A Phase I, open-label, randomized, 2-panel, sequential treatment study in healthy subjects to investigate the potential pharmacokinetic interactions between multiple doses of phenytoin or carbamazepine and telaprevir at steady-state

Telaprevir is a hepatitis C virus (HCV) non structural (NS) 3 protease
inhibitor, indicated, in combination with
pegylated interferon (Peg-IFN) alfa and ribavirin (RBV), for the treatment of
genotype 1 chronic hepatitis C in adult
patients with compensated liver disease (including cirrhosis) who are treatment
naïve, or who have previously been
treated with interferon-based treatment, including prior null responders,
partial responders, and relapsers.
Telaprevir is a substrate and strong inhibitor of cytochrome P450 (CYP) 3A
enzyme. Telaprevir is also a substrate
of P-glycoprotein (Pgp), and it can inhibit and/or saturate this drug
transporter in the gut when present in high local
concentrations.
Phenytoin and carbamazepine are antiepileptic drugs (AEDs). Both drugs are
known to induce the expression of
drug metabolizing enzymes and transporters, including CYP3A and Pgp. Due to
their similar metabolic and
transport pathways, as well as their effects on these pathways, a clinically
relevant interaction between telaprevir
and phenytoin or carbamazepine may be anticipated. Telaprevir may be added to
standardized antiepileptic
regimens during the treatment of HCV infections within epileptic populations,
therefore understanding the
interaction between telaprevir and common AEDs is important to maintain seizure
control and inhibition of viral
replication. Hence, in this study the drug-drug interaction between telaprevir
and a stable phenytoin regimen and
between telaprevir and a stable carbamazepine regimen will be assessed. The
results of this study will provide
guidance on the need for dosage adjustment for coadministration of telaprevir
with phenytoin or carbamazepine.
.

OBJECTIVES AND HYPOTHESIS
Primary Objectives
The primary objectives are to determine
- the effect of steady-state telaprevir 750 mg every 8 hours (q8h) on the
multiple dose pharmacokinetics of
phenytoin 200 mg every 12 hours (q12h) in healthy subjects, and vice versa.
- the effect of steady-state telaprevir 750 mg q8h on the multiple dose
pharmacokinetics of carbamazepine
200 mg q12h in healthy subjects, and vice versa.
Secondary Objectives
The secondary objectives are to determine:
- the effect of multiple dose pharmacokinetics of phenytoin 200 mg q12h or
carbamazepine 200 mg q12h on the
single dose pharmacokinetics of telaprevir 750 mg in healthy subjects.
- to evaluate the short-term safety and tolerability of telaprevir in
combination with phenytoin or carbamazepine.
Exploratory Objective
The exploratory objective is to assess serial plasma 4β-hydroxycholesterol
levels as a potential endogenous marker
of relative CYP3A4 activity.
Hypothesis
This study is designed to obtain a sufficiently reliable estimate of the
drug-drug interaction between telaprevir and
phenytoin (Panel 1) and between telaprevir and carbamazepine (Panel 2),
expressed as a ratio of pharmacokinetic
(PK) parameters and its 90% confidence interval (CI). No formal hypothesis will
be tested.

OVERVIEW OF STUDY DESIGN
This is a Phase I, open-label, randomized, 2-panel, sequential treatment study
in healthy subjects to investigate the
potential PK interactions between multiple doses of phenytoin or carbamazepine
and telaprevir at steady-state. The
study population will consist of 24 healthy subjects, randomized equally into 2
panels. All subjects in individual
panels will receive the same sequence of treatments.
Panel 1:
• Part 1: telaprevir 750 mg q8h from Day 1 to Day 9 followed by a single 750-mg
dose in the morning on Day 10.
• Part 2: phenytoin 200 mg q12h from Day 1 to Day 16 followed by a single
200-mg dose in the morning on
Day 17; and telaprevir 750 mg q8h from Day 8 to Day 16 followed by a single
750-mg dose in the morning on
Day 17.
Panel 2:
• Part 1: telaprevir 750 mg q8h from Day 1 to Day 9 followed by a single 750-mg
dose in the morning on Day 10.
• Part 2: carbamazepine 200 mg q12h from Day 1 to Day 16 followed by a single
200-mg dose in the morning on
Day 17; and telaprevir 750 mg q8h from Day 8 to Day 16 followed by a single
750-mg dose in the morning on
Day 17.
In both panels, Part 1 and Part 2 are separated by a washout period of at least
2 weeks, but not longer than 4 weeks,
between the last intake of study drug in Part 1, and the first intake of study
drug in Part 2. Day 10 of Part 1 is the
first day of the washout period.
On Days 1 and 10 (Part 1) and Days 8 and 17 (Part 2) and for both panels,
samples for the determination of plasma
concentrations for telaprevir will be collected at several time points.
On Days 7 and 17 of Part 2 (days of intensive PK sampling), samples for the
determination of plasma
concentrations for phenytoin (Part 2 - Panel 1) or carbamazepine (Part 2 -
Panel 2) will be collected at several time
points.
Additional samples will be taken for the determination of plasma concentrations
prior to intensive PK sampling to
document steady-state.
Safety and tolerability evaluations will be recorded throughout the study

See section E4.

Telaprevir is a registered drug (trade name: Incivek and Incivo) has been
previously tested in humans and was generally well tolerated. A number of
side-effects, possibly linked to use of the test medication, were reported.
Very common side effects included: anaemia, skin itching (pruritus) and red
eruption of the skin (rash), nausea, diarrhea, hemorrhoids, vomiting, pain in
the rectum (proctalgia).

Phenytoin and carbamazepin are both registered drugs for the treatment of
epilepsy.
For phenytoin the following side-effects have been reported: central nervous
system disorders, including involuntary eye movement (nystagmus), problems with
coordination (ataxia), slurred speech, decreased co-ordination, mental
confusion, a sensation of tingling, burning, pricking, or numbness of a
person's skin (paraesthesia), somnolence, drowsiness and vertigo; suicidal
thoughts or behavior and hypersensitivity reactions, including skin rash.

(Very) common side effects observed with carbamazepine intake are: blood and
lymphatic system disorders (e.g. a decrease/increase in the number of certain
types of blood cells in the blood), endocrine disorders such as, but not
limited to, oedema, fluid retention and weight increase, nervous system
disorders (e.g. dizziness, problems with coordination (ataxia), drowsiness,
fatigue, headache, double vision (diplopia), inability of the eye to
automatically change focus (accommodation disorders)), gastro-intestinal
disorders (e.g. nausea, vomiting, dry mouth), diseases that affect the liver
and/or biliary tract (hepatobiliary disorders) and skin and subcutaneous tissue
disorders (inflammation of the skin due to allergy or a kind of skin rash
notable for pale red, raised, itchy bumps (urticarial, which may be severe)).

The dose levels are selected on the basis of research results in animals and
humans. The risk to health at these dose levels is limited but they may
experience one of the above mentioned side-effects or other symptoms not
previously reported. The health will be closely monitored during the trial to
minimize these risks.

The blood collection procedure is not dangerous, but may cause discomfort or
bruising. Occasionally, fainting or an infection at the blood sampling site can
occur.