The effect of CYP3A inhibition on the PK of RO5186582
Research type
Research Study
Full title
A non-randomized, open label, three treatment, fixed sequence crossover study to investigate the effect of CYP3A inhibition on the pharmacokinetics of RO5186582 in healthy subjects
IRAS ID
173343
Contact name
Sunu Valasseri
Contact email
Sponsor organisation
F. Hoffmann-La Roche Ltd
Eudract number
2015-000261-31
Duration of Study in the UK
0 years, 3 months, 3 days
Research summary
GABA is a signalling chemical in the brain which acts on specific receptors. These receptors are associated with mental processing, understanding and memory. The effect of GABA on these receptors is inhibitory which means it reduces cognitive and memory function. RO5186582 decreases the effect of GABA on its receptors and therefore could potentially improve cognitive function and memory. RO5186582 is being developed with an intention of helping people with mental disability associated with Down syndrome.
RO5186582 is mainly metabolized (broken down) by CYP3A4 (an enzyme responsible for metabolism). Therefore, other drugs which block CYP3A4 (e.g., itraconazole) have the potential to raise RO5186582 blood concentrations. This study is conducted to evaluate the change in blood concentration of RO5186582 when administered along with a strong CYP3A4/5 inhibitor itraconazole, in order to verify and assess the involvement of CYP3A in the elimination of RO5186582. Itraconazole is a strong CYP3A inhibitor and is commonly used in this type of drug-drug interaction study. This study also intends to assess the change in electrical conduction of the heart (based on ECGs) associated with administration of itracanazole, and RO5186582. This data may be useful in planning future studies to look at ECG changes associated with RO5186582 administration.
The first 4 volunteers will receive the following treatments, from day 1 to 9, 120 mg RO5186582 two times a day (b.i.d) and 120 mg RO5186582 once on day 10. From day 15 to 18, 200 mg itraconazole b.i.d. From day 19 to 29 one dose of 200 mg itraconazole and 120 mg RO5186582 b.i.d from day 20 to day 28 and a single 240 mg dose of RO5186582 on day 29. The safety, tolerability and pharmacokinetic data from the first 4 volunteers will be reviewed and if none of the dose escalation stopping criteria are met, the dose of RO5186582 will be increased up to a maximum of 240 mg. The decision to keep the dose level at 120 mg or to reduce the dose level may be made.
In healthy volunteers, RO5186582 has been administered up to a dose of 1250 mg in single dose studies and up to 1000 mg in multiple dose studies. A maximum dose of 240 mg b.i.d. has been selected because this is the highest dose being tested in the ongoing Phase 2 proof-of-concept study in people with Down syndrome.REC name
North West - Greater Manchester Central Research Ethics Committee
REC reference
15/NW/0242
Date of REC Opinion
29 Apr 2015
REC opinion
Further Information Favourable Opinion