Javier Zarzoso-Foj (1,2), Karine Rodriguez-Fernandez (1,2), Marina Saez-Bello (3), Elena Gras-Colomer (4), Matilde Merino-Sanjuan (1,2), Monica Climente-Marti (1,3), Almudena Mateu-Puchades (5), Victor Mangas-Sanjuan (1,2).
(1) Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Valencia, Spain; (2) Interuniversity Institute of Recognition Research Molecular and Technological Development; (3) Department of Pharmacy, University Hospital Doctor Peset of Valencia, Spain; (4) Department of Pharmacy, University Hospital of Manises, Valencia, Spain; (5) Department of Dermatology, University Hospital Doctor Peset of Valencia, Spain.
Introduction: Psoriasis (Pso) is an inflammatory skin disease triggered by genetic, environmental, and immunological factors (1,2). Monoclonal antibodies represent a major therapeutic option in psoriasis diseases. Ustekinumab (USTE) inhibits IL-12 and IL-23 (3), showing efficacy on the major pharmacodynamic (PD) outcome: Psoriasis Area and Sensitivity Index (PASI) (4,5). USTE is approved for subcutaneous administration at initial doses of 45 or 90 mg in weeks 0 and 4, following additional doses of 45 or 90 mg every 12 weeks (6). Nevertheless, the off-label use of ustekinumab in clinical practice is common in order to improve the individual benefit/risk balance. The pharmacokinetic (PK) properties of USTE have been characterized by a two-compartment model in patients with Pso (7). Although an exposure-efficacy model has been developed (8), there is no longitudinal PK/PD model in the literature able to describe the temporal evolution of PASI according to the administration regimen received by the patient.
Objectives: The aims of this study are (i) to develop a population-based PK/PD model of USTE and (ii) to evaluate individualized dosing regimens accounting for the individual parameter uncertainty.
Methods: A post-authorization, prospective, multicenter, and observational clinical practice follow-up study was conducted on psoriatic patients undergoing USTE treatment. The study received approval from Dr. Peset University Hospital’s ethics committee in Valencia, Spain (VMS-UST-2020-01 EPA-SP). A population PK model in patients with Pso (7) was used to retrieve the individual PK parameters through a Bayesian approach. An indirect response model with PASI synthesis inhibition was considered to describe the PK/PD relationship between USTE plasma concentrations and PASI. Baseline PASI levels were calculated using the B2 method (9). Linear, Emax, and sigmoid drug effects functions were evaluated. Individual dosing regimen optimization was performed through a simulation analysis (n=1,000) to estimate the probability of having minimum therapeutic USTE plasma concentrations (0.1-1.43 mg/L) (10), a satisfactory PASI response (PASI ≤3) or both simultaneously, considering the uncertainty of the individual parameters. Model selection was based on the statistical decrease of the OFV and the GOF plots. Model evaluation was performed through pc-VPC and individual profile evaluation. All data analyses were performed based on the population approach with the software NONMEM v7.4.
Results: A total of 23 patients (mean age: 58 years [SD=11.5%], mean weight: 84.8 kg [SD=15.9%]), with 78 plasma samples and 117 PASI observations were included in the analysis. The dosage regimens used in clinical practice were 45mg/12w (n=1), 45mg/14w (n=2), 45mg/16w (n=2), 45mg/18w (n=1), 90mg/4w (n=3), 90mg/8w (n=2), 90mg/10w (n=1), 90mg/12w (n=11), 90mg/14w (n=2), 90mg/15w (n=2) and 90mg/16w (n=3), considering that some patients received different dosing regimens during study period. An indirect response model with five concatenated compartments linked through first-order rate constants was developed. A PASI baseline of 18.08 and a first-order elimination constant (kout = 0.081 day-1) were estimated. The zero-order synthesis rate constant (kin = 1.46 day-1) was derived. Individual PK parameters were estimated with MAXEVAL=0 and then imputed to describe the effect of USTE concentration. An Emax drug effect model (IC50 = 0.072 mg/L and Imax =0.99) was selected. The simulation analysis showed that 16/23 (70%), 5/23 (22%) and 1/23 (4%) patients would achieve simultaneously a satisfactory PASI response and therapeutic plasma concentrations of USTE within the dosing interval with less, equal, and more intensive dosing regimens respectively.
Conclusions: A population PK/PD model of USTE has been developed from sparse data obtained in clinical practice in psoriatic patients. The results demonstrate that 70% of patients would achieve effective USTE plasma levels and a satisfactory PASI response with less intensive dosing regimens than those currently prescribed. This analysis has proved its usefulness and application as a tool for the selection of individualized dosing regimens in clinical practice with a view to optimize the efficiency of USTE use in patients with psoriasis, as well as the need to include USTE in monitoring programs.
References:
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Reference: PAGE 32 (2024) Abstr 10881 [www.page-meeting.org/?abstract=10881]
Poster: Drug/Disease Modelling - Other Topics