Pharmacology: Mechanism of Action: Leflumine is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an 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, Leflumine is metabolized to an active metabolite A77 1726 (hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. Plasma levels of Leflumine are occasionally seen at very low levels.
Absorption: Following oral administration, peak levels of the active metabolite, M1, occurred between 6-12 hrs after dosing. Due to the very long half-life of M1 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly 2 months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional.
Relative to an oral solution, Leflumine tablets are 80% bioavailable. Co-administration of Leflumine tablets with a high-fat meal did not have a significant impact on M1 plasma levels.
Distribution: M1 has a low volume of distribution (Vss= 0.13 L/kg) and is extensively bound (>99.3%) to albumin in healthy subjects. Protein-binding has been shown to be linear at therapeutic concentrations. The free fraction of M1 is slightly higher in patients with rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown.
Metabolism: Leflumine is metabolized to 1 primary (M1) and many minor metabolites. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occuring at low levels in the plasma of some patients. The parent compound is rarely detectable in plasma. At the present time, the specific site of Leflumine metabolism is unknown. In vivo and in vitro studies suggest a role for both the gastrointestinal wall and the liver in the drug metabolism. No specific enzyme has been identified as the primary route of metabolism of Leflumine; however, hepatic cytosolic acid and microsomal cellular fractions have been identified as sites of drug metabolism.
Elimination: The active metabolite M1 is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28-day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces.
Special Populations: Age and Gender: Neither age nor gender has been shown to cause a consistent change in the in vivo pharmacokinetics of M1.
Smoking: A population-based pharmacokinetic analysis of the phase III data indicated that smokers had a 38% increase in clearance over nonsmokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.
Chronic Renal Impairment: In single-dose studies in patients (n=6) with chronic renal insufficiency requiring either chronic ambulatory peritoneal dialysis (CAPD) or hemodialysis, neither had a significant impact on circulating levels of M1. The free fraction of M1 was almost doubled, but the mechanism of this increase is not known. In light of the fact that the kidney plays a role in drug elimination and without adequate studies of Leflumine use in subjects with renal insufficiency, caution should be used when Leflumine is administered to these patients.
Hepatic Impairment: Studies of the effects of hepatic impairment on M1 pharmacokinetics have not been done. Given the need to metabolized Leflumine into the active species, the role of the liver in drug elimination/recycling and the possible risk of increased hepatic toxicity, the use of Leflumine in patients with hepatic insufficiency is not recommended.
Take Leflumine exactly as prescribed by your doctor. Before you start treatment with Leflumine, 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.
Leflumine 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 Leflumine, you may need to be treated with other medicines to help your body eliminate Leflumine quickly. If you do not undergo this drug elimination procedure, Leflumine 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 Leflumine.
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.
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 Leflumine, 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.
Leflumine 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 Leflumine, you may need to be treated with other medications to help your body eliminate Leflumine quickly. Without receiving this drug elimination procedure, Leflumine 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.
Leflumine 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.
Following oral administration, Leflumine is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of Leflumine's in vivo activity. Plasma concentrations of the parent drug, Leflumine, have been occasionally seen at very low concentrations. Studies of the pharmacokinetics of Leflumine have primarily examined the plasma concentrations of the active metabolite, teriflunomide.
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 Leflumine tablets with a high fat meal did not have a significant impact on teriflunomide plasma concentrations.
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.
Teriflunomide, the active metabolite of Leflumine, 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.
In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19 and 3A4 are involved in Leflumine metabolism. In vivo, Leflumine 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.
Teriflunomide, the active metabolite of Leflumine, 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.
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 have been conducted with both Leflumine (Leflumine) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.
Following concomitant administration of a single dose of Leflumine to subjects receiving multiple doses of rifampin, teriflunomide peak concentrations were increased (~40%) over those seen when Leflumine was given alone
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.
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.
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.
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).
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.
The efficacy of Leflumine 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:
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 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 was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36).
In all Leflumine 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 Leflumine 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, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to Leflumine 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 Leflumine, 101 methotrexate, 36 placebo). Leflumine 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 Leflumine, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment.
Trial 2 randomized 358 patients with active RA to Leflumine 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 Leflumine 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 Leflumine, 60 sulfasalazine, 26 placebo/ sulfasalazine). Patients continued on the same daily dosage of Leflumine or sulfasalazine that they had been taking at the completion of Trial 2. A total of 121 patients (53 Leflumine, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment.
Trial 3 randomized 999 patients with active RA to Leflumine 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 Leflumine, 320 methotrexate). Patients continued on the same daily dosage of Leflumine or methotrexate that they had been taking at the completion of Trial 3. There were 533 patients (256 Leflumine, 277 methotrexate) who completed 2 years of double-blind treatment.
The ACR20 Responder at Endpoint rates are shown in Figure 1. Leflumine 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 Leflumine treatment were consistent across the 6 and 12 month studies (41 - 49%). No consistent differences were demonstrated between Leflumine and methotrexate or between Leflumine and sulfasalazine. Leflumine 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*
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. Leflumine 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, Leflumine 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*
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.
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Information checked by Dr. Sachin Kumar, MD Pharmacology