Abstract
Pharmacokinetic (PK) evaluation was performed prior to each of two prospective, multicenter studies (1 each in US and EU) to guide dosing of a VWF/FVIII concentrate (Humate-P®; Haemate P; “HP”) in subjects with VWD. The results reported herein question the usefulness of these early pharmacokinetic measurements in preparation for surgery.
Methods: In the US, 41 subjects received 60 IU/kg VWF: RCo, and in the EU study 28 subjects received approximately 80 IU/kg VWF:RCo HP. Median plasma levels, half-life, mean change from baseline and in-vivo recovery (IVR) values were determined for VWF:RCo, VWF:Ag, and FVIII: C at various time points following administration. Area under the plasma time-concentration curve (AUC), mean residence time (MRT), clearance, volume of distribution and dose linearity were also assessed for VWF:RCo. Collagen-binding activity (VWF:CBA) was correlated with VWF:RCo and FVIII.
Results: In the US and EU studies, baseline VWF:RCo levels were 13 (6–124) IU/dL (median, range)and 18.1 (5–58) IU/dL, respectively; the highest median post-infusion values were 163 (84–330) IU/dL and 147 (53–387)IU/dL. Mean change from baseline in the US study was >100 IU/dL immediately after the infusion, decreasing to about 10 IU/dL at 48 hours post-infusion. In the US and EU studies, respectively, median terminal half-life (T½) of VWF:RCo was 11.7 (3.5–74.9) hours and 9.9 (2.8–51.1) hours; alpha T½ was 1.2 (0.2–3.2) hours and 1.5 (0.3–13.9) hours. The group median incremental in vivo recovery (IVR) for VWF:RCo in the US and EU studies was 2.4 and 1.9 IU/dL/IU/kg, respectively. Dose linearity was demonstrated over a wide range of dosages (10–151 IU/kg). Median incremental IVR values for VWF:Ag were 2.3 IU/dL (US) and 2.1 IU/dL (EU). In the US and EU studies, median baseline levels of FVIII: C were 39 (0.5–96) and 33 (range, 2–106) IU/dL. Mean change of FVIII: C from baseline (US) was approximately 60 IU/dL post-infusion, levels decreasing to slightly above 20 IU/dL at 48 hours. Median incremental IVRs for FVIII in the US and EU studies were 2.7 and 2.8 IU/dL/IU/kg. Median baseline levels of VWF:CB were 13.0 (1.5–101) (US) and 10.4 (1.0–84) (EU) IU/dL. The highest median VWF:CBA value was 131.5 (60–204) IU/dL (US) 15 minutes post-infusion and 147 (21–330) IU/dl (EU) 30 minutes post-infusion. By 48 hours, median levels decreased to near baseline in both studies. Multimer analysis confirmed HMW multimers were detectable for ≥8 hours post infusion. In the US study patients, very weak correlation was observed between IVR of VWF:RCo performed in the steady state and IVR just prior to or after HP infusions for surgery, on the day of surgery (r= 0.48), days 2 to 3 post-surgery (r=0.09) and >3 days post-surgery (r=0.41), indicating substantial intra-subject variability. Each individual patient demonstrated wide variability in IVR for VWF:RCo, when correlating the IVR from repeated HP infusions.
Conclusions: Pharmacokinetics of FVIII and VWF:RCo after repeated HP infusions were characterized by a biphasic profile, dose linearity over a wide range of dosages, and good correlation with VWF:CB values. The median IVR values for VWF:RCo (2.4, 1.9) and FVIII (2.7, 2.8) were consistent with those reported in previous experience with HP. Although group median values were fairly consistent among repeated IVR measurements in the US subjects, the intra-individual IVR values for VWF:RCo with repeated HP infusions showed a large degree of variability, with no trend over time. IVR values obtained from pharmacokinetic analyses performed in advance of anticipated surgery do not reliably predict post-infusion circulating levels of VWF:RCo or FVIII attained pre-operatively or with subsequent post-operative infusions. To assure adequate hemostasis for surgical procedures in these patients, close perioperative monitoring of plasma VWF:RCo and FVIII levels are recommended.
O20 Dose-linearity of the pharmacokinetics of an intravenous [14C]midazolam microdose in children