Teriflunomide is the active metabolite of Leflunomide, a drug employed since 1994 for the treatment of rheumatoid arthritis (Baselt, 2011).

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1 Page 1 of 10 ANALYTE NAME AND STRUCTURE TERIFLUNOMIDE Teriflunomide TRADE NAME Aubagio CATEGORY Antimetabolite TEST CODE PURPOSE Therapeutic Drug Monitoring GENERAL RELEVANCY BACKGROUND sclerosis. The recommended dose is 7 mg or 14 mg once per day. The drug was approved by the Food and Drug Administration (FDA) in September The FDA approval was based on efficacy data from the Teriflunomide Multiple Sclerosis Oral (TEMSO) trial. Teriflunomide is the active metabolite of Leflunomide, a drug employed since 1994 for the treatment of rheumatoid arthritis (Baselt, 2011). An accelerated elimination protocol for teriflunomide is recommended for those individuals discontinuing the drug because it takes an average of 8 months, and in some cases as long as 2 years, to achieve plasma concentrations of <0.02 mcg/ml. This is

2 Page 2 of 10 especially relevant for women who desire to become pregnant or who may suspect pregnancy while using the drug. Effective elimination of teriflunomide should be confirmed with plasma concentration measurements (Aubagio Prescribing Information). MECHANISM OF ACTION Teriflunomide inhibits a mitochondrial enzyme, dihydroorotate dehydrogenase, which is involved in de novo pyrimidine synthesis. This inhibition interferes with DNA synthesis, particularly in rapidly dividing cells such as lymphocytes. Reduced lymphocyte activation may lead to the observed immunosuppression and reduced inflammation (Aubagio Prescribing Information). ADVERSE EFFECTS Teriflunomide carries a black box warning for hepatotoxicity and teratogenicity. This warning reads as follows: WARNING: HEPATOTOXICITY AND RISK OF TERATOGENICITY Hepatotoxicity Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Concomitant use of AUBAGIO with other potentially hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)]. If drug induced liver injury is suspected, discontinue AUBAGIO and start an accelerated elimination procedure with cholestyramine or charcoal [see Warnings and Precautions (5.3)]. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1)]. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Risk of Teratogenicity Based on animal data, AUBAGIO may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment or prior to the completion of an accelerated elimination procedure after AUBAGIO

3 Page 3 of 10 treatment [see Contraindications (4.2), Warnings and Precautions (5.2), and Use in Specific Populations (8.1)]. The most common short-term adverse effects are abnormal liver function, alopecia, diarrhea, influenza, nausea, and paresthesias. Liver function abnormalities are seen in up to 5% of treated patients, usually within the first year of treatment, and are generally mild and reversible with discontinuation of therapy. 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 (Aubagio Prescribing Information). Based on a population analysis of teriflunomide in healthy volunteers and MS patients, median t 1/2 was approximately 18 and 19 days after repeated doses of 7 mg and 14 mg, respectively (Aubagio Prescribing Information). The half-life range has been reported to be between 4-28 days and the blood to plasma ratio is 0.5 to 0.7. (Baselt, 2011). It takes approximately 3 months to reach steady-state concentrations. The estimated AUC accumulation ratio is approximately 30 after repeated doses of 7 or 14 mg (Aubagio Prescribing Information). The following information is from the Aubagio Prescribing Information: Absorption Median time to reach maximum plasma concentrations is between 1 to 4 hours postdose following oral administration of teriflunomide. Food does not have a clinically relevant effect on teriflunomide pharmacokinetics. Distribution

4 Page 4 of 10 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. TECHNICAL CONSIDERATIONS ANALYTES TO BE DETERMINED Teriflunomide PROPER SPECIMEN TYPES Serum/Plasma, Blood and Urine RECOMMENDED COLLECTION TUBES Whole blood Lavender top tube (EDTA) Serum/Plasma Plastic container (preservative-free) Serum: Collect sample in Red top tube

5 Page 5 of 10 Plasma: Collect sample in Lavender top tube (EDTA) or Pink top tube. Promptly centrifuge and separate Serum or Plasma into a plastic screw capped vial using approved guidelines. Urine Plastic container (preservative free) CALIBRATION RANGE LLOQ: mcg/ml Even though therapeutic levels are expected to be much greater (up to ~65 mcg/ml), the LLOQ needs to be this sensitive to appropriately monitor patients undergoing the drug discontinuation process. MAXIMUM ACCEPTABLE ERROR The interpretation of concentrations in biological specimens is facilitated by analytical methods with <20% total error. INTERFERING SUBSTANCES Leflunomide REFERENCE COMMENTS CLINICAL B: sclerosis. The half-life range has been reported to range between 4-28 days. It takes approximately 3 months to reach steady-state concentrations. Teriflunomide is also the active metabolite of leflunomide, a drug used in the treatment of rheumatoid arthritis. Recommended doses of teriflunomide and leflunomide result in a similar range of teriflunomide plasma concentrations. Based on this, the expected therapeutic range is

6 Page 6 of 10 between 18 mcg/ml and 63 mcg/ml. Plasma concentrations less than 0.02 mcg/l are expected to have minimal risk. The blood to plasma ratio is 0.5 to 0.7. The drug carries a black box warning for hepatotoxicity and teratogenicity. SP: sclerosis. The half-life range has been reported to range between 4-28 days. It takes approximately 3 months to reach steady-state concentrations. Teriflunomide is also the active metabolite of leflunomide, a drug used in the treatment of rheumatoid arthritis. Recommended doses of teriflunomide and leflunomide result in a similar range of teriflunomide plasma concentrations. Based on this, the expected therapeutic range is between 18 mcg/ml and 63 mcg/ml. Plasma concentrations less than 0.02 mcg/l are expected to have minimal risk. The drug carries a black box warning for hepatotoxicity and teratogenicity. U: sclerosis. Teriflunomide is also the active metabolite of leflunomide, a drug used in the treatment of rheumatoid arthritis. A single oral labeled leflunomide dose is eliminated in urine as teriflunomide over a 28 day interval. FORENSIC B: sclerosis. The recommended dose is 7 mg or 14 mg once per day. The half-life range has been reported to range between 4-28 days. It takes approximately 3 months to reach

7 Page 7 of 10 steady-state concentrations. Teriflunomide is also the active metabolite of leflunomide, a drug used in the treatment of rheumatoid arthritis. Recommended doses of teriflunomide and leflunomide result in a similar range of teriflunomide plasma concentrations. Based on this, the expected therapeutic range is between 18 mcg/ml and 63 mcg/ml. Plasma concentrations less than 0.02 mcg/l are expected to have minimal risk. The blood to plasma ratio is 0.5 to 0.7. Effective elimination of teriflunomide should be confirmed with plasma concentration measurements. The drug carries a black box warning for hepatotoxicity and teratogenicity. The most common short-term adverse effects are abnormal liver function, alopecia, diarrhea, influenza, nausea, and paresthesias. SP: sclerosis. The recommended dose is 7 mg or 14 mg once per day. The half-life range has been reported to range between 4-28 days. It takes approximately 3 months to reach steady-state concentrations. Teriflunomide is also the active metabolite of leflunomide, a drug used in the treatment of rheumatoid arthritis. Recommended doses of teriflunomide and leflunomide result in a similar range of teriflunomide plasma concentrations. Based on this, the expected therapeutic range is between 18 mcg/ml and 63 mcg/ml. Plasma concentrations less than 0.02 mcg/l are expected to have minimal risk. Effective elimination of teriflunomide should be confirmed with plasma concentration measurements. The drug carries a black box warning for hepatotoxicity and teratogenicity. The most common short-term adverse effects are abnormal liver function, alopecia, diarrhea, influenza, nausea, and paresthesias.

8 Page 8 of 10 U: sclerosis. Teriflunomide is also the active metabolite of leflunomide, a drug used in the treatment of rheumatoid arthritis. A single oral labeled leflunomide dose is eliminated in urine as teriflunomide over a 28 day interval.

9 Page 9 of 10 REFERENCES 1. Baselt RC. Disposition of Toxic Drugs and Chemicals in Man. 9 th Edition. Leflunomide Monograph; pages Moffat AC, Osselton MD and Widdop B. Clarke s Analysis of Drugs and Poisons. 3 rd Edition. Leflunomide Monograph; pages Aubagio Prescribing Information.

10 Page 10 of 10 SIGNATURES: Specification Prepared By: Laura M. Labay, Ph.D., DABFT, DABCC-TC December 13, 2012