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. 2022 Apr;15(4):1027-1035.
doi: 10.1111/cts.13233. Epub 2022 Feb 25.

Population pharmacokinetic modeling and simulations of berotralstat for prophylactic treatment of attacks of hereditary angioedema

Amanda Mathis  1 , Mark Sale  2 , Melanie Cornpropst  1 , William P Sheridan  1 , Shu Chin Ma  1
Affiliations

Population pharmacokinetic modeling and simulations of berotralstat for prophylactic treatment of attacks of hereditary angioedema

Amanda Mathis et al. Clin Transl Sci. 2022 Apr.

Abstract

Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by recurrent episodes of swelling of the skin, larynx, gastrointestinal tract, genitals, and extremities that can be disruptive to patient quality of life. Dysregulation of plasma kallikrein activity leads to increased production and accumulation of bradykinin in HAE and causes attacks of angioedema. Plasma kallikrein is a serine protease essential for the formation of bradykinin. Berotralstat is a potent, highly selective, orally bioavailable small-molecule plasma kallikrein inhibitor that has been approved to prevent attacks of HAE in adults and children 12 years of age and older. Population pharmacokinetic (PK) analyses were conducted to describe the PK of berotralstat (BCX7353; Orladeyo™ ) and to evaluate the covariates that may explain variability in PK. The PK of berotralstat were characterized by population PK modeling of data from 13 clinical studies and a total of 771 healthy subjects and patients with HAE. The PK profile was well described by a three-compartment model with first-order absorption including an absorption lag time and linear elimination. Among the covariates tested, the effects of bilirubin and food were found not to be clinically significant and were removed from the model. Covariate analysis indicated significant effects of dose on bioavailability and weight on berotralstat clearance and volume. Despite the covariate effect of weight, simulations in adolescents and adults who were underweight, low weight, and overweight demonstrated similar predicted exposures to those observed at therapeutic doses in a clinical trial. Therefore, no dose adjustment is required in these HAE patient subpopulations.

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Conflict of interest statement

M.C. and W.P.S. are current employees at BioCryst Pharmaceuticals, Inc. A.M. and S.M. were previously employed by BioCryst Pharmaceuticals, Inc. M.S. is a compensated consultant to BioCryst Pharmaceuticals, Inc.

Figures

FIGURE 1
FIGURE 1
Final population pharmacokinetic (PK) model schematic for berotralstat. The pharmacokinetics were described by a three‐compartment linear model, with first‐order absorption, and an absorption lag time. Bioavailability is a function of dose, with higher doses predicting lower bioavailability. Clearance and central volume of distribution were functions of weight
FIGURE 2
FIGURE 2
Forest plots to assess effects of weight and dose on area under the curve (AUC) and maximum concentration (Cmax). AUCtau = area under the curve for berotralstat concentration at steady state for one dose interval (150 mg q.d.). Cmax SS = maximum concentration at steady state at 150 mg q.d. dosing. AUCtau/Dose is the dose‐corrected AUC, Cmax SS/Dose is the dose‐corrected Cmax. Upper plot is the predicted range of AUCtau across the 95% interval for weight. The second plot is the predicted range for the Cmax across the 95% interval for weight. The third plot is the dose‐corrected AUC across the 95% interval for dose, and the lower plot is the predicted 95% interval for dose‐corrected Cmax across the 95% interval for dose. The center red dot is the expected value for the parameter at the median value for covariates (weight and dose). The upper and lower limits of the red lines are the expected values for the parameters at the upper and lower 95% interval for covariates
FIGURE 3
FIGURE 3
Goodness‐of‐fit plots. (a) Visual predictive checks (VPCs), (b) VPC for the single‐dose studies, and (c) for the final berotralstat population pharmacokinetic model. Goodness‐of‐fit plots include the individual predicted values versus the observed values (a, upper left), population predicted values versus the observed values (a, upper right), time versus the conditional weighted residual (CWRES; a, lower left), the population predicted concentration versus the absolute value of the CWRES (a, lower right), a VPC of time versus concentration (b), and VPC of time after dose versus concentration (c)
FIGURE 4
FIGURE 4
Predicted pharmacokinetic profiles for key weight groups following (a) initial dose of berotralstat and (b) at steady state. (a) Predicted median concentration profile after the initial two doses for different weight groups. (b) Predicted median concentration profile at steady state for different weight groups. Underweight was defined as 40–60 kg, low weight as 60–80 kg, normal weight as 80–100 kg, and overweight as 100–120 kg. Adolescent weight distribution was derived from the CDC tables for ages 144 to 216 months
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