Inter and Intra-Individual Variation of Factor VIII Half-Life In Severe Haemophilia A

Conventional dosing of FVIII prophylaxis in adults with hemophilia is based on 3 weekly or alternate day regimes of 20–40IU/kg, aiming for a trough level above 1IU/dL. However, pharmacokinetics of FVIII widely varies between individuals, thus the amount of factor concentrate required to maintain trough levels above 1IU/dL is also disparate. Mathematical modeling indicates that half-life has a significant influence over trough level. An individualized dose based on FVIII half-life may therefore allow for more appropriate dosing of prophylaxis in adults. For this approach to be effective, half-life results obtained from pharmacokinetic studies need to be consistent and representative of an individual's steady state. Although it is recognised that half-life increases from early childhood until adolescence, intra-individual variation of half-life in adults has not been examined.

We hypothesized that for patients >18years significant inter-individual variation, but minimal intra-individual variation, in half-life would be detected.

This single center study investigated inter- and intra-individual variation in FVIII half-life based on 140 pharmacokinetic studies conducted in 73 individuals with severe hemophilia A (FVIII:C < 1IU/dL). Data for all FVIII pharmacokinetic studies performed over a 5-year period were extracted from an in-house database. Patient demographics and laboratory results were verified against electronic patient records. All half-life studies were performed according to a set protocol and analyzed within the same clinical pathology accredited reference laboratory. Results were tested using the non-parametric Wilcoxin signed rank test. Data is presented as median and range and p-values < 0.001 were considered significant.

The median age of patients was 17.5 years (range 5.0– 54.0).

The wide range in FVIII half-life data indicated substantial inter-individual variation within the complete population (median 9.9hrs, range 2.3–19hrs), replicated upon division of data into age specific categories (Fig. 1).

Figure 1.

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Inter-individual variation of half-life

Figure 1.

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Inter-individual variation of half-life

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36 patients had undergone multiple studies over the 5-year period. Of these, 21 had at least 3 data sets. FVIII half-life showed considerable intra-individual variation with 17 patients (81%) demonstrating a range of half-life greater than 2hrs.

FVIII half-life data was normalized to nullify the effect of extensive inter-individual variation in half-life within the population. Figure 2 demonstrates mean difference in normalized FVIII half-life for all patients with multiple half-life results. Testing against a null hypothesis of no variation, we found significant intra-individual variation upon examination of the entire population (n= 36, p<0.0001). Following exclusion of data from children less than 6 years, significant intra-individual variation could still be detected for children 6–18 years (n=19, p< 0.0001), and adults (n= 16, p<0.0001).

Figure 2.

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Mean intra-individual difference in half-life

Figure 2.

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Mean intra-individual difference in half-life

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This study verifies expected inter-individual variation of pharmacokinetic profiles and appears to support the concept of individualized prophylaxis regimes in adults based on half-life data. However, considerable intra-individual variation in FVIII half-life in adult patients was registered. Mathematical models have indicated that even modest changes in half-life influence dosing requirements for FVIII prophylaxis. Intra-individual fluctuations in FVIII half-life will necessitate regular pharmacokinetic studies to ensure appropriate dosing. This will naturally affect the cost, utility and acceptability of treatment.

No relevant conflicts of interest to declare.