Woo Yul Lee1,2,, Dongwoo Chae1, Chur Woo You3, Ki Young Yoo4, Jung Woo Han5 and Kyungsoo Park1*
1 Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea 2 Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea 3 Department of Pediatrics, Eulji University College of Medicine, Daejeon, Korea 4 Korea Hemophilia Foundation, Seoul, Korea 5 Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
Objectives: Although several population pharmacokinetic (PK) models for recombinant coagulation factor VIII are presently available, no such model has been developed in Korean population. Population PK (PPK) model, however, has many applications if developed, one important example of which is therapeutic drug monitoring (TDM) which is widely used for patient care. In TDM, PPK model is used as a basis to estimate individual PK parameters to be used to find an optimal individual dose. Thus, PPK model is a key to monitoring and controlling drug concentrations, particularly useful for drugs with a narrow therapeutic window or wide interindividual variation. In the case of hemophilia patients who have little or no endogenous coagulation factor VIII, the use of TDM based on PPK model is further important as maintaining factor VIII concentrations above a certain effective level with an exogenous coagulation factor VIII given regularly is crucial for them to avoid suffering from life-threatening bleeding tendency.
In this respect, our study aims to develop a population PK model of recombinant coagulation Factor VIII and investigate its relationship with covariates such as age, body weight and Von Willebrand Factor (VWF) in Korean patients with hemophilia A, with an expectation of improving their quality of life and possibly saving medical expenses given the high price of recombinant factor VIII preparations.
Methods: Data were acquired from a prospectively designed coagulation factor VIII PK study conducted by Korea Hemophilia Foundation in 2018. In total, after a brief infusion of factor VIII, 85 samples from 21 subjects with hemophilia A were used for analysis. The severity of hemophilia was classified into 3 categories according to the baseline concentration of coagulation factor VIII (1 mild, 2 moderate, 18 severe). Age ranged from 9 to 75yr, with the median value being 26 yr. Body weight ranged from 27.5 to 110 kg, with the median value being 66 kg. The concentration of VWF ranged from 71.7 to 229 IU/dl, with the median value being 116.7 IU/dl. Based on theory-based allometry [1,2], body weight was incorporated into the volume of distribution (V) linearly and into clearance (CL) with a power function. Significant relationships of covariates with PK parameters were initially explored using R and then formally tested using stepwise covariate model building. All analyses were performed using R ver 3.5.2 and NONMEM ver 7.3.
Results: One compartment model with 1st order elimination described the data. Results showed that CL (dL/hr) of factor VIII decreased by 0.53% per one year increase in age and it also decreased with the increase of VWF concentration. The typical parameter estimates evaluated at the median body weight (66kg) were 44.04 dL for V, 2.977 dL/hr for CL and 2.33 IU/dL for coagulation factor VIII baseline concentration. The inter-individual variabilities (CV%) were 12.3% for CL, 18.1% for V and 94.9% for baseline factor VIII concentration. The proportional residual error (CV%) was estimated to be 15.1%. Our model successively described the time course of observed coagulation factor VIII concentrations.
Conclusions: One compartment model competently described our data although two compartment models are more commonly suggested by previous studies. This could be due to small sample size and sparse sampling points of our data. Nevertheless, these preliminary results demonstrated that clearance of recombinant coagulation factor VIII in Korean hemophilia A patient is negatively influenced by age and the concentration of VWF binding with coagulation factor VIII, where the former relation was as shown by previous PK studies. Given a small sample size used in current study, further work in a larger patient population would be needed to generalize the results.
References:
[1] Hendrika H, Fijnvandraat K, Lock J, Driessens M, van deer Meer F, Meijer K, et al. A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients. Haematologica. 2016;101(10):1159-1169
[2] Bjo¨rkman S, Oh M, Spotts G, Schroth P, Fritsch S, Ewenstein BM, et al Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood. 2012;119(2):612-618
Reference: PAGE 28 (2019) Abstr 8925 [www.page-meeting.org/?abstract=8925]
Poster: Drug/Disease Modelling - Other Topics