Karine Rodriguez-Fernandez (1), E Gras-Colomer (2), M Climente-Martà (3,4), V Mangas-Sanjuán(1,5), M Merino-Sanjuan (1,5)
(1) Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia. Valencia, Spain. (2) Department of Pharmacy, Hospital Manises of Valencia, Spain. (3) Department of Pharmacy, University Hospital Doctor Peset of Valencia, Spain. (4) Foundation for the Promotion of Healthcare and Biomedical Research in the Valencian Community (FISABIO), Valencia, Spain. (5) Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia-University of Valencia. Valencia, Spain.
Background: Hidradenitis suppurativa (HS) is a chronic skin disease characterized by the presence of difficult-to-manage inflammatory nodules that can progress to abscesses and fistulas in intertriginous areas [1]. The causes of HS involve endogenous factors, which include genetic predisposition, aberrant immunity, and hormonal influences, and exogenous factors such as smoking, obesity, bacterial infections, friction, and probably socioeconomic factors [2,3]. The medical treatment is based on the use of antibiotics, retinoids, and anti-inflammatory drugs, in which tumor necrosis factor-α (TNF-α) blockers, such as Adalimumab (ADA), play a central role and have the highest level of scientific support [4].
Objectives: The aims of this work is to externally validate a previously developed population pharmacokinetic model of ADA in patients with HS.
Methods: A retrospective observational study was conducted at the Dr. Peset University Hospital and Manises Hospital of Valencia, performed on patients diagnosed with HS undergoing treatment with subcutaneous (SC) ADA. The experimental dataset consisted of 39 patients including 65 observations in plasma samples. The modelling strategy used a previously developed population PK model [5] in patient with HS from a phase II and III studies. Inter-individual variability (IIV) associated to CL and Vd parameters was modeled exponentially and residual unexplained variability (RUV) was described with an additive model on the logarithmic scale. Three different approaches were conducted to externally validate the population PK model: (i) Bayesian analysis to estimate the individual PK parameters using MAXEVAL=0, (ii) conduct a pc-VPC using the final population PK parameters from [5], and (iii) update the final PK parameters and covariate effects to our dataset. The population PK parameters were estimated using the first-order conditional estimation method with INTERACTION. Model selection was based on the statistically decrease of the OFV and the GOF plots. Model evaluation was performed through pc-VPC (n=1000). Experimental data were logarithmically transformed. All data analyses were performed based on the population approach with the software NONMEM v7.4.
Results: The ADA PK was described with a one-compartment model with first-order absorption. Strategies (i) and (ii) did not allow to properly describe the observed data. Therefore, strategy (iii) was conducted. The apparent clearance (CL) were kept fix to the value of the reference model [5] and the rest of the PK parameters were estimated. The absorption rate constant (ka=0.01 1/d) and volume of distribution (Vd =1.75 L) were similar to those reported in HS patients in treatment with ADA. Bodyweight and baseline C-reactive protein (CRP) were significant covariates on CL and CRP on Vd in the population PK reference model and in our model. In addition, we identified baseline albumin levels to be a significant covariate on CL and it was incorporated in the final model. The significance of the non-diagonal elements of the Ω variance-covariance matrix was also evaluated but did not improve model fit. The results from the model evaluation exercise indicate that the model was capable of capturing the longitudinal profiles of the median and the dispersion of the data based on the pc-VPC and the standard GOF plots.
Conclusion: A previously population PK model has been successfully applied in a real-world HS data set to characterize the absorption and disposition processes of ADA in patients after SC administration. In addition to bodyweight and CRP as significant covariates, it was concluded the impact of baseline albumin levels on CL in order to better understand the variability in exposure levels.
References:
[1] M. Smith, C. Nicholson, A. Miller, I. Hamzavi, 2017.Hidradenitis suppurativa: an update on connecting the tracts. 28 (6): 1272.
[2] Sabat R, Jemec GBE, Matusiak Ł, Kimball AB, Prens E, Wolk K., 2020. Hidradenitis suppurativa. Nature reviews Disease primers. 6(1): 18.
[3] I.E. Deckers, H.H. van der Zee, E.P. Prens, 2013. Epidemiology of hidradenitis suppurativa: prevalence, pathogenesis, and factors associated with the development of HS, Curr. Derm. Rep. 3: 54-60.
[4] Kim, E.S., Garnock-Jones, K.P., Keam, S.J., 2016. Adalimumab: A Review in Hidradenitis Suppurativa. American journal of clinical dermatology. 17: 545-552.
[5] Nader A, Beck D, Noertersheuser P, Williams D, Mostafa N., 2017. Population Pharmacokinetics and Immunogenicity of Adalimumab in Adult Patients with Moderate-to-Severe Hidradenitis Suppurativa. Clinical pharmacokinetics. 56(9): 1091-102
Reference: PAGE 30 (2022) Abstr 10068 [www.page-meeting.org/?abstract=10068]
Poster: Drug/Disease Modelling - Other Topics