Pharmacokinetics of Continuous Infusion Therapy of Factor VIII Concentrates in Hemophilia A Patients with Inhibitors,
Authors: Nishiya Katsumi , Tanaka Ichiro , Nogami Keiji , Ogiwara Kenichi , Yada Koji , Matsumoto Tomoko , Shima Midori 
Published: October 2019

Abstract
Abstract 3320
Continuous infusion (CI) of factor VIII (FVIII) concentrates is aimed at maintaining a steady hemostatic level of FVIII activity (FVIII:C) in hemophilia A patients during various surgeries. However, there are few reports that mentioned the difference of pharmacokinetics of CI therapy in hemophilia A patients with inhibitors. We investigated the relationship between the FVIII:C levels and the rate of CI, and the difference of clearance (CL) and volume of distribution (Vd) of FVIII in hemophilia A patients with/without inhibitors. 8 severe hemophilia A patients without inhibitors (arthroscopic synovectomy; 4 cases, total knee arthroplasty; 2 cases, total nephrectomy; 1 case, partial hepatectomy; 1 case), 3 patients with low-titer (2.0–2.9 BU) inhibitors and 3 patients with high-titer (6.0–9.0 BU) inhibitors (insertion or removal of a central venous access device), were enrolled in this study between 2005 and 2010. According to the Japanese guideline for hemophilia treatment, we should do CI therapy to keep target level 80–100% for 5–10 days for joint surgery and other major surgeries. An initial bolus infusion (BI) of FVIII concentrates was administered to achieve this level prior to CI. In addition, we have to neutralize the inhibitors by FVIII concentrates in case of the patients with inhibitors. FVIII:C was measured using one-stage clotting assays and FVIII inhibitor assays were performed using the Bethesda method. All therapy was conducted after obtaining fully informed consent. The median FVIII:C level after BI was 120.2% (range: 90–150) in the patients without inhibitors, 72.0% (range: 68–160) with low-titer inhibitors, and 20.0% (range: 9.4–30) with high-titer inhibitors, respectively. The target level of FVIII:C was adjusted to approximately 100%. The initial infusion rate was 3.7 U/kg/hr (range: 2.2–5.0), 8.3 U/kg/hr (range: 8.0–8.5) and 18.5 U/kg/hr (range: 15–22), respectively. After adjustment for the target level, the final infusion rate decreased to 2.6 U/kg/hr (range: 1.5–5.4), 4.7 U/kg/hr (range: 3.0–5.6) and 8.0 U/kg/hr (range: 7.0–9.0), respectively. CL was 2.3 ml/hr/kg (range: 1.5–3.9), 4.0 ml/hr/kg (range: 2.3–5.1) and 9.3 ml/hr/kg (range: 9.0–9.6), respectively. Vd was 0.04 L/kg (range: 0.031–0.047), 0.18 L/kg (range: 0.12–0.29) and 1.54 L/kg (range: 0.95–2.43), respectively. No unexpected safety concerns associated with CI, such as thrombosis, was identified during the study. On CI therapy, we could keep target level of the patients without inhibitors and with low-titer inhibitors easier than those with high-titer inhibitors. One of the reason is that CL and Vd in patients with inhibitors are higher than those in patients without inhibitors. CI with appropriate monitoring of FVIII:C level and concerning CL and Vd forms a safe method for perioperative care in hemophilia A patients with inhibitors.

Disclosures:
No relevant conflicts of interest to declare.