Pharmacokinetic Modelling to Predict FVIII:C Response to Desmopressin and Its Reproducibility in Nonsevere Haemophilia A Patients

Abstract

Background Nonsevere haemophilia A (HA) patients can be treated with desmopressin. Response of factor VIII activity (FVIII:C) differs between patients and is difficult to predict.

Objectives Our aims were to describe FVIII:C response after desmopressin and its reproducibility by population pharmacokinetic (PK) modelling.

Patients and Methods Retrospective data of 128 nonsevere HA patients (age 7–75 years) receiving an intravenous or intranasal dose of desmopressin were used. PK modelling of FVIII:C was performed by nonlinear mixed effect modelling. Reproducibility of FVIII:C response was defined as less than 25% difference in peak FVIII:C between administrations.

Results A total of 623 FVIII:C measurements from 142 desmopressin administrations were available; 14 patients had received two administrations at different occasions. The FVIII:C time profile was best described by a two-compartment model with first-order absorption and elimination. Interindividual variability of the estimated baseline FVIII:C, central volume of distribution and clearance were 37, 43 and 50%, respectively. The most recently measured FVIII:C (FVIII-recent) was significantly associated with FVIII:C response to desmopressin (p < 0.001). Desmopressin administration resulted in an absolute FVIII:C increase of 0.47 IU/mL (median, interquartile range: 0.32–0.65 IU/mL, n = 142). FVIII:C response was reproducible in 6 out of 14 patients receiving two desmopressin administrations.

Conclusion FVIII:C response to desmopressin in nonsevere HA patients was adequately described by a population PK model. Large variability in FVIII:C response was observed, which could only partially be explained by FVIII-recent. FVIII:C response was not reproducible in a small subset of patients. Therefore, monitoring FVIII:C around surgeries or bleeding might be considered. Research is needed to study this further.

Keywords

desmopressin - factor VIII - haemophilia A - haemostasis - pharmacokinetics

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