Most medicines are developed to be taken orally in the form of a pill. The drug is conveniently swallowed by the patient, dissolves in gastrointestinal fluid and is then absorbed across the intestinal wall. After transport to the liver, it enters the bloodstream and is delivered to its therapeutic target. This is a complex process, and the amount of oral drug absorbed (bioavailability) can be influenced by many factors. There are situations, however, where it is preferable for a drug to be administered intravenously: when a drug is poorly absorbed from the intestine (e.g. antibody-based therapies), when a patient is unable to take a drug by mouth (e.g. neonates, unconscious patients), or when doses of drug need to be given rapidly (e.g. antibiotics in serious situations).
If new drugs are developed that are designed to be administered intravenously, their preclinical safety should also be assessed when given by the same route. Various options exist when intravenous dosing is required in rodent cardiovascular safety studies. Animal restraint and placement of a temporary catheter in the tail vein may be the most straightforward method, but this is unsuitable for longer duration infusions, and stress-induced cardiovascular changes may mask effects caused by the test drug. Implantation of intravenous catheters requires surgery and has other welfare issues, including using harnesses and permanent single housing of the animal. Our standard method uses vascular access buttons (VABs) (Instech Ltdand SAI Infusion Technologies), which offer advantages over traditional techniques.
Effects on blood pressure and heart rate during intravenous infusion of a vehicle using VABs (green and red) compared to traditional restraint and tail vein method (blue). Restraint-induced increase in heart rate and blood pressure can be observed with the traditional method. Bars and lines indicate infusion times.
Rats are implanted with telemetry transducers (Datasciences Inc) for the recording of arterial blood pressure and ECG using standard methods and analgesic regimens. Following recovery (usually 2 weeks), animals undergo a second separate surgery in which a femoral vein is catheterised and connected to a VAB. The animals are recovered, and welfare checks made post-surgery. Analgesia protocols are again applied at the time of and after the VAB surgery.
Using VABs allows the animals to be returned to group housing 1-2 days after surgery and animals are fit for use on safety pharmacology studies from approximately 5 days after implantation. On study days, animals are moved to single housing cages for dosing and telemetry recording but are returned to group housing at the end of the recording periods (e.g. 24h post start of dose). To administer the dose of test drug, only light, transient restraint (approx. 10s) is required to connect the drug infusion apparatus to the VAB. No restraint is applied during the intravenous dosing and the infusion line is quickly disconnected after completion of the dose. This technique requires minimal handling of the animal and allows the cardiovascular effects of intravenous test drug to be assessed without confounding stress-induced artefact caused by traditional restraint methods. Use of VABs is also a welfare refinement since it allows group housing of animals during recovery and non-dosing periods.
Matt is a highly trained scientist with many years of experience working in drug discovery and safety pharmacology groups in large pharmaceutical companies and CROs.
