Nimodipine dosing and pharmacokinetic variability in subarachnoid hemorrhage patients

Nimodipine remains the only prophylaxis for delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (SAH). The multifactorial etiology and variable presentation of DCI preclude dosing decisions based on clinical status. Despite this, nimodipine is routinely administered at a fixed dose, irrespective of patient-specific factors such as body weight, organ function, or penetration into target site. Characterizing nimodipine pharmacokinetics may enable individualized dosing approaches to improve treatment efficacy. Our objective is to describe the plasma and cerebrospinal fluid (CSF) pharmacokinetics of enteral nimodipine in SAH patients.

SAH patients ≥ 18 years with a clinical indication for nimodipine underwent serial plasma and CSF sampling. Nimodipine concentrations were quantified using ultra-high performance liquid chromatography coupled with tandem mass spectrometry. Pharmacokinetics were analysed using noncompartmental methods and nonlinear mixed-effects modelling. The effects of route of administration (oral versus nasogastric tube) and feeding state (fed versus fasted) were assessed.

Thirty patients were included (70% females; mean weight 78.6 ± 20 kg; mean age 57 ± 12 years; 30% ≥65 years). A two-compartment population pharmacokinetic model with first-order absorption and linear elimination best fit the data, with age identified as a significant covariate on clearance. The median CSF-to-plasma exposure ratio was 0.35%, indicating minimal CSF penetration with high interindividual variability. Food markedly reduced nimodipine bioavailability, with lower plasma exposure observed for both oral and nasogastric administration in the fed versus fasted state.

Nasogastric administration and non-fasting states may reduce nimodipine's bioavailability. CSF penetration was minimal and highly variable. The population pharmacokinetic model identified age as a significant determinant of clearance. Optimizing the administration of nimodipine may be required. Further large-scale studies focusing on the definition of nimodipinés optimal dosing are warranted.