Population Pharmacokinetics of Orally Administered Duloxetine in Patients Implications for Dosing Recommendation

Objectives: The objectives of this analysis were to characterize the pharmacokinetics of duloxetine at steady state in patients, estimate the variability, identify significant covariates that may influence duloxetine pharmacokinetics and provide appropriate dosing recommendations for patients on duloxetine treatment. Methods: The pharmacokinetic meta-analysis dataset was created from one open-label clinical study and four double-blind, placebo-controlled clinical studies. Duloxetine concentrations (N = 2002) were obtained from 594 patients diagnosed with major depressive disorder (n = 223), diabetic peripheral neuropathic pain (n = 112), stress urinary incontinence (n = 128) and fibromyalgia (n = 13 1). Patients were given 20-60 mg/day of oral duloxetine once or twice daily (the highest dose studied was 120 mg/day). A population pharmacokinetic model was developed using a nonlinear mixed-effects modelling method. Covariates including bodyweight, age, sex, ethnicity, smoking status, disease condition, dose, dosing regimen and creatinine clearance were tested for their influence on duloxetine pharmacokinetics. The final model was used to predict steady-state duloxetine concentration-time profiles in various patient subgroups. Results: Duloxetine pharmacokinetics in patients were described by a one-compartmental pharmacokinetic model. The interpatient variability in apparent oral clearance (CL/F) was 59% and the interpatient variability in the apparent volume of distribution after oral administration (V-d/F) was 97%. The residual error was 31%. Sex, smoking status, age and dose had a statistically significant effect on CL/F, whereas the V-d/F was influenced by ethnicity. CL/F was 40% lower in females than in males and 30% lower in nonsmokers than in smokers. CL/F decreased with increasing dose and age. The V-d/F in Hispanic patients was twice that of non-Hispanic patients. Simulations showed a considerable overlap in duloxetine exposure between the identified patient subgroups. Conclusion: Given the clinically insignificant change in the magnitude of duloxetine steady-state exposure and the considerable overlap in duloxetine exposure between the patient subgroups, specific dose recommendations based on sex, smoking status, age, dose and ethnicity are not warranted.