Individualized dosing regimen optimization using a population pharmacokinetic-pharmacodynamic model for secukinumab in clinical practice psoriatic patients
Karine Rodriguez-Fernandez (1,2), Elena Gras-Colomer (3), Matilde Merino-Sanjuan (1,2), Monica Climente-Marti (1,4), 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 of Manises, Valencia, Spain; (4) Department of Pharmacy, University Hospital Doctor Peset of Valencia, Spain; (5) Department of Dermatology, University Hospital Doctor Peset of Valencia, Spain.
Introduction/Objectives: Psoriasis (Pso) is an inflammatory skin disease resulting from genetic, environmental, and immunological factors [1]. One of its main medical treatments is based on the use of human monoclonal antibodies (mAb) drugs, for instance, the IL-17A blocker secukinumab (SECU) [2]. This mAb has shown efficacy in real-world clinical studies due to the observed reduction of the main pharmacodynamic (PD) outcome: Psoriasis Area and Severity Index (PASI) [3,4]. As indicated in the summary of product characteristics, SECU should be administered subcutaneously in doses of 150 and 300 mg in weeks 0,1, 2, 3, and 4, and then every 4 weeks. However, in clinical practice, other dosing regimens, such as 300 mg every 5 or 6 weeks, which are not supported by any research are also prescribed. The pharmacokinetic (PK) properties of SECU have been characterized by a 2-compartment model in patients with Pso through a population approach [5], but there is still no longitudinal PK/PD model in the literature capable of linking the concentrations of SECU versus the levels of PASI observed. The aims of this study are (i) to develop a population-based pharmacokinetic-pharmacodynamic model of SECU in patients and (ii) to evaluate individualized dosing regimens accounting for the individual parameter uncertainty.
Methods: A post-authorization, prospective, multicenter (national), and observational clinical practice follow-up study was conducted on psoriatic patients undergoing subcutaneous SECU treatment. The study received approval from Dr. Peset University Hospital's ethics committee in Valencia, Spain; its protocol code was VMS-UST-2020-01 EPA-SP. A population PK model in patients with Pso [5] 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 SECU plasma concentrations and PASI observations. Linear, Emax, and sigmoid drug effects functions were evaluated. Individual dosing regimen optimization was performed through a simulation analysis (n=1000) to estimate the probability of having therapeutic SECU plasma concentrations (16.0-55.2 mg/L) and a satisfactory PASI response (PASI<5), considering the uncertainty on the estimation of the individual PK and PD parameters. Model selection was based on the statistical decrease of the OFV and the GOF plots. Model evaluation was performed through pc-VPC (n=1000) and individual profile evaluation. Experimental PK and PD data were logarithmically transformed. All data analyses were performed based on the population approach with the software NONMEM v7.4.
Results: A total of 22 patients (mean age: 49 years [SD=13.4%] and mean weight: 75.2 kg [SD=15%]), with 85 plasma samples and 104 PASI observations were included in the analysis. The dosage regimens used in clinical practice were 150mg/4w (n=2), 300mg/4w (n=18), 300/5w (n=1), and 300/6w (n=1). An indirect response model was developed with five concatenated compartments linked through first-order rate constants. A zero-order synthesis rate constant (kin = 0.0304 mg/L/day) and first-order elimination constant (kout = 0.0547 day-1) were estimated. Individual PK parameters estimated in the previous step were considered to describe the effect of SECU concentration, which assumed an Emax model (IC50 = 0.3 mg/L and Imax =0.132). The simulation analysis showed that 14/22 (63.3%) and 2/22 (9.1%) patients would achieve with a probability greater than 90% therapeutic plasmatic concentrations of SECU with less intensive dosing regimens of 150 mg every 4 weeks and 300 mg every 5 weeks respectively.
Conclusions: A population PK/PD model of SECU has been developed to characterize sparse and clinical routine data in psoriatic patients. The results demonstrate that using this methodology, close to 72.7% of patients would achieve effective SECU plasma levels and a satisfactory PASI response with less intensive dosing regimens than those currently prescribed. This analysis has demonstrated its usefulness and application as a tool for the selection of individualized dosing regimens in clinical practice to optimize the efficiency for the use of SECU in patients with psoriasis Although more prospective, follow-up, and observational studies of clinical practice are required, it would be appropriate to put these results into clinical practice to demonstrate its suitability and application.
References:
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