATP1B1/1B3 Substrates
There was an increase in mean rosuvastatin Cmax and AUC (2.65-and 2.51-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3).
Oral Contraceptives
There was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58-and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0-24 (1.33-and 1.41-fold, respectively) following repeated doses of teriflunomide.
- Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate), and metoprolol (a CYP2D6 substrate).
Clinical Studies
The efficacy of Leflunomid-Mepha 20mg in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms, and inhibition of structural damage. In two placebo controlled trials, efficacy was demonstrated for improvement in physical function. In these trials, efficacy was evaluated by:
Reduction of Signs And Symptoms
Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR) 20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An “ACR20 Responder” is a patient who had ≥ 20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure [Modified Health Assessment Questionnaire (MHAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An “ACR20 Responder at Endpoint” is a patient who completed the study and was an ACR20 Responder at the completion of the study.
Inhibition of Structural Damage
Inhibition of structural damage compared to control was assessed using the Sharp Score, a composite score of X-ray erosions and joint space narrowing in hands/wrists and forefeet.
Improvement In Physical Function
Improvement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36).
In all Leflunomid-Mepha 20mg trials, participants of at least 18 years of age and in ARA functional class of I, II or III received an initial loading dosage of 100 mg Leflunomid-Mepha 20mg per day for three days, followed by 20 mg per day thereafter.
Exclusion criteria included patients with a history of hypersensitivity to the study medication; women who were pregnant or breast feeding and men or women of child bearing age and potential who had not received contraceptives for at least 4 weeks before entering the study and to be maintained throughout the study and for at least 6 months after discontinuing treatment; Patients with a history of inflammatory disease, impaired renal function or liver impairment, cardiac failure, congenital or acquired immunodeficiency, impaired coagulation, or a history of recent major traumatic injury; patients taking intra-articular or systemic concomitant medications which could affect the safety and/or efficacy of the study medication.
Trial 1
Trial 1, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to Leflunomid-Mepha 20mg 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg BID. The primary analysis was at 52 weeks with blinded treatment to 104 weeks.
Overall, 235 of the 508 randomized treated patients (482 in primary data analysis and an additional 26 patients), continued into a second 12 months of double-blind treatment (98 Leflunomid-Mepha 20mg, 101 methotrexate, 36 placebo). Leflunomid-Mepha 20mg dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. In total, 190 patients (83 Leflunomid-Mepha 20mg, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment.
Trial 2
Trial 2 randomized 358 patients with active RA to Leflunomid-Mepha 20mg 20 mg/day (n=133), sulfasalazine 2.0 g/day (n=133), or placebo (n=92). Treatment duration was 24 weeks. An extension of the study was an optional 6-month blinded continuation of Trial 2 without the placebo arm, resulting in a 12-month comparison of Leflunomid-Mepha 20mg and sulfasalazine.
Of the 168 patients who completed 12 months of treatment, 146 patients (87%) entered a 1-year extension study of double blind active treatment; (60 Leflunomid-Mepha 20mg, 60 sulfasalazine, 26 placebo/ sulfasalazine). Patients continued on the same daily dosage of Leflunomid-Mepha 20mg or sulfasalazine that they had been taking at the completion of Trial 2. A total of 121 patients (53 Leflunomid-Mepha 20mg, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment.
Trial 3
Trial 3 randomized 999 patients with active RA to Leflunomid-Mepha 20mg 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was used in 10% of patients. Treatment duration was 52 weeks.
Of the 736 patients who completed 52 weeks of treatment in study Trial 3, 612 (83%) entered the double-blind, 1-year extension study (292 Leflunomid-Mepha 20mg, 320 methotrexate). Patients continued on the same daily dosage of Leflunomid-Mepha 20mg or methotrexate that they had been taking at the completion of Trial 3. There were 533 patients (256 Leflunomid-Mepha 20mg, 277 methotrexate) who completed 2 years of double-blind treatment.
Clinical Trial Results
Clinical Response
The ACR20 Responder at Endpoint rates are shown in Figure 1. Leflunomid-Mepha 20mg was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study Trial 1 (at the primary 12 months endpoint) and Trial 2 (at 6 month endpoint). ACR20 Responder at Endpoint rates with Leflunomid-Mepha 20mg treatment were consistent across the 6 and 12 month studies (41 - 49%). No consistent differences were demonstrated between Leflunomid-Mepha 20mg and methotrexate or between Leflunomid-Mepha 20mg and sulfasalazine. Leflunomid-Mepha 20mg treatment effect was evident by 1 month, stabilized by 3 - 6 months, and continued throughout the course of treatment as shown in Figure 1.
Figure 1: Percentage of ACR20 Responders at Endpoint in Patients with Active RA in Trials 1, 2, and 3
Figure 2: ACR20 Responders over Time in Patients with Active RA in Trial 1*
ACR50 and ACR70 Responders are defined in an analogous manner to the ACR 20 Responder, but use improvements of 50% or 70%, respectively (Table 3). Mean change for the individual components of the ACR Responder Index are shown in Table 4.
Table 3: Summary of ACR Response Rates in Patients with Active RA in Trials 1,2, and 3*
Physical Function Response
The Health Assessment Questionnaire (HAQ) assesses a patient's physical function and degree of disability. The mean change from baseline in functional ability as measured by the HAQ Disability Index (HAQ DI) in the 6 and 12 month placebo and active controlled trials is shown in Figure 4. Leflunomid-Mepha 20mg was statistically significantly superior to placebo in improving physical function. Superiority to placebo was demonstrated consistently across all eight HAQ DI subscales (dressing, arising, eating, walking, hygiene, reach, grip and activities) in both placebo controlled studies.
The Medical Outcomes Survey Short Form 36 (SF-36), a generic health-related quality of life questionnaire, further addresses physical function. In Trial 1, at 12 months, Leflunomid-Mepha 20mg provided statistically significant improvements compared to placebo in the Physical Component Summary (PCS) Score.
Figure 4: Change in Functional Ability Measure in Patients with Active RA in Trials 1, 2, and 3*
Maintenance of effect
The improvement in physical function demonstrated at 6 and 12 months was maintained over two years. In those patients continuing therapy for a second year, this improvement in physical function as measured by HAQ and SF-36 (PCS) was maintained.
References
- DailyMed. "LEFLUNOMIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Leflunomide: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Leflunomide: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
