Effects of varying degrees of renal impairment on the pharmacokinetics of
duloxetine: analysis of a single-dose phase I study and pooled steady-state data
from phase II/III trials.
Author(s): Lobo ED, Heathman M, Kuan HY, Reddy S, O'Brien L, Gonzales C, Skinner M, Knadler
MP.
Affiliation(s): Eli Lilly and Company, Drug Disposition, Global Pharmacokinetic/Pharmacodynamic
Trial Simulation, Indianapolis, Indiana 46285-0724, USA. loboev@lilly.com
Publication date & source: 2010, Clin Pharmacokinet. , 49(5):311-21
BACKGROUND: Duloxetine is indicated for patients with a variety of conditions,
and some of these patients may have mild to moderate degrees of renal impairment.
Renal impairment may affect the pharmacokinetics of a drug by causing changes in
absorption, distribution, protein binding, renal excretion or nonrenal clearance.
As duloxetine is highly bound to plasma proteins and its metabolites are renally
excreted, it is prudent to evaluate the effect of renal insufficiency on exposure
to duloxetine and its metabolites in the systemic circulation.
OBJECTIVE: The aim of this study was to evaluate the effects of varying degrees
of renal impairment on duloxetine pharmacokinetics in a single-dose phase I study
and using pooled steady-state pharmacokinetic data from phase II/III trials.
METHODS: In the phase I study, a single oral dose of duloxetine 60 mg was given
to 12 subjects with end-stage renal disease (ESRD) and 12 matched healthy control
subjects. In the phase II/III trials (n = 463 patients), duloxetine 20-60 mg was
given as once- or twice-daily doses. Duloxetine and metabolite concentrations in
plasma were determined using liquid chromatography with tandem mass spectrometry.
Noncompartmental methods (phase I: duloxetine and its metabolites) and population
modelling methods (phase II/III: duloxetine) were used to analyse the
pharmacokinetic data.
RESULTS: The maximum plasma concentration (C(max)) and the area under the plasma
concentration-time curve (AUC) of duloxetine were approximately 2-fold higher in
subjects with ESRD than in healthy subjects, which appeared to reflect an
increase in oral bioavailability. The C(max) and AUC of two major inactive
conjugated metabolites were as much as 2- and 9-fold higher, respectively,
reflecting reduced renal clearance of these metabolites. Population
pharmacokinetic results indicated that mild or moderate renal impairment,
assessed by creatinine clearance (CL(CR)) calculated according to the
Cockcroft-Gault formula, did not have a statistically significant effect on
pharmacokinetic parameters of duloxetine. Values for the apparent total body
clearance of duloxetine from plasma after oral administration (CL/F) in subjects
with ESRD were similar to CL/F values in patients with normal renal function or
with mild or moderate renal impairment.
CONCLUSION: Dose adjustments for duloxetine are not necessary for patients with
mild or moderate renal impairment (CL(CR) > or =30 mL/min). For patients with
ESRD or severe renal impairment (CL(CR) <30 mL/min), exposures of duloxetine and
its metabolites are expected to increase; therefore, duloxetine is not generally
recommended for these patients.
|