Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B

Abstract

Background: Pharmacokinetic (PK)-guided dosing is used to individualize factor (F)VIII and FIX replacement therapy.

Objectives: This study investigates the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B.

Methods: In this multicenter, prospective cohort study, people of all ages with hemophilia received prophylactic treatment with factor concentrates based on individual PK parameters. During follow-up, at least 4 measured FVIII/FIX levels per patient were compared with corresponding predicted levels obtained by Bayesian forecasting. Predictive performance was defined as adequate when ≥80% of measured FVIII/FIX levels were within ±25% of prediction (relative error). Additionally, mean absolute error and mean error were calculated. In post hoc analyses, predictive performance was assessed allowing maximum absolute errors of 1 (trough), 5 (mid), and 15 (peak) IU/dL. Five-point scale questionnaires addressed feasibility of PK guidance.

Results: We included 50 patients (median age, 19 years; range: 2-72 years). Median follow-up was 36 weeks. Seventy-one percent of levels (58% trough, 83% mid, and 80% peak) were within ±25% of prediction. Mean absolute errors were 0.8 (trough), 2.0 (mid), and 8.6 (peak) IU/dL. In post hoc analyses, 81% (trough), 96% (mid), and 82% (peak) of levels were within set limits. Patients reported low burden and high satisfaction.

Conclusion: PK-guided dosing was reliable according to post hoc analyses, based on low absolute errors that were regarded as clinically irrelevant in most cases. The predefined predictive performance was achieved in mid and peak factor levels but not in trough factor levels due to measurement inaccuracy. PK guidance also seemed feasible.

Keywords: factor IX; factor VIII; hemophilia A; hemophilia B; pharmacokinetics; preventive medicine.

Figure 1

Study design OPTI-CLOT TARGET. ABR, annualized bleeding rate; FIX, factor FIX; FVIII, factor FVIII; PK, pharmacokinetic.

Figure 2

Predictive performance of follow-up factor levels during pharmacokinetic-guided dosing. The predicted factor levels based on the individual pharmacokinetic parameters are plotted against the observed factor levels. The blue lines represent ±25% limits of deviation, and in green (top right), the percentage of samples within these limits is depicted (70.7%). The various factor concentrates are depicted in different colors. No obvious differences between factor concentrates are observed. The shape of the markers characterizes the nature of the factor level according to time after dose and dosing schedule (trough, mid, and peak). For readability, factor levels <15 IU/dL are enlarged in the right corner of the plot. As is demonstrated, more trough levels fall outside the limits in the detail of this figure.

Figure 3

The absolute error is presented for trough, mid, and peak factor (F)VIII/FIX levels. Observed factor levels that were within ±25% of the predicted values are depicted in green, while levels outside these boundaries are red. Median observed factor activity levels for trough, mid, and peak levels were 2.2 (IQR, 1.5-4.9), 11.8 (IQR, 6.9-17.2), and 47.0 (IQR, 28.5-82.0) IU/dL, respectively. The mean absolute error (MAE, accuracy) and mean error (ME, bias) and including 95% CIs are presented in the bottom of the plot. The figure shows that the proportion of adequately predicted factor levels (in green) is higher for peak levels, though the absolute error is low for trough levels. Furthermore, in the prediction of the peak levels, a significant bias is observed. These predicted levels are generally overestimated.

Figure 4

Time with factor levels <1 and <5 IU/dL during the prospective and retrospective study periods for (A) all patients and (B) patients previously treated with body weight–based therapy. The boxes of the boxplots present the median (middle line) and IQR with whiskers extending to the first quartile or third quartile + 1.5 IQR. The lines represent individual patients, and darker lines indicate multiple patients. For (A) all patients, time spent with factor levels <1 and <5 IU/dL decreased in the prospective period (P < .001 and P = .003, respectively). For 29 patients who were previously on body weight–based prophylaxis (B), time spent with factor levels <1 IU/dL reduced in the prospective period in comparison with the retrospective period (P = .001). The time spent with factor levels <5 IU/dL did not differ between the 2 periods in this group (P = .54).

Figure 5

Annualized bleeding rates (ABRs) of 25 patients who switched from body weight–based therapy in the retrospective study period to PK-guided dosing in the prospective study period and completed follow-up. The first panel shows ABRs of all bleeds, the second panel shows ABRs of joint and muscle bleeds, and the third panel shows ABRs of spontaneous joint and muscle bleeds. The boxes of the boxplots present the median (middle line) and IQR with whiskers extending to Q1 or Q3 + 1.5 IQR. The lines represent the individual bleeding rates. The ABR of the prospective period was calculated and extrapolated, since the follow-up period was shorter than an entire year. Overall, a minimal fluctuation is observed, and no statistically significant differences were found between study periods for all bleeds (P = .76), joint and muscle bleeds (P = .98), and spontaneous joint and muscle bleeds (P = .96).

Figure 6

Patient- and physician-reported outcomes regarding the feasibility of pharmacokinetic (PK)-guided dosing. All questions utilized a 1- to 5-point visual analog scale, ranging from very low/very easy (1) to very high/very difficult (5). At study initiation and closure, patients answered questions in the following domains: 1) difficulties combining prophylaxis with daily activities (barrier daily activities), 2) difficulties combining prophylaxis with traveling (barrier traveling), 3) extent of the burden of additional hospital visits for PK profiling (burden visits), 4) extent of the burden of additional blood sampling (burden sampling), 5) expectations and satisfaction with PK-guided dosing (satisfaction), and 6) importance of knowledge of factor levels during the week (importance knowledge). At study closure, patients answered 2 additional questions regarding 7) willingness to construct PK profiles in the future in case of a factor VIII/IX concentrate switch (future) and 8) if the patient would recommend PK-guided dosing to other patients (recommendation). Physicians were asked the same questions as patients at study initiation. At study closure, questions 1, 2, and 5 were repeated and physicians answered the following additional question: Would the physician like to dose other patients under PK guidance as well (others)? It is apparent from this graph that the burden of PK guidance is low (blue) and the satisfaction with PK guidance is high (orange).