F8 gene variants influence the response to desmopressin in hemophilia A carriers

Abstract

Desmopressin is often administered to correct factor VIII (FVIII) levels in female hemophilia A carriers (HAC). However, the post-desmopressin FVIII pharmacokinetic profiles have been reported only in small case series in this population. Therefore, this study analyzed the post-desmopressin FVIII and von Willebrand factor response in 361 HAC included at 14 French hemophilia treatment centers. A population pharmacokinetic/pharmacodynamic model was developed to analyze the VWF and FVIII levels by taking into account the F8 gene variants (n=143, 39.6%, with null, and n=218, 60.4%, with non-null variants), demographic and laboratory covariates. The prior/after desmopressin mean basal, peak and recovery FVIII:C levels were 0.34 IU.mL-1 (0.08-0.65), 1.13 IU.mL-1 (0.19-2.69), and 2.85 (1.06-7.13), respectively. Peak FVIII:C was ≥0.5 IU.mL-1 in 95.6% (345/361) and ≥0.8IU.mL-1 in 78.7% (284/361) of patients. The covariate analysis showed a poorer desmopressin FVIII response for null than non-null F8 variants: lower mean peak (1.04 vs 1.23 IU.mL-1, p<5.10-5) and lower percentage of patients with normalized FVIII:C (91.6% vs 98.1%, p=0.0068), higher mean clearance (5898.83 vs 2704.06 IU.h-1, p=1.58.10-15), lower mean AUC0-12h (7.73 vs 9.06 IU.mL-1.h, p<5.10-6), and shorter mean time with FVIII:C ≥0.8 IU.mL-1 (1.9 vs 4.1h, p<6.10-6). HAC with body weight <35 kg had lower peak FVIII:C, higher FVIII clearance, lower AUC0-12h, and shorter time with FVIII:C ≥0.8 IU.mL-1 than HAC with body weight 35-70 kg. The ABO blood type did not influence the response to desmopressin. In HAC, the post-desmopressin FVIII response is strongly influenced by the F8 genotype and body weight.