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Abstract Background: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who experience severe and frequent bleeding episodes. Prophylactic therapy may be individualised by pharmacokinetic (PK)-guided dosing. Effective clinical implementation of PK-guided dosing requires knowledge of both the interpatient PK variability and the relationship between drug exposure and bleeding risk. Objective: To develop a population PK model for the plasma-derived VWF/factor VIII (FVIII) 1:1 concentrate (Wilate®) in patients with severe VWD and to explore the relationship between VWF/FVIII activity and bleeding events during prophylaxis. Methods: A nonlinear mixed-effects PK modelling approach was applied to VWF:ristocetin cofactor (VWF:RCo) and FVIII activity (FVIII:C) data from pediatric and adult patients participating in a prospective single-dose (WIL-12) and a 1-year prospective, prophylaxis phase 3 trial (WIL-31; NCT04052698). Individual post-hoc PK profiles were constructed, and VWF/FVIII activity levels were retrospectively assessed at the time of bleeding events. Results: 658 VWF:RCo and 692 FVIII:C levels were obtained from 53 patients with a median age of 23 years (range: 7-68 years) with VWD, comprising 11 with severe type 1, 10 with type 2A, 1 with type 2B, 2 with type 2M, and 29 with type 3. One- and two-compartment turnover population PK models best described the PK profiles for VWF:RCo and FVIII:C, respectively. For VWF:RCo, the typical value of clearance and its interpatient variability were 3.4 dL/h/70 kg and 47%, respectively; for FVIII:C, the corresponding values were 1.8 dL/h/70 kg and 57%. Post hoc analysis revealed that 50% of the 71 spontaneous bleeds during WIL-31 occurred at levels <3.7 IU/dL VWF:RCo and <9.1 IU/dL FVIII:C. Similarly, 50% of the 49 traumatic bleeds occurred at VWF:RCo levels <4.6 IU/dL and FVIII:C levels <14.7 IU/dL. Conclusion: In this study, we developed a population PK model for the plasma-derived VWF/FVIII 1:1 concentrate that can support clinicians in optimising VWD therapy by assessment of exposure PK metrics (trough levels, area under the curve, time above a defined threshold) and VWF:RCo and FVIII:C levels at the time of bleeding. As the population PK model of the VWF/FVIII 1:1 concentrate creates parallel PK profiles of VWF:RCo and FVIII:C, PK-guided may be performed by monitoring FVIII as well as VWF. Our population PK model enables informed treatment decisions, advancing the personalisation of long-term prophylaxis for plasma-derived VWF/FVIII in severe VWD.