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Aubagio

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Aubagio

CLINICAL PHARMACOLOGY

Mechanism Of Action

Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is unknown but may involve a reduction in the number of activated lymphocytes in CNS.

Pharmacodynamics

Potential to Prolong the QT Interval

In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence that teriflunomide caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).

Pharmacokinetics

Teriflunomide is the principal active metabolite of leflunomide and is responsible for leflunomide's activity in vivo. At recommended doses, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.

Based on a population analysis of teriflunomide in healthy volunteers and MS patients, median t½ was approximately 18 and 19 days after repeated doses of 7 mg and 14 mg respectively. It takes approximately 3 months respectively to reach steady-state concentrations. The estimated AUC accumulation ratio is approximately 30 after repeated doses of 7 or 14 mg.

Absorption

Median time to reach maximum plasma concentrations is between 1 to 4 hours post-dose following oral administration of teriflunomide.

Food does not have a clinically relevant effect on teriflunomide pharmacokinetics.

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.

Metabolism

Teriflunomide is the major circulating moiety detected in plasma. The primary biotransformation pathway to minor metabolites of teriflunomide is hydrolysis, with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.

Elimination

Teriflunomide is eliminated mainly through 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). After a single IV administration, the total body clearance of teriflunomide is 30.5 mL/h.

Drug Interaction Studies

Teriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes.

The Potential Effect of AUBAGIO on Other Drugs
  • CYP2C8 Substrates
    There was an increase in mean repaglinide C max 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 [see DRUG INTERACTIONS].
  • CYP1A2 Substrates
    Repeated doses of teriflunomide decreased mean C max 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 [see DRUG INTERACTIONS].
  • 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) [see DRUG INTERACTIONS].
  • Oral Contraceptives
    There was an increase in mean ethinylestradiol C max and AUC 0-24 (1.58-and 1.54-fold, respectively) and levonorgestrel C max and AUC 0-24 (1.33-and 1.41-fold, respectively) following repeated doses of teriflunomide [see DRUG INTERACTIONS].
  • 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).
The Potential Effect of Other Drugs on AUBAGIO
  • Potent CYP and transporter inducers: Rifampin did not affect the pharmacokinetics of teriflunomide.

Specific Populations

  • Hepatic Impairment
    Mild and moderate hepatic impairment had no impact on the pharmacokinetics of teriflunomide. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Use In Specific Populations].
  • Renal Impairment
    Severe renal impairment had no impact on the pharmacokinetics of teriflunomide [see Use In Specific Populations].
  • Gender
    In a population analysis, the clearance rate for teriflunomide is 23% less in females than in males.
  • Race
    Effect of race on the pharmacokinetics of teriflunomide cannot be adequately assessed due to a low number of non-white patients in the clinical trials.

Clinical Studies

Four randomized, controlled, double-blind clinical trials established the efficacy of AUBAGIO in patients with relapsing forms of multiple sclerosis.

Study 1 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 26 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course, with or without progression, and to have experienced at least one relapse over the year preceding the trial or at least two relapses over the two years preceding the trial. Patients were required not to have received interferon-beta for at least four months, or any other multiple sclerosis medication for at least six months before entering the study, nor were these medications permitted during the study. Neurological evaluations were to be performed at screening, every 12 weeks until week 108, and after suspected relapses. MRI was to be performed at screening, and at Week 24, 48, 72, and 108. The primary endpoint was the annualized relapse rate (ARR).

In Study 1, 1088 patients were randomized to receive AUBAGIO 7 mg (n=366), AUBAGIO 14 mg (n=359), or placebo (n=363). At entry, patients had an Expanded Disability Status Scale (EDSS) score ≤ 5.5. Patients had a mean age of 38 years, mean disease duration of 5 years, and mean EDSS at baseline of 2.7. A total of 91% of patients had relapsing remitting multiple sclerosis, and 9% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 635, 627, and 631 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 75%, 73%, and 71% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively.

There was a statistically significant reduction in ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg, compared to patients who received placebo (see Table 2). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.

There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS ≤ 5.5 or a 0.5 point increase for those with a baseline EDSS > 5.5) in the AUBAGIO 14 mg group compared to placebo (see Table 2 and Figure 1).

The effect of AUBAGIO on several magnetic resonance imaging (MRI) variables including the total lesion volume of T2 and hypointense T1 lesions, was assessed in Study 1. The change in total lesion volume from baseline was significantly lower in the AUBAGIO 7 mg and AUBAGIO 14 mg groups than in the placebo group. Patients in both AUBAGIO groups had significantly fewer gadolinium-enhancing lesions per T1-weighted scan than those in the placebo group (see Table 2).

Table 2: Clinical and MRI Results of Study 1

  AUBAGIO 7 mg
N=365
AUBAGIO 14 mg
N=358
Placebo
N=363
Clinical Endpoints
Annualized relapse rate 0.370 (p = 0.0002) 0.369 (p = 0.0005) 0.539
  Relative risk reduction 31% 31%  
Percent of patients remaining relapse-free at week 108 53.7% 56.5% 45.6%
Percent disability progression at week 108 21.7% (p = 0.084) 20.2% (p = 0.028) 27.3%
  Hazard ratio 0.76 0.70  
MRI Endpoints
Median change from baseline in Total lesion volume1 (mL) at week 108 0.755 (p= 0.0317 )2 0.345 (p = 0.0003 )2 1.127
Mean number of Gd-enhancing T1-lesions per scan 0.570 (p < 0.0001) 0.261 (p < 0.0001) 1.331
1 Total lesion volume: sum of T2 and hypointense T1 lesion volume in mL
2 p-values based on cubic root transformed data for total lesion volume

Figure 1: Kaplan-Meier plot of time to disability progression sustained for 12 weeks (Study 1)

Kaplan-Meier plot of time to disability progression sustained for 12 weeks - Illustration

Study 2 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 40 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course and to have experienced at least one relapse over the year preceding the trial, or at least two relapses over the two years preceding the trial. Patients were required not to have received any multiple sclerosis medication for at least three months before entering the trial, nor were these medications permitted during the trial. Neurological evaluations were to be performed at screening, every 12 weeks until completion, and after every suspected relapse. The primary end point was the ARR.

A total of 1165 patients received AUBAGIO 7 mg (n=407), AUBAGIO 14 mg (n=370), or placebo (n=388). Patients had a mean age of 38 years, a mean disease duration of 5 years, and a mean EDSS at baseline of 2.7. A total of 98% of patients had relapsing remitting multiple sclerosis, and 2% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 552, 567, and 571 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 67%, 66%, and 68% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively.

There was a statistically significant reduction in the ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg compared to patients who received placebo (see Table 3). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.

There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS ≤ 5.5 or a 0.5 point increase for those with a baseline EDSS > 5.5) in the AUBAGIO 14 mg group compared to placebo (See Table 3 and Figure 2).

Table 3: Clinical Results of Study 2

  AUBAGIO 7 mg
N=407
AUBAGIO 14 mg
N=370
Placebo
N=388
Clinical Endpoints
Annualized relapse rate 0.389 (p = 0.0183) 0.319 (p = 0.0001) 0.501
  Relative risk reduction 22% 36%  
Percent of patients remaining relapse- 58.2% 57.1% 46.8%
free at week 108  
Percent disability progression at week 108 21.1% (p = 0.762) 15.8% (p = 0.044) 19.7%
  Hazard ratio 0.96 0.69  

Figure 2: Kaplan-Meier plot of time to disability progression sustained for 12 weeks (Study 2)

Kaplan-Meier plot of time to disability progression sustained for 12 weeks (Study 2) - Illustration

Study 3 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 108 weeks in patients with relapsing multiple sclerosis. Patients were required to have had a first clinical event consistent with acute demyelination occurring within 90 days of randomization with 2 or more T2 lesions at least 3 mm in diameter that were characteristic of multiple sclerosis. A total of 614 patients received AUBAGIO 7 mg (n=203), AUBAGIO 14 mg (n=214), or placebo (n=197). Patients had a mean age of 32 years, EDSS at baseline of 1.7, and mean disease duration of two months. The proportion of patients free of relapse was greater in the AUBAGIO 7 mg (70.5%, p < 0.05) and AUBAGIO 14 mg (72.2%, p < 0.05) groups than in the placebo group (61.7%).

The effect of AUBAGIO on MRI activity was also demonstrated in Study 4, a randomized, double-blind, placebo-controlled clinical trial of multiple sclerosis patients with relapse. In Study 4, MRI was to be performed at baseline, 6 weeks, 12 weeks, 18 weeks, 24 weeks, 30 weeks, and 36 weeks after treatment initiation. A total of 179 patients were randomized to AUBAGIO 7 mg (n=61), AUBAGIO 14 mg (n=57), or placebo (n= 61). Baseline demographics were consistent across treatment groups. The primary endpoint was the average number of unique active lesions/MRI scan during treatment. The mean number of unique active lesions per brain MRI scan during the 36-week treatment period was lower in patients treated with AUBAGIO 7 mg (1.06) and AUBAGIO 14 mg (0.98) as compared to placebo (2.69), the difference being statistically significant for both (p=0.0234 and p=0.0052, respectively).

Last reviewed on RxList: 11/3/2014
This monograph has been modified to include the generic and brand name in many instances.

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