A new approach for evaluation of the in vitro haemolytic potential of a solution of a new medicine

In the process of developing an intravenously injectable drug, its haemolytic potential must be considered. There are no Regulatory Guidelines for this kind of test. Many authors have set up different models, attempting to obtain early information about the behaviour of test compounds when injected into the bloodstream. In the present work, an in vitro 'static' model is presented, which takes into account the injection rate (R(inj.)) of the drug, and the blood flow rate (Q(v)) of the vein in which the drug must be injected. From the relationship between these two parameters, the C-max, expressed as mg/ml, can be calculated. This latter parameter allows us to calculate the drug concentration which, at any moment during injection, comes into contact with a known aliquot of 'new' blood passing through the injection site. Furthermore, a 'dynamic' test has been developed, which simulates an injection into the blood flow using a tubing system and infusion pumps set for the same R(inj.) and Q(v) values used in 'static' test. Two injectable drugs, Valium(R) and Lanoxin(R), and a commonly used vehicle, propylene glycol, have been tested by both the methods. These compounds have also been tested with another in vitro method (Prieur et al. 1973), in which a volumetric blood-to-test solution ratio of 1:1 is adopted for every drug tested, with neither R(inj.) nor Q(v) being taken into account. Results of the haemolytic potential obtained with the three tests have been compared. A good correlation has been observed between the 'static' and the 'dynamic' tests, whereas Prieur's model, which uses a drug-to-blood ratio which is far higher than in vivo, has been shown to give false positive results. It is concluded that a test for the evaluation of the haemolytic potential of drugs must take into account the pharmacodynamic characteristics of the formulation intended to be injected, and at least the blood flow rate. The proposed 'static' test has been demonstrated to be an easy and reliable method of obtaining a true picture of the in vivo situation.