Inter-individual variability in pharmacokinetics and clinical features in pediatric patients with severe hemophilia A

Kun Huang; Yan Wang; Yingzi Zhen; Gang Li; Xinyi Wu; Ningning Zhang; Zhenping Chen; Runhui Wu

doi:10.1016/j.thromres.2022.03.008

Inter-individual variability in pharmacokinetics and clinical features in pediatric patients with severe hemophilia A

Thromb Res. 2022 May:213:71-77. doi: 10.1016/j.thromres.2022.03.008. Epub 2022 Mar 12.

Authors

Kun Huang¹, Yan Wang², Yingzi Zhen³, Gang Li⁴, Xinyi Wu³, Ningning Zhang⁵, Zhenping Chen⁶, Runhui Wu⁷

Affiliations

¹ Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China, 100045; Hematologic Disease Laboratory, Hematology Center, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China, 100045.
² Rehabilitation Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, China.
³ Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China, 100045.
⁴ Hematologic Disease Laboratory, Hematology Center, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China, 100045.
⁵ Radiology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, China.
⁶ Hematologic Disease Laboratory, Hematology Center, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China, 100045. Electronic address: chenzhenping@outlook.com.
⁷ Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China, 100045. Electronic address: runhuiwu@hotmail.com.

PMID: 35305529
DOI: 10.1016/j.thromres.2022.03.008

Abstract

Introduction: As the most commonly used FVIII concentrate in China, the individualized pharmacokinetics (PK) and clinical outcomes of Kovaltry (BAY81-8973) are not fully investigated in this population.

Materials and methods: Pediatric patients with severe hemophilia A were enrolled in Beijing Children's Hospital. After a three-day washout, they received PK tests after a single-dose infusion of 50 IU/kg. The blood samples were collected with a six-point assay. One-stage-based activated partial thromboplastin time was used for FVIII activity. The PK parameters were generated by WinNonlin software. The bleeding rates were calculated by their routine therapy record. The ultrasound was used to evaluate their both sides of knees, elbows and ankles.

Result: Sixty-one boys with severe hemophilia A were enrolled and their median age was 5.73 years. Twenty-nine of them were blood group-O. Compared with blood group-O patients, those non-O patients showed longer t_1/2 (15.26 vs. 13.03 h, P < 0.001) and reduced CL (3.04 vs. 3.66 mL/kg/h, P < 0.05). Patients with higher VWF:Ag level had longer half-life time (t_1/2) (r = 0.60, P < 0.0001) and lower clearance (CL) (r = -0.45, P < 0.001). Patients with higher trough level showed decreased bleeding rates compared with those owning a trough level below 1 IU/dL (P < 0.05). In general, the zero bleeding rates raised with elevation of trough level. However, 20-30% of patients with low trough level (<1 IU/dL) also showed no bleeds and 10-20% of patients with high trough level (>5 IU/dL) still suffer bleeds. An inconsistency of 28% between joint bleeds and ultrasound evaluation was showed.

Conclusion: This study revealed the great inter-individual variability in PK parameters, clinical bleeding phenotype and joint vulnerability, which all should be considered in treating hemophilia A.

Keywords: Bleeds; Factor VIII; Hemophilia A; Pharmacokinetics; Variability.

MeSH terms

Blood Group Antigens*
Child
Factor VIII* / pharmacokinetics
Factor VIII* / therapeutic use
Half-Life
Hemarthrosis
Hemophilia A* / drug therapy
Hemorrhage / drug therapy
Humans

Substances

Blood Group Antigens
F8 protein, human
Factor VIII