Study drugs and dose selection
MDD, emesis, antitussive
ANTITUSSIVE
Esmethadone doses of 25 mg, 75 mg (3x planned therapeutic dose and planned loading dose for the treatment of MDD, and 150 mg (6x therapeutic dose and the maximum tolerated dose [MTD]) [Oxycodone, a Schedule II opioid, was selected as the positive control in the Oxycodone Study (Study 1). The dose of oxycodone (40 mg; administered as 20 mg over-encapsulated tablets) was consistent with those previously evaluated in HAP studies [Ketamine, a Schedule III NMDAR antagonist, was selected as the positive control in the Ketamine Study (Study 2). The dose and infusion duration of IV ketamine (0.5 mg/kg over 40 min) was consistent with a previous HAP study (CDER review of NDA 211243 [esketamine]). DXM, an unscheduled, over-the-counter, NMDAR antagonist, and antitussive drug, was selected as an exploratory comparator in the Ketamine Study. The oral dose of DXM (300 mg capsule) was based on a prior single ascending dose study showing that this dose had detectable subjective effects but was not associated with prominent emesis that was more commonly observed at higher supratherapeutic doses of 400 to 800 mg [To ensure blinding, study drugs were administered in a double- (Oxycodone Study) or triple- (Ketamine Study) dummy fashion, where participants received the same number of tablets and capsules (and a 40-min IV infusion in the Ketamine Study) administered as a combination of active or placebo product in each treatment period.