Andexanet alfa is a recombinant form of human FXa protein that has been modified to lack FXa enzymatic activity. The active site serine was substituted with alanine, rendering the molecule unable to cleave and activate prothrombin, and the gamma-carboxyglutamic acid (Gla) domain was removed to eliminate the ability of the protein to assemble into the prothrombinase complex, thus removing any anti-coagulant effects.
Andexanet alfa is a specific reversal agent for FXa inhibitors. The predominant mechanism of action is the binding and sequestration of the FXa inhibitor. In addition, andexanet alfa has been observed to bind to, and inhibit tissue factor pathway inhibitor (TFPI). Inhibition of TFPI activity can increase tissue factor-initiated thrombin generation inducing a pro-coagulant effect.
The effects of andexanet alfa can be measured through pharmacodynamic markers, including free fraction of available FXa inhibitor as well as through restoration of thrombin generation. In addition, andexanet alfa has been shown to inhibit TFPI-activity.
Commercial anti-FXa-activity assays are unsuitable for measuring anti-FXa activity following administration of andexanet alfa. Due to the reversible binding of andexanet alfa to the FXa inhibitor, the high sample dilution currently used in these assays leads to dissociation of the inhibitor from andexanet alfa, resulting in detection of erroneously elevated anti-FXa activity levels, thereby causing a substantial underestimation of the reversal activity of andexanet alfa.
In prospective, randomised, placebo-controlled, dose-ranging studies in healthy subjects, the dose and dose regimen of andexanet alfa required to reverse anti-FXa activity and restore thrombin generation for FXa inhibitors (apixaban or rivaroxaban) were determined with modified assays that are not commercially available.
The maximal reversal of anti-FXa activity was achieved within two minutes of completing the bolus administration. Administration of andexanet alfa as a bolus followed by continuous infusion resulted in a sustained decrease in anti-FXa activity. The anti-FXa activity returned to the placebo levels and above approximately two hours after the end of a bolus or infusion dependent on dosage.
When andexanet alfa was administered as a bolus followed by a continuous infusion, the maximum decrease in unbound FXa inhibitors was rapid (within two minutes of the end of the bolus) and was sustained over the course of the infusion then gradually increased over time, reaching a maximum at approximately two hours following the end of infusion.
Restoration of thrombin generation following administration was dose- and dose-regimen-dependent and did not correlate with anti-FXa-activity beyond approximately four hours.
Plasma TFPI activity has been shown to be inhibited completely from 2 minutes to 14.5 hours after andexanet alfa bolus-administration in healthy subjects, and returned to baseline within 3 days. Tissue-factor (TF)-initiated thrombin generation immediately increased above the baseline (prior to anticoagulation) and remained elevated for >20 hours in contrast to placebo. Plausibility of a procoagulant effect of TFPI-inhibition is supported by consecutive and sustained slopes of D-Dimers, TAT, and F1+2.
PK/PD modelling and simulations rely on the interplay between andexanet alfa and FXa inhibitor PK and on the relationships between biomarkers, here anti FXa-activity, TFPI-activity, and ETP. There remain uncertainties regarding the differing effect of the anticoagulant apixaban or rivaroxaban, duration of the reversal effect dependent on the anti-TFPI-effect, and on the necessity of continuous infusion. Precision of simulations in bleeding patients is less than that within healthy volunteers due to the high inter-individual variability.
Studies of andexanet alfa in the presence of direct FXa inhibitors in healthy subjects demonstrated dose proportional pharmacokinetics over the intended therapeutic dose range evaluated for both Cmax and area under the curve (AUC). The pharmacokinetics of andexanet alfa has not been studied in bleeding patients due to feasibility reasons.
Pharmacokinetic parameters for Andexanet bolus-injection of 400 and 800mg:
| PK Parameter | 400 mg Bolus | 800 mg Bolus |
|---|---|---|
| AUC0-∞ (hr*μg/mL) | 61.3 [43.8, 94.9] | 127 [57.5, 209] |
| Cmax (μg/mL) | 61.0 [40.3, 98.5] | 118 [50.2, 191] |
| Clearance (L/hr) | 6.52 [4.21, 9.13] | 6.29 [3.83, 13.9] |
| T1/2 (hr) | 3.78 [2.59, 6.39] | 4.24 [2.47, 6.52] |
| Vss (L) | 9.47 [6.08, 15.3] | 8.94 [5.36, 23.1] |
Source: Study 19-514
Data presented are geometric mean [min, max]
In a study comparing andexanet alfa pharmacokinetics in elderly (65-69 years) and younger (26-42 years) healthy subjects who had received apixaban, the pharmacokinetics of andexanet alfa in the elderly subjects were not statistically different than those in the younger subjects.
No trials have been conducted to investigate the pharmacokinetics of andexanet alfa in renally impaired patients. Based on the available PK data, andexanet alfa has little to no renal clearance, and thus would not require dose adjustment for patients with renal impairment.
No trials have been conducted to investigate the pharmacokinetics of andexanet alfa in patients with hepatic impairment. Biliary and/or faeces elimination of protein therapeutics is not a known route of protein elimination. Therefore, dose adjustment is not considered needed for patients with hepatic impairment.
Based on population pharmacokinetics analysis, gender does not have a clinically meaningful effect on the pharmacokinetics of andexanet alfa.
The pharmacokinetics of andexanet alfa has not been studied in paediatric patients.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity studies up to two weeks in rats and monkeys.
Studies to evaluate the mutagenic and carcinogenic potential of andexanet alfa have not been performed. Based on its mechanism of action and on the characteristics of proteins, no carcinogenic or genotoxic effects are anticipated.
Animal reproductive and developmental studies have not been conducted with andexanet alfa.
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