Model Informed Dose Evaluation for Aticaprant in Adolescent Patients Following the Adult Dose Regimen
Xia Li1, Anne-Gaelle Dosne1, Chakradhar Lagishetty2, Juan Jose Perez Ruixo1
1. Clinical Pharmacology and Pharmacometrics, Janssen Research & Development LLC, Beerse, Belgium 2. Clinical Pharmacology and Pharmacometrics, Janssen Research & Development LLC, Spring House, USA
Introduction and Objectives: Aticaprant is a small molecule, high-affinity, selective kappa receptor antagonist, under development by Janssen Research & Development for the adjunctive treatment of major depressive disorder (aMDD). An aticaprant dose of 10 mg QD dose is evaluated in adult patients in on-going Phase 3 studies. The current exercise was aimed to determine whether the aticaprant dose of 10 mg QD for adults is appropriate in adolescents (12 to <18 years).
Methods: A population pharmacokinetic (popPK) model has been developed with aticaprant plasma concentrations from 4 clinical studies [I2Z-MC-LAFA (single-ascending dose study), I2Z-MC-LAFB (multiple-ascending dose study), I2Z-MC-LAFC (PET receptor occupancy study), and MDD2001 (efficacy, safety, and pharmacokinetics study in subjects with aMDD)], using nonlinear mixed-effects modeling (NONMEM 7.4.1)1.
The model-based simulations were performed to predict the steady-state AUC0-24h and trough concentration (Ctrough) for both adult (as reference) and adolescent populations following the dose of 10 mg QD. For adults, a dataset containing 10,000 virtual adults was generated by sampling the demographic distribution (i.e., body weight and race) from the adult study MDD2001. For adolescent, a dataset of 69,574 virtual adolescents (12 to <18 years) was generated across age and gender with body weight simulated for each year in age group and gender based on CDC growth charts weight-for-age statistical tables2. For age category, a total of 60,000 virtual adolescent subjects (12 to <18 years) were sampled from the virtual adolescent subject database. For body weight category, a total of 560,000 virtual adolescent subjects (45 to 100 kg) were sampled. The race distribution of adolescents was sampled from the adult study MDD2001.
The aticaprant dose for adolescents was considered appropriate if ≥ 80% of the adolescents would have aticaprant exposures (i.e., AUC0-24h and Ctrough at steady state) within the 5th and 95th percentiles of the corresponding adult population exposure after a dose of 10 mg QD.
Results: The popPK model in adult was based on 2,258 aticaprant plasma concentrations from 151 healthy subjects and patients. Observed data were well described by an open two-compartment model with first-order absorption (Ka) and linear clearance (CL). Body weight was a covariate, with the allometric scaling exponent of 0.75 for CL and Q, and 1 for V2 and V33. The interindividual variability in CL, V2, F1 (relative bioavailability factor), and Ka was assumed to be log normally distributed. The residual error was described by a proportional error model.
The model-based simulations in the 10,000 virtual adults receiving aticaprant 10 mg QD, resulted in median (5th and 95th percentiles) steady-state AUC0-24h and Ctrough of 312.7 (141.1-685.1) ng*h/ml and 7.6 (3.0-17.7) ng/ml, respectively, which served as reference for comparison with adolescent simulations.
The model-based simulations in virtual adolescents across body weight categories demonstrated that the aticaprant dose of 10 mg QD resulted in ≥ 80% of the adolescents with aticaprant exposures within the adult reference exposure for both steady-state AUC0-24h and Ctrough, across both body weight and age category.
Conclusion: The adult clinical dose of aticaprant10mg QD is expected to achieve systemic aticaprant exposures in the simulated virtual adolescent population comparable to those in adult population. The dose currently proposed will be further updated based on emerging data from adult Phase 3 clinical studies.
Reference:
- Beal SL, Sheiner LB, Boeckmann AJ, et al. NONMEM 7.1.0 users guides. Ellicott City: Icon Development Solutions; 1989-2009.
- National Center for Health Statistics (Center for Disease Control and Prevention). Percentile data files with LMS values. WTAGE. https://www.cdc.gov/growthcharts/percentile_data_files.htm
- Anderson BJ and Holford NHG. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu. Rev. Pharmacol. Toxicol. 2008, 48: 303-332.
