Optimizing memantine dose, by TDM, for preserving cognitive function in brain metastatic patients undergoing...

Memantine demonstrated neuroprotective potential during radiotherapy but optimal dosing and pharmacokinetics in brain metastases patients need further investigation.

Brain metastatic patients undergoing hippocampal-avoiding/whole-brain radiotherapy/stereotactic radiosurgery, received memantine at 5-10 mg once or twice daily (OD or BID). Plasma samples were collected at trough (pre-dose) and peak (4 h post-dose) after ≥7 days of dosing and analysed by liquid chromatography-tandem mass spectrometry. Cognitive function was assessed using the Addenbrooke's Cognitive Examination at baseline, 4 and 6 months. We used nonlinear mixed-effects modeling to assess exposure-response pharmacokinetic analysis.

Plasma concentration of Memantine (16 patients; mean age: 57.5 ± 11.06 years, 50 % male) was dose-dependent from 5 mg OD to 10 mg BID. At 5 mg OD memantine touched subtherapeutic trough levels (median 16.7 ng/mL). While 5 mg BID achieved therapeutic levels (median118.06 ng/mL), 10 mg BID group exceeded laboratory alert threshold (>300 ng/mL).Median peak memantine concentrations were higher after Hippocampal-avoiding/whole-brain radiotherapy (median 430 ng/mL) than stereotactic radiosurgery (median 339 ng/mL). Prior systemic chemotherapy increased inter-individual variability in trough levels (172.1 ng/mL, in the 10 mg BID group). However, plasma memantine levels were stabler in the absence of chemotherapy (median 90.8 ng/mL in the 5 mg BID group). Prior intracranial surgery lowered trough concentrations (23.9 ng/mL, at 5 mg OD.

Hippocampal-avoidant or whole-brain radiotherapy patients required lower memantine doses for neuroprotection than stereotactic radiosurgery patients. Prior surgery/chemotherapy also influences memantine plasma levels.