Contributions
Abstract: EP1420
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Background: Teriflunomide is a once-daily oral immunomodulator for treatment of relapsing-remitting MS. The primary mechanism of action involves selective, reversible, noncompetitive inhibition of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme required for de novo pyrimidine synthesis. In animal studies, teriflunomide is found to be embryo-toxic and teratogenic and thus is contraindicated in human pregnancy. Animals are generally more sensitive to the effects of teriflunomide than humans; thus, it is not unexpected that to date, no teratogenic signal has been observed in humans.
Objectives: To determine critical intervals of rat embryo-foetal development susceptible to teriflunomide and to further correlate nonclinical species" pharmacological differences with clinical pregnancy outcomes.
Methods: Groups of pregnant rats received oral teriflunomide (10 mg/kg/d, plasma concentration below the human therapeutic dose) for either a 12-day dosing interval (covering the major period of organogenesis, gestation days [GD] 6-17) or 1 of 4 consecutive 3-day intervals that spanned the 12-day period (GD 6-8, 9-11, 12-14, 15-17). Foetal examinations were performed on GD 21. Human foetal exposure data came from the teriflunomide clinical programme. Enzyme kinetics were determined in human and rat cells.
Results: Abnormal embryo-foetal development, including lethality, occurred in rats at all dosing intervals, showing that teriflunomide produced adverse effects regardless of when exposure occurred. In a clinical development program, no signal of teratogenicity was reported with teriflunomide (83 pregnancies with 31 live births, 37 induced abortions, 14 spontaneous abortions, and 1 pregnancy with an unknown outcome). A higher binding affinity of teriflunomide was observed for rat DHODH (Ki: 25.8 nM) versus human DHODH (Ki: 1050 nM). Inhibition of rat DHODH (IC50: 18 nM) was more pronounced than human DHODH
(IC50: 773 nM). Antiproliferative activity of teriflunomide was 145 times greater in rats than in humans.
Conclusions: This study emphasizes the unique susceptibility of rats to teriflunomide-induced embryo-foetal toxicity. Differences in enzyme kinetics may be responsible for species" differences in teriflunomide pharmacology, with animals being more sensitive to teriflunomide than humans. Differences in enzyme kinetics may also help explain the embryo-foetal toxicity observed in rats but not in humans at similar exposures based on currently available data.
Disclosure: Study supported by Sanofi Genzyme.
LD: Employee of Sanofi.
BB: Employee of Sanofi.
PT: Employee of Sanofi Genzyme, with ownership interest.
MM: Employee of Sanofi Genzyme.
Abstract: EP1420
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Background: Teriflunomide is a once-daily oral immunomodulator for treatment of relapsing-remitting MS. The primary mechanism of action involves selective, reversible, noncompetitive inhibition of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme required for de novo pyrimidine synthesis. In animal studies, teriflunomide is found to be embryo-toxic and teratogenic and thus is contraindicated in human pregnancy. Animals are generally more sensitive to the effects of teriflunomide than humans; thus, it is not unexpected that to date, no teratogenic signal has been observed in humans.
Objectives: To determine critical intervals of rat embryo-foetal development susceptible to teriflunomide and to further correlate nonclinical species" pharmacological differences with clinical pregnancy outcomes.
Methods: Groups of pregnant rats received oral teriflunomide (10 mg/kg/d, plasma concentration below the human therapeutic dose) for either a 12-day dosing interval (covering the major period of organogenesis, gestation days [GD] 6-17) or 1 of 4 consecutive 3-day intervals that spanned the 12-day period (GD 6-8, 9-11, 12-14, 15-17). Foetal examinations were performed on GD 21. Human foetal exposure data came from the teriflunomide clinical programme. Enzyme kinetics were determined in human and rat cells.
Results: Abnormal embryo-foetal development, including lethality, occurred in rats at all dosing intervals, showing that teriflunomide produced adverse effects regardless of when exposure occurred. In a clinical development program, no signal of teratogenicity was reported with teriflunomide (83 pregnancies with 31 live births, 37 induced abortions, 14 spontaneous abortions, and 1 pregnancy with an unknown outcome). A higher binding affinity of teriflunomide was observed for rat DHODH (Ki: 25.8 nM) versus human DHODH (Ki: 1050 nM). Inhibition of rat DHODH (IC50: 18 nM) was more pronounced than human DHODH
(IC50: 773 nM). Antiproliferative activity of teriflunomide was 145 times greater in rats than in humans.
Conclusions: This study emphasizes the unique susceptibility of rats to teriflunomide-induced embryo-foetal toxicity. Differences in enzyme kinetics may be responsible for species" differences in teriflunomide pharmacology, with animals being more sensitive to teriflunomide than humans. Differences in enzyme kinetics may also help explain the embryo-foetal toxicity observed in rats but not in humans at similar exposures based on currently available data.
Disclosure: Study supported by Sanofi Genzyme.
LD: Employee of Sanofi.
BB: Employee of Sanofi.
PT: Employee of Sanofi Genzyme, with ownership interest.
MM: Employee of Sanofi Genzyme.