Pharmacokinetic and pharmacodynamic interactions between almorexant, a dual
orexin receptor antagonist, and desipramine.
Author(s): Cruz HG(1), Hay JL(2), Hoever P(1), Alessi F(3), te Beek ET(2), van Gerven JM(2),
Dingemanse J(4).
Affiliation(s): Author information:
(1)Actelion Pharmaceuticals Ltd, Clinical Pharmacology, Gewerbestrasse 16,
CH-4123 Allschwil, Switzerland. (2)Centre for Human Drug Research, Leiden, The
Netherlands. (3)Actelion Pharmaceuticals Ltd, Biostatistics, Allschwil,
Switzerland. (4)Actelion Pharmaceuticals Ltd, Clinical Pharmacology,
Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Electronic address:
jasper.dingemanse@actelion.com.
Publication date & source: 2014, Eur Neuropsychopharmacol. , 24(8):1257-68
Almorexant is a dual orexin receptor antagonist (DORA) with sleep-enabling
effects in humans. Insomnia is often associated with mental health problems,
including depression. Hence, potential interactions with antidepressants deserve
attention. Desipramine was selected as a model drug because it is mainly
metabolized by CYP2D6, which is inhibited by almorexant in vitro. A
single-center, randomized, placebo-controlled, two-way crossover study in 20
healthy male subjects was conducted to evaluate the pharmacokinetic and
pharmacodynamic interactions between almorexant and desipramine. Almorexant 200mg
or matching placebo (double-blind) was administered orally once daily in the
morning for 10 days, and a single oral dose of 50mg desipramine (open-label) was
administered on Day 5. Almorexant increased the exposure to desipramine 3.7-fold,
suggesting that almorexant is a moderate inhibitor of desipramine metabolism
through inhibition of CYP2D6. Conversely, desipramine showed no relevant effects
on the pharmacokinetics of almorexant. Pharmacodynamic evaluations indicated that
almorexant alone reduced visuomotor coordination, postural stability, and
alertness, and slightly increased calmness. Desipramine induced a reduction in
subjective alertness and an increase in pupil/iris ratio. Despite the increase in
exposure to desipramine, almorexant and desipramine in combination showed the
same pharmacodynamic profile as almorexant alone, except for prolonging reduced
alertness and preventing the miotic effect of almorexant. Co-administration also
prolonged the mydriatic effect of desipramine. Overall, repeated administration
of almorexant alone or with single-dose desipramine was well tolerated. The lack
of a relevant interaction with antidepressants, if confirmed for other DORAs,
would be a key feature for a safer class of hypnotics.
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