Van Moort I.1*, Preijers T.2*, Goedhart M.H.J.1, Hazendonk H.C.A.M.1, Schutgens R.E.G.3, Laros-van Gorkom B.A.P.4, Nieuwenhuizen L.5, van der Meer F.J.M.6, Fijnvandraat K.7,8, Leebeek F.W.G.9, Meijer K.10, Mathôt R.A.A.2, Cnossen M.H.1, for the “OPTI-CLOT” study group
1Department of Pediatric Hematology, Erasmus University Medical Center, Sophia Children’s Hospital Rotterdam, the Netherlands; 2Department of Clinical Pharmacology, Hospital Pharmacy, Amsterdam University Medical Centers, the Netherlands; 3Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands; 4Department of Thrombosis and Hemostasis, Radboud university medical center, Nijmegen, the Netherlands; 5Department of Thrombosis and Hemostasis, Maxima Medical Center, Veldhoven, the Netherlands; 6Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands; 7Department of Pediatric Hematology, Amsterdam University Medical Centers, Amsterdam, the Netherlands; 8Department of Molecular and Cellular Hemostasis, Sanquin Research, Amsterdam, the Netherlands; 9Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands; 10Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands.
* Corresponding author; e-mail i.vanmoort@erasmusmc.nl
Background
- Under-and especially overdosing of replacement therapy in hemophilia A patients with varying BMI may be prevented using other morphometric variables than actual body weight to dose factor VIII (FVIII) concentrates.
- Population pharmacokinetics (PK) enables to investigate how morphometric variables correlate with PK of FVIII.
Aim
- To explore the extent to which morphometric variables describe inter-individual variability of FVIII concentrate PK in normal weight, overweight and obese hemophilia A patients.
Patients & Methods
- Fifty-seven hemophilia A patients (FVIII:C≤0.05 IU/mL) underwent individual PK profiling: FVIII bolus 50 IU/kg, measurement of FVIII:C at t=4, t=24, t=48 hours.
- A population PK model was constructed, in which inter-individual variability (IIV) for clearance (CL) and central volume of distribution (V1) was quantified in NONMEM® software.
- Relationships between CL, V1 and five morphometric variables e.g. body weight, ideal body weight (IBW), lean body weight (LBM), adjusted body weight (ABW), and body mass index (BMI) were evaluated.
Table 1. General characteristics of the study population
Table 2. Summary of the covariate relationship selection process
Figure 1. Clearance and volume of distribution versus ideal body weight. (A) Clearance. (B) Volume of distribution of the central compartment. The individual PK parameter estimates were obtained by posthoc analysis using the final model. The blue line depicts the typical values, as calculated using the final model, versus ideal body weight (IBW).
Figure 2. Boxplots of the individual PK parameters for each BMI category. (A) Clearance (B) Volume of distribution of the central compartment. (C) Terminal elimination half-life. (D) Calculated in vivo recovery. For each boxplot, the whiskers depict the 2.5th and 97.5th percentile of the data, whereas the box depicts the interquartile range. The median of the data is depicted by the black horizontal line inside the boxplot.
Figure 3. Boxplots of simulated peak and trough FVIII levels in steady-state. The FVIII peak levels (upper panels) were obtained 5 minutes after the simulated loading-dose of 50 IUkg-1 that was followed by twice daily dosing of 25 IUkg-1 to treat a life-threatening bleed. The trough FVIII levels (lower panels) were obtained immediately before the 6th dose, which corresponded with 72 hours after administration of the loading-dose. The individual FVIII levels were simulated using the individual PK parameters from each patient of the studied population. The blue bar depicts the median FVIII level.
Conclusions
Doses of FVIII concentrate in overweight and obese hemophilia A patients are most accurately calculated based on ideal body weight.