Therapeutic Drug Monitoring of Rivastigmine and Donepezil Under Consideration of CYP2D6 Genotype-Dependent Metabolism of Donepezil.

BACKGROUND

The efficacy of acetylcholinesterase inhibitors (AChE-I) might depend on blood concentration. While rivastigmine metabolism is independent of the cytochrome P450 system, its isoenzymes, especially CYP2D6, metabolize donepezil.

OBJECTIVE

We investigated correlations between clinical efficacy and serum concentrations of rivastigmine and donepezil under special consideration of

METHODS

Serum concentrations of donepezil and rivastigmine were measured by liquid chromatography - tandem mass spectrometry (LC-MS/MS). Real-time quantitative polymerase chain reaction (PCR) and allele-specific PCR were performed to assess

RESULTS

Patients treated with rivastigmine (n=28) or donepezil (n=48) were included in the study. Both gene dose and metabolism type significantly predicted the level of donepezil serum concentration (p=0.019 and p=0.013, respectively). In the rivastigmine group, changes of the word list delayed recall subtest before treatment and under stable medication were significantly associated with rivastigmine serum levels (β=0.465; p=0.018). Drug serum concentrations were outside the recommended range in a substantial percentage of participants, which might have contributed to poor correlations between changes in cognitive measures and drug concentrations. Donepezil serum concentrations significantly depended on

CONCLUSION

Testing AChE-I serum concentration should be considered in patients without clinical response to treatment or those with severe side effects. Patients with donepezil drug levels outside the recommended range might additionally profit from

Informations de copyright

© 2020 Ortner et al.

Déclaration de conflit d'intérêts

Outside the submitted work, Dr Grimmer reports having received consulting fees from Actelion, Biogen, Eli Lilly, Iqvia/Quintiles; MSD; Novartis, Quintiles, Roche Pharma, lecture fees from Biogen, Lilly, Parexel, Roche Pharma, and grants to his institution from Actelion and PreDemTech. Outside the submitted work, Dr Diehl-Schmid reports having received lecture fees from Novartis. Outside the submitted work, Prof. Steimer reports having received consulting fees, support or lecture fees from Roche Diagnostics, Abbott, Siemens, Microgenics, Thermo Fisher. Dr Katharina Buerger is the advisory board member for Biogen GmbH Germany, and acts as an advisor to Ernst&Young Consulting, during the conduct of the study. Miss Marion Stange reports grants from Novartis, during the conduct of the study. The authors report no other conflicts of interest in this work.