Page 135 - 2021_07-Haematologica-web

FVIII activity and bleeding risk in hemophilia A
Figure 1. Patients’ time spent in dif- ferent FVIII:C activity ranges predict- ed from dosing diaries. The first week of prophylaxis is illustrated for two representative patients on turoctocog alfa dosed three times weekly. Predicted profiles of FVIII:C activity were calculated from the reported patients’ diary information on doses and timing of doses. Both patients exhibited a dosing interval pattern of 2-2-3 days in their first week, although the last two doses were delayed and higher for patient 2 than for patient 1. Triangles represent the area under the curve (AUC) of FVIII:C contributing to the mean FVIII:C value for each range. The horizontal span of each triangle defines the time spent in the relevant FVIII:C range. Both the AUC and time spans were calculated across dosing intervals and patient years. Actual trough FVIII:C was meas- ured inconsistently and locally, and was not generally used to guide treat- ment decisions.
Discussion
We used a population PK model and diary-recorded dos- ing data to estimate FVIII levels in patients with severe hemophilia A undergoing prophylaxis with turoctocog alfa and assessed the relationship between FVIII:C and ABR using diary-recorded data on bleeds. This approach confirmed an association between higher FVIII activity levels and reduced risk of spontaneous bleeding, apparent across all ages and trial phases. Bleeding rates were lower in the extension phase than in the pivotal phase at the same FVIII:C levels, consistent with previous spontaneous ABR data from these studies.13 The FVIII exposure–bleed- ing relationship was also apparent for both adults/adoles- cents and children. This effect, however, disappeared dur- ing the extension phase; after a period of 6 months of pro- phylaxis during the pivotal studies, the bleeding risk in adult patients approached that of the pediatric population. This suggests that patients’ characteristics at baseline accounted for the difference in bleeding risk between the age groups. The use of a large number of data on out- comes and their potential modifiers, combined from patients in different age groups and trial phases, is a strength of our study. It is reasonable to assume that the observed relationship between FVIII:C and ABR, as well as the role of modifying factors, is largely independent of the factor concentrate used in the source studies. The main conclusions conveyed by our work are therefore for prophylaxis with any factor concentrate in severe hemo- philia A.
Although our analysis showed that ABR decreased with higher FVIII:C, it was not possible to identify a single FVIII:C level that would prevent bleeding in all patients. For example, an ABR of <2 was achieved when FVIII:C was >15% in the pivotal phase but had already been achieved when FVIII was >1% in the extension phase. We would speculate that, over time, the patients’ clinical con- dition (including joint disease activity) improved and the bleeding risk decreased. In addition, the effect of previous on-demand treatment on ABR would have diminished over time and may have contributed to the lower bleeding
Table 2. Population pharmacokinetic parameters.
Parameter
CL70 kg, 20 y (mL/h)a
V70 kg (L)b
Allometric scaling exponent for body weight
on clearance (eCL)
Allometric scaling exponent for body weight on V (eV) Age effect on CL (1/year)
Population parameter estimate (CV)
302 (0.32)
3.46 (0.22) 0.95
0.86
-0.01
aReference value for a 70-kg, 20-year-old patient. bReference value for a 70-kg patient. CL: clearance; CV: inter-individual variability;V: volume of distribution.
rates in the extension phase. Over a third of adult/adoles- cent patients received only on-demand treatment prior to entering the pivotal trial,9 potentially affecting joint disease and bleeding risk at study entry, even at higher FVIII:C levels. In children (who commonly start prophylactic reg- imens early on), an ABR <2 was achieved at any FVIII:C level ≥1%, consistent with the notion that pristine joints have a lower risk of bleeding during prophylaxis. The lower bleeding rates in adults in the extension phase com- pared with the pivotal phase could therefore indicate a “calming-down” effect of prophylaxis on joint disease activity.
These results support the notion that treatment out- comes (and study endpoints) such as ABR would not only be influenced by FVIII exposure, but also by patient-relat- ed factors such as age, activity level, or joint status. Different hemophilia products, including extended half- life factor concentrates, can transform FVIII exposure, but direct comparison of outcomes across studies may be con- founded by such patient-related factors. Similar con- founders may have to be considered when comparing results of non-factor replacement therapy or even gene therapy to results achieved with FVIII replacement.
Our findings on the FVIII exposure-response relation- ship support and build on data from other modeling analy- ses using negative binomial distribution in patients with hemophilia A. Collins et al.6 established the importance of
haematologica | 2021; 106(7)
1905