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Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics

The Pharmacogenomics Journal volume 24, Article number: 19 (2024) Cite this article

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Abstract

Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.

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Fig. 1: Proposed CYP3A4 and CYP3A5 nimodipine metabolizer types as extensive, intermediate, average, and poor metabolizers.
Fig. 2: Sankey flow diagram showing heterogeneity of multiple dose changes (60 mg, 30 mg, 15 mg, or 0 mg) in aSAH patients during hospital stay and until discharge.
Fig. 3: Distribution of mRS scores at discharge among dose reduced patients.
Fig. 4: Distribution of mRS scores at discharge among the different metabolizer groupings.

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Data availability

The datasets generated during and/or analyzed during the current study are available in the Mayo Clinic pharmacogenomics SAH red cap repository. The datasets generated during and/or analyzed during the current study are not publicly available due HIPAA confidentiality but could become available from the corresponding author on reasonable consortium limited data set request for collaborative research. All the pharmacogenomic data and demographics reported and analyzed during this study are included in this published article.

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Acknowledgements

Presented in part at Mayo Clinic’s 14th Annual Stroke and Cerebrovascular Disease Review Continuous Professional Development course, Amelia Island, FL, Sept 23, 2022. The Scientific Publications staff at Mayo Clinic provided copyediting, proofreading, administrative, and clerical support.

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Mayo Clinic.

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Authors and Affiliations

  1. University of Puerto Rico, Medical Sciences Campus School of Medicine, San Juan, Puerto Rico

    Adriana Vázquez-Medina

  2. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

    Marion T. Turnbull, James F. Meschia & W. David Freeman

  3. Department of Emergency Medicine, Mayo Clinic, Jacksonville, FL, USA

    Courtney L. James

  4. Division of Hospital Internal Medicine, Mayo Clinic, Jacksonville, FL, USA

    Jennifer B. Cowart

  5. Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL, USA

    Elizabeth Lesser & Rickey E. Carter

  6. Department of Artificial Intelligence and Informatics, Mayo Clinic, Jacksonville, FL, USA

    Rickey E. Carter

  7. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Owen A. Ross

  8. Department of Neurologic Surgery, Mayo Clinic, Jacksonville, FL, USA

    David A. Miller, James F. Meschia & W. David Freeman

  9. Division of Neuroradiology, Mayo Clinic, Jacksonville, FL, USA

    David A. Miller

  10. Department of Neurosurgery, University of Puerto Rico, San Juan, Puerto Rico

    Aixa De Jesús Espinosa

  11. Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA

    Richard Weinshilboum

  12. Department of Critical Care Medicine, Mayo Clinic, Jacksonville, FL, USA

    W. David Freeman

Authors
  1. Adriana Vázquez-Medina
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  2. Marion T. Turnbull
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Contributions

AVM, CLJ, and JBC contributed to collection, analysis, and interpretation of data; drafting and critical revision of the manuscript; and collection/generation of figures and tables. MTT and WDF contributed to conception and design; experiments; collection, analysis, and interpretation of data; drafting and critical revision of the manuscript; and collection/generation of figures and tables. EL, REC, OAR, DAM, JFM, ADJE, and RW contributed to analysis and interpretation of data and critical revision of the manuscript. All authors approved the final article.

Corresponding author

Correspondence to W. David Freeman.

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The authors declare no competing interests.

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Our study was approved by the Mayo Clinic Institutional Review Board (IRB 18-001392).

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Vázquez-Medina, A., Turnbull, M.T., James, C.L. et al. Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics. Pharmacogenomics J 24, 19 (2024). https://doi.org/10.1038/s41397-024-00340-3

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