G. Dalnegro et P. Cristofori, A NEW APPROACH FOR EVALUATION OF THE IN-VITRO HEMOLYTIC POTENTIAL OF A SOLUTION OF A NEW MEDICINE, Comparative haematology international, 6(1), 1996, pp. 35-41
In the process of developing an intravenously injectable drug, its hae
molytic potential must be considered. There are no Regulatory Guidelin
es for this kind of test. Many authors have set up different models, a
ttempting to obtain early information about the behaviour of test comp
ounds when injected into the bloodstream. In the present work, an in v
itro 'static' model is presented, which takes into account the injecti
on rate (R(inj.)) of the drug, and the blood flow rate (Q(v)) of the v
ein 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. Furthermor
e, a 'dynamic' test has been developed, which simulates an injection i
nto the blood flow using a tubing system and infusion pumps set for th
e same R(inj.) and Q(v) values used in 'static' test. Two injectable d
rugs, Valium(R) and Lanoxin(R), and a commonly used vehicle, propylene
glycol, have been tested by both the methods. These compounds have al
so been tested with another in vitro method (Prieur et al. 1973), in w
hich a volumetric blood-to-test solution ratio of 1:1 is adopted for e
very drug tested, with neither R(inj.) nor Q(v) being taken into accou
nt. 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 t
o give false positive results. It is concluded that a test for the eva
luation of the haemolytic potential of drugs must take into account th
e pharmacodynamic characteristics of the formulation intended to be in
jected, and at least the blood flow rate. The proposed 'static' test h
as been demonstrated to be an easy and reliable method of obtaining a
true picture of the in vivo situation.