Pharmacokinetic studies on a new purified factor IX concentrate

Abstract

Elstree, Herts. UKIn recent years, several purified factor IX concentrates have been produced with a much higher specific activity for factor IX activity than prothrombin concentrate complexes (PCCs). As a result of additional purification steps, these new concentrates are essentially free of other clotting factors [l-61. The rationale that led to the development of these products has been the hypothesis that the presence of clotting factors other than factor IX contributes to the risk of thrombogenicity previously associated with the use of PCCs [7-lo]. Recent experience with purified factor IX concentrates, both in animals and man, suggests that they may prove to be less thrombogenic than PCCs [4,11-141.The prothrombin concentrate complex produced for many years by the Bio Products Laboratory, Elstree (BPL), has a specific activity of 2.0-3.0 idmg. This product, known as 9A, has an excellent record for haemostatic efficacy, but as with other PCCs there have been occasional reports of thromboembolic complications [ 151. Accordingly, a new purified factor IX concentrate was developed by BPL that was essentially free of other clotting factors (see page 12). Following demonstrations in vitro and in animal studies that it was likely to be less thrombogenic than PCCs (see page 16), studies were carried out in man to establish the pharmacokinetic profile of the new product. Phamacokinetic studies in patients with haemophilia BA cross-over study was carried out on 19 patients with haemophilia B given on different occasions, a conventional three-factor PCC (9A) and the new high-purity factor IX (Replenine) developed by BPL [16]. Both preparations were given intravenously with at least a 7-day period between the infusions, Factor IX levels were measured pre-infusion, and at 10 and 30 min, 1, 3,6, 9,24, 30,46 and 50 h postinfusion. Sixteen severe (<lo/,) and three moderate (< 5%) haemophilia B patients were studied. Four haemophilia centres participated in the study.9A is a conventional PCC prepared at BPL by ionexchange chromatography. The product contains factor I1 and X, as well as factor IX, and has a specific factor IX activity of 2.0-3.0 idmg [17,18]. The new high-purity factor IX concentrate is prepared using a metal chelate affinity chromatography process (see page 12) and has a specific activity of 150-170 iu/mg. To ensure viral safety, both products were subjected to specific viral inactivation steps. The PCC was subjected to dry heat at a temperature of 80°C for 72 h, whereas the high-purity concentrate was subjected to a solvenddetergent step, known to be highly effective in destroying lipid-coated viruses, including HIV, HBV and HCV [19]. The half-life of circulating factor IX from each infusion was calculated using the two-phase linear regression model [20], and recovery was defined as the highest factor IX concentration in the first hour post-infusion [21]. Dose-adjusted recovery was calculated by dividing actual recovery by the dose of factor IX concentrate given expressed as iu per kg body weight. Clearan...