Impact of Pharmacokinetic and Pharmacodynamic Properties of Monoclonal Antibodies in the Management of Psoriasis

Abstract

The treatment of psoriasis has been revolutionized by the emergence of biological therapies. Monoclonal antibodies (mAb) generally have complex pharmacokinetic (PK) properties with nonlinear distribution and elimination. In recent years, several population pharmacokinetic/pharmacodynamic (PK/PD) models capable of describing different types of mAb have been published. This study aims to summarize the findings of a literature search about population PK/PD modeling and therapeutic drug monitoring (TDM) of mAb in psoriasis. A total of 22 articles corresponding to population PK/PD models of tumor necrosis factor (TNF)-α inhibitors (adalimumab and golimumab), interleukin (IL)-23 inhibitors (guselkumab, tildrakizumab, and risankizumab), IL-23/IL-12 inhibitor (ustekinumab), and IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab) were collected. A summary of the clinical trials conducted so far in psoriasis was included, together with the current structural population PK and PD models. The most significant and clinical covariates were body weight (BW) and the presence of immunogenicity on clearance (CL). The lack of consensus on PK/PD relationships has prevented establishing an adequate dosage and, therefore, accentuates the need for TDM in psoriasis.

Population pharmacokinetic/pharmacodynamic analysis of AK111, an IL-17A monoclonal antibody, in subjects with moderate-to-severe plaque psoriasis

“…The higher RSE% was also observed in Brodalumab (49.7%) and Ixekizumab (60.3%) ( Salinger et al, 2014 ; Tham et al, 2014 ), this is because the subpopulations of the responder and non-responder make the distribution of the post hoc IC 50 parameter as a bimodal distribution ( Zhou et al, 2010 ; Tham et al, 2014 ; Pan et al, 2020 ), but in our study, the sample size was too small to distinguish two subpopulations. K in and K out were parameters that related to the disease, the reported K in was 0.615–0.890 PASI/day, K out was 0.0313–0.064 day −1 ( Zhou et al, 2010 ; Salinger et al, 2014 ; Tham et al, 2014 ; Rodriguez-Fernandez et al, 2022 ). In our study, K in was 0.474 PASI/day, K out was 0.024 day −1 , and both of them were lower than those reported in the literature.…”

“…Although the pathogenesis of psoriasis is still not fully elucidated, molecular and genetic studies have identified the main inflammatory pathways involved in the pathogenesis of psoriasis ( Rendon and Schakel 2019 ). Several mAbs designed to block either specific receptors or soluble mediators of the main pathways were approved for treating psoriasis, including TNF-α, IL-12/23, and IL-17 antibodies ( Rodriguez-Fernandez et al, 2022 ). Secukinumab, ixekizumab, and brodalumab are three anti-IL-17 mAbs which are already available in the market ( Mrowietz et al, 2021 ), AK111 is also targeting IL-17A.…”

“…The most common clinical covariates for mAbs treating psoriasis were body weight and the presence of immunogenicity on CL ( Bruin et al, 2017 ; Rodriguez-Fernandez et al, 2022 ). For AK111, none of the covariate (age, gender, weight, disease duration, baseline PASI score, and BSA) relationships were identified in the developed population PK model.…”

“…Finding the source of interindividual variation of IC 50 is important because its large IIV and different individuals have different treatment outcomes; higher doses may be required for non-responder subpopulations ( Tham et al, 2014 ). Lai-San Tham reported the PASI75 responder status at week 12 as a significant covariate for the EC 50 parameter ( Tham et al, 2014 ; Rodriguez-Fernandez et al, 2022 ), some literatures reported that the covariate analysis identified high-sensitivity C-reactive protein (hs-CRP) as a statistically significant covariate for risankizumab EC 50 ( Khatri et al, 2020 ; Suleiman et al, 2020 ). In our analysis, the addition of any covariable does not reduce the IIV of this parameter; one possible reason is that the sample of 47 is too small.…”

Weighing in on weight‐based secukinumab dosing for psoriasis

“…One step further towards dose optimization of biologics would be therapeutic drug monitoring (TDM), in which therapeutic decision making is guided by drug concentration measurements. 8 Aiming to develop a TDM strategy for secukinumab in psoriasis, Soenen et al confirmed the secukinumab underexposure in real-world overweight patients and determined a minimal effective secukinumab threshold of 39Á1 mg L -1 associated with achieving PASI ≤ 2 or DPASI ≥ 90%. 9 This trial provides high-quality evidence to support above-label dosing of secukinumab to improve treatment outcomes in an otherwise difficult-to-treat patient population.…”