Pharmacometric modeling to explore 4F-PCC dosing strategies for VKA reversal in patients with INR below 2

Abstract

The indicated dose of 4-factor prothrombin complex concentrate (4F-PCC) for urgent vitamin K antagonist (VKA) reversal in patients with an international normalized ratio (INR) of 2 to 4 is 25 IU/kg, but there is no indicated dose for INR <2. We explored 4F-PCC dosing strategies for baseline INR <2. Clinical trial data were used to develop pharmacometric models for Factor X (FX) and FII, accounting for covariates including baseline INR. FX and FII levels over time were simulated for mean baseline INR levels of the clinical trial participants plus baseline INRs 3.1, 1.9, and 1.6. For each INR, 200 virtual male patients were simulated to evaluate 4F-PCC doses of 35, 25, 20, 15, 12.5, and 10 IU/kg. Given an elevated bleeding risk with VKA therapy in Japanese vs Western populations, results were stratified by Japanese and non-Japanese patients. Target levels of FX and FII were ≥50% activity at 30 minutes after dosing in ≥80% of patients. FX- and FII-time models were developed with 1088 FX observations from 193 patients and 1074 FII observations from 192 patients. Model-based simulations indicated that at baseline INR 3.1, ≥80% of patients achieved ≥50% FX and FII activity with 25 IU/kg and 20 IU/kg 4F-PCC, respectively; at baseline INR 1.9, corresponding doses were 20 IU/kg and 15 IU/kg 4F-PCC, and at baseline INR 1.6, corresponding doses were 15 IU/kg, and 10 IU/kg 4F-PCC. Trends in Japanese and non-Japanese patients were similar. In conclusion, low 4F-PCC doses (15-20 IU/kg) may be sufficient to achieve hemostatic levels of FX and FII in Japanese and non-Japanese patients with baseline INR <2.

Graphical abstract

Figure 1.

Comparison of model prediction of FX and FII relationship with baseline INR vs published data to validate the models. (A-B) The FX relationship is shown in panel A and the FII relationship in panel B. The black line represents the baseline factor level–baseline INR relationship from model simulations. The observed data from the phase 3 trials (used to generate the models) is plotted with black circles. Observed data obtained from published studies, which investigated the FX-INR relationship (Gulati et al) and the FII-INR relationship (Gulati et al and Baumann Kreuziger et al) in patients are represented by lavender squares and red crosses, respectively. *Model predictions for baseline INR levels of 1.6 to 10.

Figure 2.

Relationship of FX and FII levels with INR levels at baseline and post-4F-PCC. (A-B) FX data are shown in panel A and FII data in panel B. The observed data from the phase 3 trials (used to generate the models) is plotted with lavender squares representing baseline (pre-infusion) data and black circles representing post-infusion data.

Figure 3.

Prediction-corrected visual predictive checks to validate the models: comparison of FX- and FII-time modeled relationships using the final covariate models with observed data from the phase 3 trials. (A-B) FX-time relationship is shown in panel A and FII-time relationship in panel B. The black circles represent observed patient data from the phase 3 trials. The blue solid and dashed lines represent the observed median, 20th, and 80th percentiles, respectively. The red solid and dashed lines indicate the corresponding percentiles from the model simulations. The pink shaded regions are the 95% confidence intervals for the simulated percentiles.