IngentaConnect Steady-state pharmacokinetics and safety of donepezil HCl in subj...

Abstract:

Aims

To characterize the pharmacokinetic, pharmacodynamic and safety profiles of donepezil in subjects with moderate renal impairment and matched healthy controls during single-dose and multiple-dose phases. Methods

This open-label study enrolled subjects with moderate renal impairment (creatinine clearance [CL_Cr] 17-33 ml min⁻¹ 1.73 m⁻² body surface area) and age, weight and sex-matched healthy controls. A single-dose (5 mg donepezil) phase was followed by a 23-day multiple dose (5 mg day⁻¹ donepezil) steady-state phase. The pharmacokinetic and pharmacodynamic parameters of donepezil were determined for up to 144 h after the first dose and 168 h after the last dose. Results

Thirty-six subjects were enrolled, 19 renally impaired and 17 healthy controls. All pharmacokinetic and pharmacodynamic parameters were similar between groups after a single dose of donepezil (C_max 5.17 ± 0.36 and 6.07 ± 0.49 ng ml⁻¹; AUC₀₋₂₄ 76.05 ± 5.54 and 77.45 ± 4.49 ng·h ml⁻¹; mean maximum percentage inhibition [I_max] red blood cell (RBC) AChE activity 32.07 ± 2.00 and 31.69 ± 2.45%; for subjects with renal impairment and healthy subjects, respectively). Pharmacokinetic parameters under steady-state conditions did not differ between renally impaired and healthy subjects (C_SS 20.83 ± 1.78 and 18.38 ± 1.52 ng ml⁻¹; AUC₀₋₂₄ 500.0 ± 42.8 and 441.1 ± 36.4 ng·h ml⁻¹; degree of accumulation [R_A] 6.98 ± 0.59 and 5.94 ± 0.53; for subjects with renal impairment and healthy subjects, respectively). Main pharmacodynamic parameters were also similar in renally impaired and healthy subjects at steady state (average percentage inhibition [I_SS] RBC AChE activity 65.11 ± 2.52 and 60.62 ± 2.95, respectively). Protein binding was also similar between groups (% free donepezil 23.54 ± 1.96 and 20.23 ± 0.64, respectively). Donepezil was well tolerated by both groups. Conclusions

These results indicate that the pharmacokinetics of donepezil are not altered after dosing to steady state, and that donepezil can be administered safely to subjects with moderate renal impairment.

Keywords: acetylcholinesterase inhibitor; Alzheimer's disease; donepezil; pharmacokinetics; renal impairment

Document Type: Research article

DOI: 10.1111/j.1365-2125.2004.01803.x

Affiliations: 1: Clinical Pharmacology, 2: Biometrics Biostatistics, and 3: University of Virginia, Charlottesville, VA, USA, 4: Orlando Clinical Research Center, Orlando, FL, USA, 5: Comprehensive Phase One, Fort Lauderdale, FL, USA and

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Steady-state pharmacokinetics and safety of donepezil HCl in subjects with moderately impaired renal function