Iris van Moort1, Tim Preijers2, Hendrika C A M Hazendonk1, Roger E G Schutgens3, Britta A P Laros-van Gorkom4, Laurens Nieuwenhuizen5, Felix J M van der Meer6, Karin Fijnvandraat7,8, Frank W G Leebeek9, Karina Meijer10, Ron A A Mathôt2, Marjon H Cnossen1. 1. Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children's Hospital Rotterdam, The Netherlands. 2. Department of Clinical Pharmacology - Hospital Pharmacy, Amsterdam University Medical Centers, The Netherlands. 3. Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands. 4. Department of Thrombosis and Hemostasis, Radboud university medical center, Nijmegen, The Netherlands. 5. Department of Thrombosis and Hemostasis, Maxima Medical Center, Veldhoven, The Netherlands. 6. Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands. 7. Department of Pediatric Hematology, Amsterdam University Medical Centers, Amsterdam, The Netherlands. 8. Department of Molecular and Cellular Hemostasis, Sanquin Research, Amsterdam, the Netherlands. 9. Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands. 10. Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands.
Abstract
AIMS: Under- and, especially, overdosing of replacement therapy in haemophilia A patients may be prevented by application of other morphometric variables than body weight (BW) to dose factor VIII (FVIII) concentrates. Therefore, we aimed to investigate which morphometric variables best describe interindividual variability (IIV) of FVIII concentrate pharmacokinetic (PK) parameters. METHODS: PK profiling was performed by measuring 3 FVIII levels after a standardized dose of 50 IU kg-1 FVIII concentrate. A population PK model was constructed, in which IIV for clearance (CL) and central volume of distribution (V1) was quantified. Relationships between CL, V1 and 5 morphometric variables (BW, ideal BW [IBW], lean BW, adjusted BW, and body mass index [BMI]) were evaluated in normal weight (BMI < 25 kg m-2 ), overweight (BMI 25-30 kg m-2 ) and obese haemophilia A patients (BMI > 30 kg m-2 ). RESULTS: In total, 57 haemophilia A patients (FVIII≤0.05 IU mL-1 ) were included with median BW of 83 kg (range: 53-133) and median age of 48 years (range: 18-77). IBW best explained observed variability between patients, as IIV for CL and V1 was reduced from 45.1 to 37.6 and 26.% to 14.1%, respectively. CL, V1 and half-life were similar for all BMI categories. The national recommended dosing schedule did not result in adequate trough levels, both in case of dosing based on BW and IBW. However, dosing based on IBW prevented unnecessary high FVIII peaks. CONCLUSION: IBW is the most suitable morphometric variable to explain interindividual FVIII PK variability and is more appropriate to dose overweight and obese patients.
AIMS: Under- and, especially, overdosing of replacement therapy in haemophilia Apatients may be prevented by application of other morphometric variables than body weight (BW) to dose factor VIII (FVIII) concentrates. Therefore, we aimed to investigate which morphometric variables best describe interindividual variability (IIV) of FVIIIconcentrate pharmacokinetic (PK) parameters. METHODS: PK profiling was performed by measuring 3 FVIII levels after a standardized dose of 50 IU kg-1 FVIIIconcentrate. A population PK model was constructed, in which IIV for clearance (CL) and central volume of distribution (V1) was quantified. Relationships between CL, V1 and 5 morphometric variables (BW, ideal BW [IBW], lean BW, adjusted BW, and body mass index [BMI]) were evaluated in normal weight (BMI < 25 kg m-2 ), overweight (BMI 25-30 kg m-2 ) and obese haemophilia Apatients (BMI > 30 kg m-2 ). RESULTS: In total, 57 haemophilia Apatients (FVIII≤0.05 IU mL-1 ) were included with median BW of 83 kg (range: 53-133) and median age of 48 years (range: 18-77). IBW best explained observed variability between patients, as IIV for CL and V1 was reduced from 45.1 to 37.6 and 26.% to 14.1%, respectively. CL, V1 and half-life were similar for all BMI categories. The national recommended dosing schedule did not result in adequate trough levels, both in case of dosing based on BW and IBW. However, dosing based on IBW prevented unnecessary high FVIII peaks. CONCLUSION: IBW is the most suitable morphometric variable to explain interindividual FVIII PK variability and is more appropriate to dose overweight and obesepatients.