Subcutaneous administration of nimodipine improves bioavailability in rabbits

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Abstract

We compared subcutaneous and oral methods of nimodipine administration to determine a method of nimodipine administration that maintained serum levels at or above the optimal therapeutic concentration (7 ng/ml). Plasma concentrations of nimodipine were measured in New Zealand White rabbits (2.6–3.9 kg). First, peak plasma concentration (Cmax), time to reach peak plasma concentration (Tmax), and area under the curve (AUC) parameters were calculated and compared between animals receiving oral or subcutaneous nimodipine (5–15 mg/kg). Next, plasma concentrations were measured 24 h after subcutaneous administration of 2.5 mg/kg of nimodipine in healthy animals and animals with experimentally induced SAH. Cmax, Tmax and AUC parameters were significantly greater for subcutaneous compared to oral nimodipine administration, irrespective of dose. Mean nimodipine concentrations at 24 h were >7 ng/ml in both healthy animals (12.9 ± 10.0 ng/ml) and in animals with SAH (11.8 ± 4.6 ng/ml) that received 2.5 mg/kg of subcutaneous nimodipine. In this model, the subcutaneous method of nimodipine administration consistently maintains plasma levels at or above the optimal therapeutic concentration, whereas oral administration fails to do so.

Introduction

Vasospasm of the cerebral arteries due to subarachnoid hemorrhage (SAH) is a major source of delayed ischemic deficits in patients with ruptured aneurysms (Mayberg, 1998). The mechanisms responsible for delayed vasospasm following SAH are unclear, and therefore remain the focus of several animal studies (Dreier et al., 2002, Yasuda and Tietze, 1989).

Nimodipine is presently the only available therapy that has been proven to reduce the morbidity and mortality associated with delayed ischemic deficits in patients with SAH-related vasospasm (Dorsch, 2002). As a result, it is the benchmark which new therapies will be tested against. Future investigations that compare experimental therapies to nimodipine are essential precursors to an effective, comprehensive treatment plan for SAH.

In the investigation of various treatments for SAH, including nimodipine, the maintenance of stable, therapeutic plasma concentrations during the course of long-term, in vivo studies is an essential factor (Perez-Trepichio and Jones, 1996). However, animal studies investigating nimodipine treatment for SAH are faced with difficulties in adopting a dosing method that will maintain effective plasma levels in addition to being ethically and logistically acceptable. In humans, serum levels of nimodipine on the order of 7 ng/ml have been reported to be clinically effective (Allen et al., 1983).

In clinical practice, the standard method of dosing calls for a 60 mg oral dose of nimodipine to be given every 4 h for 21 days (Toyota, 1999). The frequency of this dosing regimen reflects the low bioavailability of orally-administered nimodipine. Pharmacokinetic studies show that the bioavailability of orally-administered nimodipine is between 4 and 13% in healthy subjects (Ramsch et al., 1985, Ramsch et al., 1986); it is also low in SAH patients, ranging from 2 to 28% (Vinge et al., 1986). Low plasma concentrations following orally-administered nimodipine are attributed to the high first-pass metabolism of nimodipine in the liver (Ramsch et al., 1985).

In a clinical setting, nimodipine can easily be administered frequently to counter the reduced bioavailability associated with oral dosing. However, administration of precise aliquots of drug orally to animals several times per day is considerably more challenging.

Intravenous nimodipine administration is an alternative to oral administration which provides greater bioavailability than oral dosing. However, continuous or frequent intravenous infusions are not well-suited to studies in animals lasting several days. Animal subjects will not typically tolerate continuous infusions, and frequent venepuncture is not practical since anesthesia is required for ethical reasons. At our institution, the animal ethics review board does not permit anesthesia more frequently than every 48 h for experimental animals. Furthermore, intravenous preparations of nimodipine presently are not commercially available, limiting the practicality of this route of administration.

Because of the limitations of the oral and intravenous routes of nimodipine administration for animal studies, a convenient, well-tolerated, and readily available alternative method for providing nimodipine in animal studies would be of value to investigators. The purposes of this study were to determine: (1) whether subcutaneous administration of nimodipine is practical; and (2) whether subcutaneous dosing offers advantages over oral administration for achieving target serum levels.

Section snippets

Study design

Blood samples were collected after oral or subcutaneous nimodipine administration from adult male specific pathogen free (SPF) New Zealand White rabbits (2.6–3.9 kg). Plasma concentrations of nimodipine were measured both in healthy animals and in animals with experimentally-induced SAH. First healthy animals that received oral nimodipine (n = 6) were compared to those that received subcutaneous nimodipine (n = 4) for doses of both 5 and 15 mg/kg. Next, following a subcutaneous dose of 2.5 mg/kg,

Oral versus subcutaneous nimodipine administration in healthy animals

Mean values for Cmax, Tmax, and AUC are reported in Table 2. Peak nimodipine concentrations were lower, and occur sooner after oral nimodipine doses than after subcutaneous administration (Fig. 1).

The results of the MANOVA revealed a significant interaction between dosing method and dose (P < 0.05). Further univariate analysis showed that this interaction occurred only for Tmax (P < 0.05).

Dosing method produced the largest effect on the parameters. Subcutaneous nimodipine administration led to

Discussion

Investigating the delayed effects of nimodipine in an animal model of SAH requires a dosing method that maintains stable, optimal, plasma levels of the drug. Ideally, this method should be safe, require infrequent drug administration, and cause minimal discomfort to the animals. In future studies of experimental therapies for SAH it will be necessary to compare new treatments to standard nimodipine therapy. Consequently, there is persistent interest in elucidating the effects of nimodipine on

Acknowledgements

This work is supported in part by funds from the Canadian Institute for Health Research (CIHR) and the American Society of Neuroradiology Foundation Scholar Award in Neuroradiology Research. A.M. Laslo receives support as a member of the CIHR Strategic Training Program in Vascular Research. The authors would like to thank Jennifer Hadway and Dominique Ouimet for their assistance with the animals used in this study.

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