Teriflunomide, a once‐daily oral immunomodulator approved for the treatment of relapsing‐remitting
multiple sclerosis, demonstrated efficacy on clinical and magnetic resonance imaging
measures of disease activity and a consistent and manageable safety profile in clinical
trials.1, 2, 3, 4, 5 Teriflunomide is contraindicated in pregnancy because data from
animal studies (observed in rats and rabbits) suggest the potential for embryotoxic
and teratogenic effects5; however, to date, there has been no human signal of teratogenticity.6
Teriflunomide undergoes enterohepatic recycling in which it is excreted into bile
and transported to the small intestine, where it is reabsorbed.7, 8 Because the mean
elimination half‐life of teriflunomide is approximately 19 days, it may take an average
of 8 months (up to 2 years owing to individual variation in substance clearance) once
dosing is halted for plasma concentrations to decrease to <0.02 μg/mL, a concentration
expected to confer minimal embryo‐fetal risk to humans based on animal data.5
The following accelerated elimination procedure (AEP) is available for patients taking
teriflunomide who become pregnant or who are planning a pregnancy, or in any case
in which it is medically desirable to rapidly reduce the plasma concentrations of
teriflunomide5:
Cholestyramine 8 g 3 times daily for 11 days (or 4 g, if the 8‐g dose is not well
tolerated) or
Activated charcoal 50 g twice daily for 11 days.
Both cholestyramine and activated charcoal sequester teriflunomide within the lumen
of the small intestine and prevent reabsorption.8
Gastrointestinal disorders are the most frequently reported adverse events (AEs) associated
with the AEP; therefore, it is desirable to identify an alternative procedure that
will minimize these effects.9 Colesevelam hydrochloride (HCl), a bile acid sequestrant
indicated as an adjunct therapy for the treatment of primary hyperlipidemia,10 has
a 3‐fold higher capacity on a per‐gram basis than cholestyramine to lower cholesterol
and appears to have less frequent and less severe gastrointestinal AEs than cholestyramine9;
however, no direct comparisons have been made.
The primary objective of this study was to investigate whether colesevelam HCl was
able to accelerate elimination of teriflunomide. The secondary objectives were to
investigate the safety and tolerability of colesevelam HCl and to assess the pharmacokinetic
(PK) parameters of teriflunomide during the AEP.
Methods
Study Design
The study protocol was reviewed and approved by an independent ethics committee. Before
any study procedures, participants provided written informed consent after having
been informed of the procedure and possible hazards and risks of the study. The study
was an open‐label, phase 1, single‐center study in healthy men and women aged 18–45
years, conducted at Biotrial (Rennes, France) in accordance with the ethical principles
set forth in the Declaration of Helsinki and in compliance with local regulations.
Participants received teriflunomide (AUBAGIO, Sanofi Genzyme, Cambridge, Massachusetts)
70 mg per day for 5 days to allow the rapid approach to steady‐state concentrations,
which would normally take several weeks with the once‐daily 14‐mg dose of teriflunomide.
This was immediately followed on day 6 by an AEP with colesevelam HCl (Figure 1).
The dose of colesevelam HCl selected was based on the prescribing information.10 A
study‐specific requirement was the administration of all study medication with a meal:
Days 1–5: teriflunomide, five 14‐mg tablets once daily at approximately 8 am (70‐mg
total daily dose)
Days 6–16: colesevelam HCl, four 625‐mg tablets in the morning at approximately 8
am plus three 625‐mg tablets in the evening at approximately 8 pm (7 tablets per day;
4.375‐g total daily dose), which is the recommended maximum dose.
Figure 1
Study design. HCl, hydrochloride.
If at the end of the AEP (day 17) the plasma teriflunomide concentration was >0.02
μg/mL, participants were given cholestyramine 4 g 3 times daily (12‐g total daily
dose) to ensure plasma teriflunomide concentrations were ≤0.02 μg/mL at study completion.6
The lowest recommended dose of cholestyramine was used to reduce the risk of gastrointestinal
AEs.9
Pharmacokinetic Evaluations
Blood was sampled on days 1, 3, 6 (before the start of the AEP with colesevelam HCl),
7, 9, 13, and 17 (before the end of the AEP with colesevelam HCl) to determine teriflunomide
concentrations in plasma using validated liquid chromatography coupled with a tandem
mass spectrometry method, with a lower limit of quantification of ≤0.01 μg/mL. This
assay is highly selective for teriflunomide; no interference from other drugs was
expected. The method (performed by Eurofins Medinet, Breda, the Netherlands) was validated
for the quantitation of teriflunomide in 50 μL of human ethylenediaminetetraacetic
acid plasma following solid‐phase extraction (SPE), using deuterated (D4)‐teriflunomide
as the internal standard and a calibration curve range of 0.1 (lower limit of quantification)
to 10 μg/mL for teriflunomide. After the addition of methanol, an internal standard,
and a buffer solution (pH 4), samples were homogenized and then injected in activated
SPE Oasis 1‐mL HLb columns. A mixture of ammonia solution (2%), ultrapure water, and
methanol 20% in 2% acetic acid solution was used as the mobile phase. Teriflunomide
was eluted using methanol, transferred to vials, and injected on a Sciex API‐4000
mass spectrometer. Separation was performed on a Zorbax Eclipse XDB‐CB 3.5‐μm (4.6
× 50 mm) column with acetonitrile/water (50/50) containing 0.1% acetic acid used as
the mobile phase. Teriflunomide was monitored after positive electrospray ionization
at a mass‐to‐charge ratio of 269. Tested at different concentrations, the accuracy
was <11% of nominal values, the within‐run precision <9.1%, the between‐run precision
<7.4%, and the total precision <11%. There was no indication of any analytical interference
with the internal standard. The lower limit of quantification for the plasma assay
is below the threshold of 0.02 μg/mL, at which there is minimal risk of teratogenicity
in humans based on animal data.1
The percentage changes in teriflunomide concentrations for PK samples taken during
the AEP from the day 6 teriflunomide concentration (pre‐AEP) were summarized with
descriptive statistics, and the mean ± standard deviation (SD) half‐life during the
AEP was calculated using noncompartmental analysis (WinNonLin; Pharsight).
Safety Evaluations
Participants were monitored for AEs, standard clinical laboratory evaluations (biochemistry,
hematology, urinalysis, and coagulation), vital signs (heart rate and systolic and
diastolic blood pressure), oral body temperature, 12‐lead electrocardiogram (automatic
readings), physical examination, and body weight.
Results
Participants
A total of 18 participants were treated and completed the study. All participants
were white, with a mean ± SD age of 37.3 ± 6.1 years and a mean ± SD body mass index
of 24.0 ± 2.2 kg/m2; the majority were male (61%). The mean ± SD half‐life of teriflunomide
during the AEP was 54.6 ± 12.5 hours. All participants were included in PK and safety
evaluations.
Pharmacokinetics
On day 5, teriflunomide plasma concentrations reached a level that approximated the
measured steady state achieved after > 13 weeks of administration of teriflunomide
14 mg once daily in a clinical setting (Figure 2). On day 6 (start of the AEP) the
mean ± SD plasma teriflunomide concentration was 36.3 ± 6.4 μg/mL. The plasma concentration
was 1.3 ± 0.8 μg/mL on day 17 (end of the 11‐day AEP), corresponding to a mean decrease
of 96.1% (coefficient of variation, 3.5%; Figure 2A and Table 1). There was no significant
difference in the rate of teriflunomide elimination between men and women (data not
shown). A semilogarithmic plot of log concentration versus time was linear, demonstrating
first‐order elimination kinetics (Figure 2B). To ensure complete elimination of teriflunomide,
all 18 participants received cholestyramine: 16 participants received cholestyramine
for 11 days, 1 participant received cholestyramine for 10 days, and 1 participant
received cholestyramine for 12 days (up to a maximum of a 12‐g total daily dose).
All plasma concentrations were below the threshold of 0.02 μg/mL after administration
of cholestyramine.
Figure 2
Mean ± SD plasma concentration of teriflunomide (linear [A] and semilog [B] plots.)
HCl, hydrochloride; LLOQ, lower limit of quantification; SD, standard deviation.
Table 1
Percentage Change in Plasma Concentrations of Teriflunomide During AEP With Colesevelam
HCl
Duration of Colesevelam HCI Administration (Study Day)
Mean Percentage Decrease (CV%)
1 day (day 7)
21.8 (28.5)
3 days (day 9)
59.3 (13.6)
7 days (day 13)
87.9 (5.8)
11 days (day 17)
96.1 (3.5)
AEP, accelerated elimination procedure; CV, coefficient of variation; HCI, hydrochloride.
John Wiley & Sons, Ltd.
Safety
A total of 11 participants experienced at least 1 AE (Table 2), all of which were
mild or moderate in nature. The most frequently reported AEs were fatigue (4 participants
in the teriflunomide group and 1 participant following colesevelam HCl) and headache
(4 participants following colesevelam HCl and 1 participant following teriflunomide).
No serious AEs were reported, and no AEs led to discontinuation of study treatment.
There were no clinically relevant changes in the laboratory parameters assessed.
Table 2
Summary of AEs
Teriflunomide
Colesevelam HCl (After Teriflunomide)
Cholestyramine (After Colesevelam HCl)
All AEs,a n (%)
6 (33.3)
6 (33.3)
1 (5.6)
AEs by MedDRA preferred term,b n (%)
Nasopharyngitis
0
1 (5.6)
0
Syphilis
0
0
1 (5.6)
Headache
1 (5.6)
4 (22.2)
0
Constipation
1 (5.6)
1 (5.6)
0
Diarrhea
1 (5.6)
1 (5.6)
0
Flatulence
1 (5.6)
0
1 (5.6)
Abdominal pain
0
1 (5.6)
1 (5.6)
Nausea
0
1 (5.6)
1 (5.6)
Fatigue
4 (22.2)
1 (5.6)
0
Safety population. AE, adverse event; HCI, hydrochloride; MedDRA, Medical Dictionary
for Regulatory Activities.
a
n = 18.
b
Participants may have experienced >1 event and therefore may be captured in >1 category.
John Wiley & Sons, Ltd.
Discussion
After 11 days of treatment with colesevelam HCl, plasma concentrations of teriflunomide
were, on average, reduced by > 96%. To achieve concentrations below 0.02 μg/mL, colesevelam
HCl would likely need to be administered for more than 11 days. This is also the case
for cholestyramine; teriflunomide plasma concentrations decreased by >98% following
11 days of administration and would therefore require additional days of treatment
to decrease to <0.02 μg/mL, a concentration expected to confer minimal embryo‐fetal
risk in patients.5 It is important to note that a reduction in teriflunomide plasma
concentrations to <0.02 μg/mL is relevant to pregnancy planning, and there is no evidence
to support the need to reduce concentrations to <0.02 μg/mL for other AEs.
During the 11‐day treatment period, colesevelam HCl was well tolerated, and there
were no particular safety concerns identified. The improved safety and tolerability
profile of colesevelam HCl may increase patient satisfaction with AEP procedures.
Conclusions
Colesevelam HCl may offer an additional effective and well‐tolerated AEP methodology
to cholestyramine and activated charcoal when rapid elimination of teriflunomide is
required.
Funding
The study was funded by Sanofi Genzyme.