Abstract
Purpose
Intra-arterial (IA) administration of nimodipine has been shown to be an effective treatment for subarachnoid hemorrhage-related cerebral vasospasm. The concentrations achieved in cerebral arteries during this procedure, though, are unknown. Therefore, there are no clinical studies investigating dose-dependent effects of nimodipine. We aimed at providing a pharmacokinetic model for IA nimodipine therapy for this purpose.
Methods
A two-compartment pharmacokinetic model for intravenous nimodipine therapy was modified and used to assess cerebral arterial nimodipine concentration during IA nimodipine infusion into the internal carotid artery (ICA).
Results
According to our simulations, continuous IA nimodipine infusion at 2 mg/h and 1 mg/h resulted in steady-state cerebral arterial concentrations of about 200 ng/ml and 100 ng/ml assuming an ICA blood flow of 200 ml/min and a clearance of 70 l/h. About 85 % of the maximal concentration is achieved within the first minute of IA infusion independent on the infusion dose. Within the range of physiological and pharmacokinetic data available in the literature, ICA blood flow has more impact on cerebral arterial concentration than nimodipine clearance.
Conclusion
The presented pharmacokinetic model is suitable for estimations of cerebral arterial nimodipine concentration during IA infusion. It may, for instance, assist in dose-dependent analyses of angiographic results.
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Abbreviations
- SAH:
-
Subarachnoid hemorrhage
- IA:
-
Intra-arterial
- ICA:
-
Internal carotid artery
- IV:
-
Intravenous
References
Velat GJ, Kimball MM, Mocco JD, Hoh BL. Vasospasm after aneurysmal subarachnoid hemorrhage: review of randomized controlled trials and meta-analyses in the literature. World Neurosurg. 2011;76:446–54.
Pluta RM, Hansen-Schwartz J, Dreier J, Vajkoczy P, Macdonald RL, Nishizawa S, Kasuya H, Wellman G, Keller E, Zauner A, Dorsch N, Clark J, Ono S, Kiris T, Leroux P, Zhang JH. Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought. Neurol Res. 2009;31:151–8.
Vergouwen MDI, Ilodigwe D, Macdonald RL. Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. Stroke. 2011;42:924–9.
Etminan N, Vergouwen MD, Ilodigwe D, Macdonald RL. Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2011;31:1443–51.
Ott S, Jedlicka S, Wolf S, eter M, Pudenz C, Merker P, Schürer L, Lumenta CB. Continuous selective intra-arterial application of nimodipine in refractory cerebral vasospasm due to aneurysmal subarachnoid hemorrhage. BioMed Res Int. 2014;2014:1–11.
Linn J, Fesl G, Ottomeyer C, Straube A, Dichgans M, Bruckmann H, Pfefferkorn T. Intra-arterial application of nimodipine in reversible cerebral vasoconstriction syndrome: a diagnostic tool in select cases? Cephalalgia. 2011;31:1074–81.
Musahl C, Henkes H, Vajda Z, Coburger J, Hopf N. Continuous local intra-arterial nimodipine administration in severe symptomatic vasospasm after subarachnoid hemorrhage: Neurosurgery. 2011;68:1541–7.
Biondi A, Ricciardi GK, Puybasset L, Abdennour L, Longo M, Chiras J, Van Effenterre R. Intra-arterial nimodipine for the treatment of symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage: preliminary results. AJNR Am J Neuroradiol. 2004;25:1067–76.
Mayer TE, Dichgans M, Straube A, Birnbaum T, Müller-Schunk S, Hamann GF, Schulte-Altedorneburg G. Continuous intra-arterial nimodipine for the treatment of cerebral vasospasm. Cardiovasc Intervent Radiol. 2008;31:1200–4.
Hui C, Lau KP. Efficacy of intra-arterial nimodipine in the treatment of cerebral vasospasm complicating subarachnoid haemorrhage. Clin Radiol. 2005;60:1030–6.
Hänggi D, Turowski B, Beseoglu K, Yong M, Steiger HJ. Intra-arterial nimodipine for severe cerebral vasospasm after aneurysmal subarachnoid hemorrhage: influence on clinical course and cerebral perfusion. AJNR Am J Neuroradiol. 2008;29:1053–60.
Dahl SG, Aarons L, Gundert-Remy U, Karlsson MO, Schneider YJ, Steimer JL, Trocóniz IF. Incorporating physiological and biochemical mechanisms into pharmacokinetic–pharmacodynamic models: a conceptual framework*. Basic Clin Pharmacol Toxicol. 2010;106:2–12.
Rämsch KD, Ahr G, Tettenborn D, Auer LM. Overview on pharmacokinetics of nimodipine in healthy volunteers and in patients with subarachnoid hemorrhage. Neurochirurgia (Stuttg). 1985;28 Suppl 1:74–8.
Loftsson T. Essential pharmacokinetics: a primer for pharmaceutical scientists. New York (NY): Academic Press; 2015.
Scheel P, Ruge C, Schöning M. Flow velocity and flow volume measurements in the extracranial carotid and vertebral arteries in healthy adults: reference data and the effects of age. Ultrasound Med Biol. 2000;26:1261–6.
Rothoerl RD, Schebesch KM, Woertgen C, Brawanski A. Internal carotid artery volume flow correlates to rCBF measurements. Acta Neurochir (Wien). 2003;145:943–7. (discussion 947).
Vinge E, Andersson KE, Brandt L, Ljunggren B, Nilsson LG, Rosendal-Helgesen S. Pharmacokinetics of nimodipine in patients with aneurysmal subarachnoid haemorrhage. Eur J Clin Pharmacol. 1986;30:421–5.
Cho W-S, Kang H-S, Kim JE, Kwon OK, Oh CW, Son YJ, Know BJ, Jung C, Hang MH. Intra-arterial nimodipine infusion for cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. Interv Neuroradiol. 2011;17:169–78.
Seker F, Hesser J, Neumaier-Probst E, Groden C, Brockmann MA, Schubert R, Brockmann C. Dose-response relationship of locally applied nimodipine in an ex vivo model of cerebral vasospasm. Neuroradiology. 2013;55:71–6.
Firat MM, Gelebek V, Orer HS, Belen D, Firat AK, Balkanci F. Selective intraarterial nimodipine treatment in an experimental subarachnoid hemorrhage model. AJNR Am J Neuroradiol. 2005;26:1357–62.
Kumana CR, Kou M, Yu YL, Fong KY, Fung CF, Chang CM, Mück W, Lauder IJ. Investigation of nimodipine pharmacokinetics in Chinese patients with acute subarachnoid haemorrhage. Eur J Clin Pharmacol. 1993;45:363–6.
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Rudolf Schubert and Carolin Brockmann contributed equally as senior authors
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Seker, F., Hesser, J., Brockmann, M. et al. Pharmacokinetic Modeling of Intra-arterial Nimodipine Therapy for Subarachnoid Hemorrhage-Related Cerebral Vasospasm. Clin Neuroradiol 27, 199–203 (2017). https://doi.org/10.1007/s00062-015-0464-1
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DOI: https://doi.org/10.1007/s00062-015-0464-1