Implementation of a New Cost-effective HPLC/UV-System for Therapeutic Drug Monitoring of Antidementia Drugs in Medical Routine Analysis Shown by the Example of Galantamine (Reminyl®)

Interpreting an individual patient's drug concentration in relation to a therapeutic and a dose-related reference range is suitable for controlling compliance, lack of clinical response, adverse effects at recommended doses, drug interactions and genetic variations of metabolism. Therefore it is an important contribution to complement pharmacovigilance programs. [1–2]

A novel high performance liquid chromatography (HPLC) assay had to be developed and validated for the detection and quantification of all four antidementia drugs (donepezil, galantamine, memantine and rivastigmine) in serum by using HPLC with UV detection.

The chromatographic analyses were performed on a Dionex system with a Phenomenex Luna Phenyl-Hexyl analytical column. The mobile phase constituted of 0,02mol/l KH2PO4/acetonitrile. The flow rate was 0,4ml/min and the detection wavelengths were kept at 208nm, 212nm, 256nm and 315nm. Interference tests with the most commonly used concomitant medications supported the valuation of suitability in routine analysis.

A standardized HPLC method was developed that allowed TDM of all four antidementia drugs currently available in analytical runs with identical columns and only two mobile-phase components. Solid phase extraction (SPE) using Oasis HLB (Waters) cartridges were used to isolate antidementia drugs from serum. As an example just the parameters are given for galantamine. Galantamine retention time was 13,5min, recovery was >90%. The method was validated according to the guidelines of GTFCh (Society of Toxicology and Forensic Chemistry) in consideration of ISO 5725 (International Organization for Standardization): The calibration curve was linear (r=0,9998, n=9) over galantamine concentrations ranging from 10 to 160ng/ml. No endogenous compounds were found to interfere with the analyte. The method had an accuracy of >90%. Intra- and interday precision were <10% and <10%, resp., at three different concentrations of 10, 40, and 160ng/ml. The limit of quantification (LOQ) was found to be 8,7ng/ml and the limit of detection (LOD) 2,5ng/ml.

Isocratic HPLC systems are very suitable for routine TDM because of the optimal cost-benefit ratio. The method reported here is simple, reliable, precise, and accurate and has the capacity to be used for detection of galantamine in human serum samples. It currently runs in gerontopsychiatric routine. Case histories of the AGATE (Arbeitsgemeinsschaft Arzneimitteltherapie bei psychiatrischen Erkrankungen) pharmacovigilance program already demonstrate the benefit of this individualized approach to drug therapies with antidementia drugs.

Literature: [1] Baumann P, Hiemke C, Ulrich S, et al. The AGNP-TDM Expert Group Consensus

Guidlines: Therapeutic Drug Monitoring in Psychiatry. Pharmacopsychiatry 2004; 37: 243–265.

[2] Haen E, Greiner C, Bader W, Wittmann M. Wirkstoffkonzentrationsbestimmungen zur Therapieleitung: Ergaenzung therapeutischer Referenzbereiche durch dosisbezogene Referenzbereiche. Nervenarzt 2008; 79, 558–566).