Variation in Nimodipine Exposure and its Effect on Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage

• Author / Creator

  Fadumo Isse

• Aneurysmal Subarachnoid Hemorrhage (SAH) is a life-threatening neurological emergency caused by a ruptured brain aneurysm leading to extravasation of blood into the subarachnoid space. SAH accounts for 5-10% of all strokes, affecting relatively younger age compared to ischemic strokes, leading to premature loss of productive life years. Neurological and medical complications are common following SAH and contribute significantly to patient outcomes. Delayed cerebral ischemia (DCI) and vasospasm are the main challenges that contribute to post SAH unfavorable patient outcomes. The Only Health Canada and FDA approved drug to prevent these two complications is nimodipine, a calcium channel blocker. Guidelines recommend that all patients with SAH to receive a fixed dose of oral nimodipine for 21 days. However, review of literature pertaining to nimodipine pharmacokinetics demonstrated extensive pharmacokinetic variability among different group of patients. Furthermore, limited evidence suggested lower exposure of the drug following enteral feeding administration compared to oral dosing. It is not clear if all patients are getting the full benefit of nimodipine. Therefore, our research aimed first to investigate retrospectively the impact of administering nimodipine via enteral feeding tubes on outcomes in patients with SAH. Second, we aimed to develop and validate an enantioselective assay for nimodipine to be utilized in our pilot study. Third, we aimed to conduct a prospective pilot study aimed to preliminarily determine potential factors that might have an influence on nimodipine exposure and to investigate whether there is a trend of possible association between nimodipine exposure and patient outcomes (vasospasm, DCI, and modified Rankin Scale (mRS) at 90 days post SAH admission). For the first objective, a retrospective chart review study was carried out that involved reviewing 85 charts for patients admitted to the University of Alberta Hospital. Following adjustment for disease severity, nimodipine administration through feeding tubes was associated with vasospasm in the first 7 days of patient admission where patients receiving nimodipine via enteral feeding tubes had increased odds of vasospasm compared to those administered it as whole tablets (OR 8.9, 95% CI 1.1-73.1, p value 0.042). When analyzed over the 21-day period, nimodipine administration by feeding tube was associated with increased odds of DCI compared to whole tablets (OR 38.1, 95% CI 1.4-1067.9, p value 0.032). For the enantioselective assay development, we presented an LC-MS/MS method for quantifying nimodipine enantiomers in human plasma using a small sample volume (0.3 ml) and a single liquid-liquid extraction step. The peak area ratios were linear over the tested concentration ranges (1.5-75 ng/ml) with r2 > 0.99. The intraday and interday CV and percent error were within ±14% while that of the interday was within ±13% making this analytical method feasible for research purposes and pharmacokinetic studies. For our third objective, we were able to recruit 7 patients admitted to the University of Alberta Hospital. Blood samples were collected following a single nimodipine 60 mg dose at steady state. Plasma nimodipine enantiomers concentrations were quantified using the LC-MS/MS method that we validated. Area under the concentration-time curve (AUC0-4h) was calculated. Factors that could influence plasma nimodipine concentrations were assessed in different patient categories. Both discharge outcomes and 3-months mRS were collected. Patients who took nimodipine through feeding tubes and those with high grade disease had a trend for lower systemic exposure. On the other hand, older patients had higher nimodipine exposure compared to younger ones. With regards to outcomes, the median AUC0-4h values for both nimodipine enantiomers were lower in the 2 patients who had developed vasospasm. There was also a trend for a lower (+)-R nimodipine exposure for patients who had modified Rankin Scale of 3 (worse outcome) than those who had an mRS of 1 (better outcome). In conclusion, the retrospective chart review findings suggested that nimodipine administration via enteral feeding tubes may be associated with vasospasm and DCI in subarachnoid hemorrhage patients possibly secondary to reduced exposure. In addition, we hope the findings of our retrospective and the pilot studies to lay the foundation of a larger prospective observational study to investigate the association between nimodipine exposure and patient outcomes, a step towards nimodipine individualization in SAH patients.

• Subjects / Keywords

  • Pharmacokinetic
  • nimodipine
  • SAH
  • enantio-selective assay

• Graduation date

  Spring 2021

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-922d-p468

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.