A. Lo,1 S. Kshirsagar,2 R.M. Baldwin,3 S. Patil,1 S. Dubé,1 D. L. Bourdet1; 1Theravance Biopharma, South San Francisco, CA, 2Consultant, Mountain View, CA, 3University of California, San Francisco, CA

BACKGROUND: TD-9855 is an NSRI being developed for the treatment of fibromyalgia (FM) and chronic pain. Three Phase I and two Phase II studies have been completed with TD-9855 administered orally at 8 dose levels ranging from 2 to 50 mg. The objectives of this study were to describe the pharmacokinetics (PK) of TD-9855 in healthy volunteers and patients with Adult ADHD or fibromyalgia (FM) and to identify significant covariates affecting its disposition using a population PK model.
METHODS: Plasma concentration-time data from healthy volunteers (n=68, full PK profiles) and patients with adult ADHD or FM (n=192 and n=239, respectively, sparsely sampled). Appropriate PK models were evaluated using nonlinear mixed effects modeling (NONMEM 7.2). Sex, age, weight, body mass index, creatinine clearance, smoking status and plasma markers of liver function were investigated as potential covariates on the population PK parameters using a forward addition and backward elimination approach.
RESULTS: TD-9855 pharmacokinetics were best described using a two-compartment model with absorption lag, first-order absorption and elimination. Statistically-significant covariates were sex (on V/F and CL/F) and smoking status (on CL/F) with ~35% higher exposures in women vs. men and ~ 33% lower exposures in smokers vs. nonsmokers. CYP2D6 genotype had no significant influence on CL/F.
CONCLUSION: A population PK model has been developed that describes the PK of TD-9855 in healthy volunteers and patients with adult ADHD or FM. No significant impact of CYP2D6 genotype on TD-9855 PK was observed, consistent with elimination via multiple metabolic pathways. The modest effect of gender and smoking on exposure to TD-9855 does not warrant a dose adjustment in the studied populations.