Nimodipine Variability in SAH

Subarachnoid Aneurysm Hemorrhage, Subarachnoid Hemorrhage, Aneurysmal

nimodipine, subarachnoid hemorrhage, pharmacokinetics

Aneurysmal subarachnoid hemorrhage (SAH) is a life-threatening neurological illness: it is bleeding in the brain after a bulging blood vessel (a brain aneurysm) ruptures. Although SAH accounts for only 5% of all strokes, it often happens in middle age and it puts a significant burden on many patients during their most productive years. Complications following SAH are common, and they can cause major long-term disability. Only one medication - nimodipine - has been proven to benefit the health and wellbeing of these patients. All SAH patients should receive nimodipine for 21 days at a fixed dose. However, our early work suggested that all patients are not getting equal amounts of nimodipine into their blood. In addition, the two different forms (structural mirror images) of nimodipine might have different effects. Reduced amounts of nimodipine in the blood may lessen its benefit and contribute to worsening health and wellbeing of SAH patients. The overall goal of this research is to see what happens with different nimodipine doses and to confirm whether the two forms of nimodipine have different effects. The investigators will conduct a multi-centre study in adult patients admitted for SAH in Canada and the USA. The investigators will collect blood samples to determine the amount of each type of nimodipine in each participant's body, and then will check to see how each participant is doing at 90 days following SAH. They will also check other factors affecting nimodipine levels, so that they can in the future suggest dose recommendations that are actually tailored to each patient.

Background and Importance: Aneurysmal subarachnoid hemorrhage (SAH) is a life-threatening neurological illness characterized by the extravasation of blood into the subarachnoid space secondary to a ruptured brain aneurysm. Although SAH accounts for only 5% of all strokes, it often places a significant burden on the most productive years of a patient's life because of the relatively young average age at onset. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH and are significant contributors to disability in those surviving the initial bleed. Several agents have been tested to target vasospasm and DCI, but nimodipine was the only drug therapy that was shown to significantly improve neurological outcomes, and current guidelines recommend that all patients receive fixed-dose racemic nimodipine for 21 days following ictus. However, the pilot data suggested significant variability of nimodipine concentrations in the plasma, but it was not clear if minimal or lack of systemic exposure to nimodipine denies its benefit and contributes to worsening patient outcomes. Furthermore, the investigators' pilot data suggested that the two enantiomers of nimodipine might have differential effects, but it was not clear if one enantiomer is preferred over the other. The overall goal of this research is to characterize the predictors and the clinical consequences of altered exposure to nimodipine enantiomers in SAH patients. Research Aims: 1. To determine the associations between systemic exposure to the two nimodipine enantiomers and the primary and secondary outcomes in SAH patients. 2. To determine whether nimodipine enantiomers differ in their effects on safety in SAH patients. 3. To determine the population pharmacokinetics of nimodipine enantiomers and to develop individualized dosing recommendations in SAH populations. Approach: This study is for a multi-centre prospective study in adult patients admitted to the hospital for SAH. Participants will have blood samples collected for the determination of plasma concentrations of nimodipine enantiomers. Participant data will be collected prospectively, and the primary outcome will be their modified Rankin Scale (mRS) score at 90 days following SAH onset. The mRS is a functional outcome scale commonly used SAH studies. Regression modeling will be used to determine if systemic exposures to nimodipine enantiomers (quantified as the area under the concentration-time curves) are independent predictors of mRS outcomes. Predictors of exposure to nimodipine enantiomers will also be determined using population pharmacokinetics, and individualized dosage regimens will be recommended.

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Canada, United States