TC-5214 (dexmecamylamine) is a nicotinic channel modulator that has previously 
been evaluated for treatment of major depression disorder (MDD) and is currently 
being evaluated by Targacept as a treatment for overactive bladder. A 
comprehensive population pharmacokinetic (POP PK) model of TC-5214 was developed 
using nonlinear mixed-effects modeling of pooled plasma concentration data from 
6 early phase I studies in 179 healthy participants or patients with non-MDD and 
1 phase II study in 68 MDD patients. Concentration-time profiles of TC-5214 
after either single or multiple oral doses of TC-5214 was described by a 
one-compartment model with first-order absorption with lag time and first-order 
elimination. Covariate analysis revealed that creatinine clearance was a 
significant covariate on clearance and that body weight significantly influenced 
the central volume of distribution. The final model (with identified covariates) 
was used to simulate steady-state exposure for patients with impaired renal 
function. Results from forest plots reveal that patients with moderate to severe 
renal impairment or end stage renal disease are associated with significantly 
higher Cssmax and AUC compared to patients with normal renal function. The 
proposed final POP PK model could be employed in defining a TC-5214 dosage 
regimen in patients with impaired renal function.