Pharmacokinetic and pharmacodynamic characterisation of JNJ-40411813, a positive allosteric modulator of mGluR2, in two randomised, double-blind phase-I studies.
Metabotropic glutamate receptor-2 positive allosteric modulator, JNJ-40411813 (ADX71149), was characterised for clinical effects in healthy volunteers in two phase-1 studies. In study 1, healthy men received 50-, 100-, 150- or 225 mg and women received 100 mg JNJ-40411813 (n=6, each cohort) or placebo (n=2, each cohort) twice daily for seven days; smoking men (n=30) received placebo twice daily on days 1-7, 100 mg JNJ-40411813 (n=20) or placebo (n=10) on days 8-14. In study 2, healthy men received intravenous 0.005 mg/kg S(+) ketamine over 60 min at 3 (n=24; cohort 1), 12 h (n=8; cohort 3), and 24 h (n=8; cohort 2) after a single oral dose of 500 mg JNJ-40411813 or placebo. The pharmacokinetics and effects of JNJ-40411813 on cognition and subjective awareness were evaluated. Plasma JNJ-40411813 exposure was dose-dependent, t max ranged from 3-4 h and t 1/2 19.4-34.2 h across the dose levels. JNJ-40411813 significantly (p=0.02) reduced continuity of attention score (150 mg dose) and ameliorated smoking withdrawal-induced changes in power of attention and quality of episodic memory versus placebo. A modest reduction in alertness was observed at 150-225 mg doses, JNJ-40411813 (500 mg) reduced S(+) ketamine-induced negative symptoms by approximately 43% and 30% in cohorts 1 and 3, respectively. JNJ-40411813 was generally well-tolerated.
Janssen Research & Development, Beerse, Belgium.
Hiba
H
Salih
Janssen Research & Development, Beerse, Belgium.
Ion
I
Anghelescu
Janssen Research & Development, Beerse, Belgium.
Iva
I
Kezic
Janssen Research & Development, Beerse, Belgium.
Vikash
V
Sinha
Janssen Research & Development, Beerse, Belgium.
Eef
E
Hoeben
Janssen Research & Development, Beerse, Belgium.
Luc
L
Van Nueten
Janssen Research & Development, Beerse, Belgium.
Heidi
H
De Smedt
Janssen Research & Development, Beerse, Belgium PDEBOER1@its.jnj.com.
Peter
P
De Boer
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000494:Allosteric Regulation / Q000187:drug effects; D001288:Attention / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D016540:Smoking Cessation / Q000523:psychology; D055815:Young Adult
C000594993:1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone; D010880:Piperidines; D011728:Pyridones; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D007649:Ketamine
JNJ-40411813; Pharmacokinetics; S(+) ketamine; metabotropic glutamate receptor-2; pharmacodynamics; positive allosteric modulator (PAM)