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.
Bibliographical noteFunding Information:
R.E.G. Schutgens has received research support from CSL Behring and Sanquin. B. Laros‐van Gorkom has received unrestricted educational grants from Baxter and CSL Behring. F.J.M. van der Meer received grants from Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Sanquin and Sobi for the development of a registry of haemophilia patients in the Netherlands (HemoNED). K. Fijnvandraat is a member of the European Hemophilia Treatment and Standardization Board sponsored by Baxalta, has received unrestricted research grants from CSL Behring, Pfizer and Bayer, and has given lectures at educational symposiums organized by Pfizer, Baxalta, Novonordisk and Bayer. F.W.G. Leebeek received research support from CSL Behring and Shire, and is consultant for uniQure, Novo Nordisk and Shire, of which the fees go to the institution. He is a member of the DSMB for a of Roche study. K. Meijer received research support from Bayer, Sanquin and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS and Aspen; consulting fees from Uniqure (all fees go to the institution). R.A.A. Mathôt has served as advisor for Bayer, CSL Behring, Merck Sharp & Dohme, Shire and Zeria (all honoraria/fees paid to the department); He has received unrestricted research grants from Bayer, CSL Behring and Shire. M.H. Cnossen has received unrestricted research/educational and travel funding from the following companies: Pfizer, Baxter, Bayer Schering Pharma, CSL Behring, Novo Nordisk, Novartis and Nordic Pharma over the years, and has served as a member on steering boards of Roche and Bayer. All received fees go to the institution. The remaining authors declare no competing financial interests.
This study is part of the international multicentre OPTI‐CLOT consortium research program (Patient tailOred PharmacokineTIc‐guided dosing of CLOTting factor concentrate and desmopressin in bleeding disorders), which aims to implement PK‐guided dosing of clotting factor replacement therapy and desmopressin by initiating studies that emphasize the impact of PK‐guided dosing, by constructing prophylactic and on‐demand population PK models, and by evaluating the cost‐effectiveness of a PK‐guided approach. A complete list of the members of the OPTI‐CLOT research program is available in the appendix. This study is part of the OPTI‐CLOT randomized controlled trial (Netherlands Trial Registry: NL3955) which was kindly funded by a grant from NWO‐ZonMw (grant number 836011011), a governmental research institution and by an unrestricted investigator‐initiated research grant provided by Baxter/Shire/Baxalta/Takeda.
This study is part of the international multicentre OPTI-CLOT consortium research program (Patient tailOred PharmacokineTIc-guided dosing of CLOTting factor concentrate and desmopressin in bleeding disorders), which aims to implement PK-guided dosing of clotting factor replacement therapy and desmopressin by initiating studies that emphasize the impact of PK-guided dosing, by constructing prophylactic and on-demand population PK models, and by evaluating the cost-effectiveness of a PK-guided approach. A complete list of the members of the OPTI-CLOT research program is available in the appendix. This study is part of the OPTI-CLOT randomized controlled trial (Netherlands Trial Registry: NL3955) which was kindly funded by a grant from NWO-ZonMw (grant number 836011011), a governmental research institution and by an unrestricted investigator-initiated research grant provided by Baxter/Shire/Baxalta/Takeda.
© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.