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Concurrent administration of donepezil HCl and levodopa/carbidopa in patients with Parkinson's disease: assessment of pharmacokinetic changes and safety following multiple oral doses.
Br J Clin Pharmacol 2004; 58 Suppl 1:41-9BJ

Abstract

AIM

The use of acetylcholinesterase inhibitors for the treatment of comorbid Alzheimer's disease in Parkinson's disease (PD) patients stabilized on a levodopa regimen may potentially disrupt cholinergic balance. This randomized, double-blind, crossover study investigated the safety of, and possible drug-drug interaction between, donepezil HCl and levodopa/carbidopa.

METHODS

Twenty-five patients with PD who were taking physician-optimized doses of levodopa/carbidopa (with daytime dosing intervals of 4-8 h) were administered once-daily doses of either donepezil HCl (5 mg) or placebo for 15 days, in two treatment periods, separated by a washout of at least 2 weeks. Some patients took a second dose of levodopa/carbidopa after 4 h, therefore subanalysis of the levodopa/carbidopa data was conducted up to 4 h and 8 h after dosing. Twenty-six healthy matched controls received open-label donepezil HCl only, for a single 15-day period. Blood samples were collected before, during and after the 15 doses of donepezil HCl for pharmacokinetic (PK) assessments. Pharmacokinetic parameters included maximum attained plasma drug concentration (C(max)), time at which C(max) is attained (t(max)), plasma drug concentration at steady state (C(ss)), and area under the drug concentration-time curve over the dosing interval. Safety assessments included monitoring adverse events, and the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination.

RESULTS

The mean age of all subjects was 72.6 +/- 1.3 years. Donepezil PK assessments of PD patients receiving levodopa/carbidopa were similar to the PK results from healthy controls who received donepezil HCl only (mean AUC(0-12 h)= 281.6 +/- 17.6 and 268.6 +/- 19.9 ng.h ml(-1), respectively). Carbidopa PK were not significantly altered by the concomitant administration of multiple doses of donepezil HCl, compared with when PD patients received placebo (mean AUC(0-8 h)= 921.8 +/- 160 and 821.8 +/- 113 ng.h ml(-1), respectively). Four hours after administration of donepezil HCl in PD patients, AUC(0-4 h), C(max) and C(ss) of levodopa were higher than when PD patients received placebo (P < 0.05). Eight hours after donepezil HCl, however, only C(max) and t(max) were observed to change compared with when PD patients received placebo (mean C(max) = 2652 +/- 429 and 2077 +/- 276 ng ml(-1), respectively; mean t(max) = 1.7 +/- 0.4 and 2.9 +/- 0.5 h, respectively; P< or = 0.05). The number of PD patients who experienced at least one adverse event during the study (13/25) was higher when they received donepezil HCl than when they received placebo (5/25), but was the same as healthy subjects who received donepezil HCl only (13/26). There were no significant differences in change from baseline on the UPDRS motor examination parameters in PD patients when they took donepezil HCl and when they took placebo.

CONCLUSIONS

No clinically significant drug-drug interactions between donepezil HCl and levodopa/carbidopa were observed at steady state. The small changes in the pharmacokinetics of levodopa did not result in any change in motor symptoms. Co-administration of the two drugs led to a small increase in adverse events compared with administration of levodopa/carbidopa alone in PD patients. These adverse events, however, were consistent with donepezil's cholinomimetic effect, and their incidence was comparable to that observed following the administration of donepezil HCl alone.

Authors+Show Affiliations

Clinical Pharmacology, Eisai Medical Research Inc., Ridgefield Park, NJ 07660, USA. chuk_okereke@eisai.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

15496222

Citation

Okereke, Chukwuemeka S., et al. "Concurrent Administration of Donepezil HCl and Levodopa/carbidopa in Patients With Parkinson's Disease: Assessment of Pharmacokinetic Changes and Safety Following Multiple Oral Doses." British Journal of Clinical Pharmacology, vol. 58 Suppl 1, 2004, pp. 41-9.
Okereke CS, Kirby L, Kumar D, et al. Concurrent administration of donepezil HCl and levodopa/carbidopa in patients with Parkinson's disease: assessment of pharmacokinetic changes and safety following multiple oral doses. Br J Clin Pharmacol. 2004;58 Suppl 1:41-9.
Okereke, C. S., Kirby, L., Kumar, D., Cullen, E. I., Pratt, R. D., & Hahne, W. A. (2004). Concurrent administration of donepezil HCl and levodopa/carbidopa in patients with Parkinson's disease: assessment of pharmacokinetic changes and safety following multiple oral doses. British Journal of Clinical Pharmacology, 58 Suppl 1, pp. 41-9.
Okereke CS, et al. Concurrent Administration of Donepezil HCl and Levodopa/carbidopa in Patients With Parkinson's Disease: Assessment of Pharmacokinetic Changes and Safety Following Multiple Oral Doses. Br J Clin Pharmacol. 2004;58 Suppl 1:41-9. PubMed PMID: 15496222.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Concurrent administration of donepezil HCl and levodopa/carbidopa in patients with Parkinson's disease: assessment of pharmacokinetic changes and safety following multiple oral doses. AU - Okereke,Chukwuemeka S, AU - Kirby,Louis, AU - Kumar,Dinesh, AU - Cullen,Edward I, AU - Pratt,Raymond D, AU - Hahne,William A, PY - 2004/10/22/pubmed PY - 2005/2/3/medline PY - 2004/10/22/entrez SP - 41 EP - 9 JF - British journal of clinical pharmacology JO - Br J Clin Pharmacol VL - 58 Suppl 1 N2 - AIM: The use of acetylcholinesterase inhibitors for the treatment of comorbid Alzheimer's disease in Parkinson's disease (PD) patients stabilized on a levodopa regimen may potentially disrupt cholinergic balance. This randomized, double-blind, crossover study investigated the safety of, and possible drug-drug interaction between, donepezil HCl and levodopa/carbidopa. METHODS: Twenty-five patients with PD who were taking physician-optimized doses of levodopa/carbidopa (with daytime dosing intervals of 4-8 h) were administered once-daily doses of either donepezil HCl (5 mg) or placebo for 15 days, in two treatment periods, separated by a washout of at least 2 weeks. Some patients took a second dose of levodopa/carbidopa after 4 h, therefore subanalysis of the levodopa/carbidopa data was conducted up to 4 h and 8 h after dosing. Twenty-six healthy matched controls received open-label donepezil HCl only, for a single 15-day period. Blood samples were collected before, during and after the 15 doses of donepezil HCl for pharmacokinetic (PK) assessments. Pharmacokinetic parameters included maximum attained plasma drug concentration (C(max)), time at which C(max) is attained (t(max)), plasma drug concentration at steady state (C(ss)), and area under the drug concentration-time curve over the dosing interval. Safety assessments included monitoring adverse events, and the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. RESULTS: The mean age of all subjects was 72.6 +/- 1.3 years. Donepezil PK assessments of PD patients receiving levodopa/carbidopa were similar to the PK results from healthy controls who received donepezil HCl only (mean AUC(0-12 h)= 281.6 +/- 17.6 and 268.6 +/- 19.9 ng.h ml(-1), respectively). Carbidopa PK were not significantly altered by the concomitant administration of multiple doses of donepezil HCl, compared with when PD patients received placebo (mean AUC(0-8 h)= 921.8 +/- 160 and 821.8 +/- 113 ng.h ml(-1), respectively). Four hours after administration of donepezil HCl in PD patients, AUC(0-4 h), C(max) and C(ss) of levodopa were higher than when PD patients received placebo (P < 0.05). Eight hours after donepezil HCl, however, only C(max) and t(max) were observed to change compared with when PD patients received placebo (mean C(max) = 2652 +/- 429 and 2077 +/- 276 ng ml(-1), respectively; mean t(max) = 1.7 +/- 0.4 and 2.9 +/- 0.5 h, respectively; P< or = 0.05). The number of PD patients who experienced at least one adverse event during the study (13/25) was higher when they received donepezil HCl than when they received placebo (5/25), but was the same as healthy subjects who received donepezil HCl only (13/26). There were no significant differences in change from baseline on the UPDRS motor examination parameters in PD patients when they took donepezil HCl and when they took placebo. CONCLUSIONS: No clinically significant drug-drug interactions between donepezil HCl and levodopa/carbidopa were observed at steady state. The small changes in the pharmacokinetics of levodopa did not result in any change in motor symptoms. Co-administration of the two drugs led to a small increase in adverse events compared with administration of levodopa/carbidopa alone in PD patients. These adverse events, however, were consistent with donepezil's cholinomimetic effect, and their incidence was comparable to that observed following the administration of donepezil HCl alone. SN - 0306-5251 UR - https://www.unboundmedicine.com/medline/citation/15496222/Concurrent_administration_of_donepezil_HCl_and_levodopa/carbidopa_in_patients_with_Parkinson's_disease:_assessment_of_pharmacokinetic_changes_and_safety_following_multiple_oral_doses_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&amp;sid=nlm:pubmed&amp;issn=0306-5251&amp;date=2004&amp;volume=58&amp;issue=&amp;spage=41 DB - PRIME DP - Unbound Medicine ER -