(753): Single-dose and repetitive-dose bicifadine pharmacokinetics in healthy adult male human subjects

Abstract

Bicifadine is a novel non-opioid analgesic whose neurochemical actions involve the modulation of monoaminergic neurotransmitters pathways involved in pain. The compound has shown activity in chronic back pain and in acute nociceptive pain. Pharmacokinetic profiles of bicifadine and its lactam metabolite have been studied in healthy adult male human subjects following single doses of 200mg and 400mg and during multiple dose regimens of 200mg BID, 200mg TID, and 400mg BID for 8 days (10 per dose group). Plasma concentration time course data were collected over a 24-hour period following single-doses and across dosing intervals on Days 1, 4, and 8 during repetitive dosing. Pharmacokinetic metrics were estimated following noncompartmental data analysis. Peak exposures (Cmax) were achieved at a tmax of approximately 1.5 to 1.8h following single-doses and 1.8 to 2.2h during repetitive dosing. Plasma concentrations increased in a linear manner across the 200mg and 400mg single doses. Linearity was further evidenced by relatively constant apparent oral clearance and mean residence times across doses. Repetitive dosing for 8 days resulted in accumulation ratios [R] of approximately 1.2 for BID dosing and 1.8 for TID dosing. Substantial increases in volume of distribution between the 200mg (V/F= 185 & 182L) and 400mg (V/F= 280L) were observed but not readily explained. Apparent terminal half-life (t1/2) values across single doses (t1/2= 2.6 & 3.4h at 200mg; t1/2= 4.6h at 400mg) were within the limits of variability. Overall, the pharmacokinetic profile of bicifadine was well behaved and inter-individual variability was modest. Steady-state is clearly established within 4 days of BID or TID dosing. Profiles of the lactam metabolite followed a similar trend. Bicifadine is a novel non-opioid analgesic whose neurochemical actions involve the modulation of monoaminergic neurotransmitters pathways involved in pain. The compound has shown activity in chronic back pain and in acute nociceptive pain. Pharmacokinetic profiles of bicifadine and its lactam metabolite have been studied in healthy adult male human subjects following single doses of 200mg and 400mg and during multiple dose regimens of 200mg BID, 200mg TID, and 400mg BID for 8 days (10 per dose group). Plasma concentration time course data were collected over a 24-hour period following single-doses and across dosing intervals on Days 1, 4, and 8 during repetitive dosing. Pharmacokinetic metrics were estimated following noncompartmental data analysis. Peak exposures (Cmax) were achieved at a tmax of approximately 1.5 to 1.8h following single-doses and 1.8 to 2.2h during repetitive dosing. Plasma concentrations increased in a linear manner across the 200mg and 400mg single doses. Linearity was further evidenced by relatively constant apparent oral clearance and mean residence times across doses. Repetitive dosing for 8 days resulted in accumulation ratios [R] of approximately 1.2 for BID dosing and 1.8 for TID dosing. Substantial increases in volume of distribution between the 200mg (V/F= 185 & 182L) and 400mg (V/F= 280L) were observed but not readily explained. Apparent terminal half-life (t1/2) values across single doses (t1/2= 2.6 & 3.4h at 200mg; t1/2= 4.6h at 400mg) were within the limits of variability. Overall, the pharmacokinetic profile of bicifadine was well behaved and inter-individual variability was modest. Steady-state is clearly established within 4 days of BID or TID dosing. Profiles of the lactam metabolite followed a similar trend.