Exposure-response characterisation of tildrakizumab in chronic plaque psoriasis: Pooled analysis of 3 randomised controlled trials

Abstract

Aims: In this exposure-response analysis, the dosing regimen for tildrakizumab, an antibody for treating moderate-to-severe chronic plaque psoriasis, was determined using data from 3 randomised controlled trials (P05495/NCT01225731: phase 2b, n = 355; reSURFACE 1/NCT01722331: phase 3, n = 772; reSURFACE 2/NCT01729754: phase 3, n = 1090).

Methods: A maximum drug effect (E_max ) logistic-regression exposure-efficacy model was used to describe the week 12 Psoriasis Area and Severity Index (PASI) responses with average concentration of tildrakizumab during weeks 1-12 (C_avg12 ) as exposure metric. The impact of covariates (e.g., body weight, region) was tested. Exposure-safety, longitudinal pharmacokinetic-pharmacodynamic and risk-benefit analyses were also conducted.

Results: At week 12, E_max was estimated at 62.2, 37.9 and 14.6% of responders for PASI75/90/100, respectively. Exposure-response curves plateaued at exposures >5 μg mL^-1 . Heavier subjects had a lower response rate to placebo as measured by PASI75/90/100 than lighter subjects. PASI100 placebo response was less in subjects with higher baseline PASI score and older age. Simulated week 12 PASI75 increased by ≤4% on increasing the dose from 100 to 200 mg every 12 weeks (Q12W). The pharmacokinetic-pharmacodynamic model adequately described the time course of PASI change after treatment in the entire population and in each subject. Risk-benefit profiles were favourable for the 100- and 200-mg doses in different weight subgroups.

Conclusions: Patients with moderate-to-severe psoriasis should receive 100-mg subcutaneous tildrakizumab Q12W. Patients with high body weight (>90 kg) may benefit from a higher dose (200-mg Q12W).

Keywords: dermatology; modelling and simulation; pharmacodynamics; pharmacokinetic-pharmacodynamic; psoriasis.

FIGURE 1

Longitudinal pharmacokinetic–pharmacodynamic model. CL V⁻¹, clearance over volume; Cp, predicted concentration–time course from the population pharmacokinetic model using post hoc parameters; ka, absorption rate constant; kin, zero‐order constant for production of the response; kout, first‐order rate constant for loss of the response; ktr, transit rate constant; Lag1–3, PASI transit compartments 1–3; PASI, Psoriasis Area and Severity Index

FIGURE 2

Week 12 PASI exposure–response relationships. C_avg12, average concentrations from weeks 1 to 12; CI, confidence interval; PASI, Psoriasis Area and Severity Index. Blue points are PASI response probabilities (error bars: 95% exact CIs) corresponding to average concentrations (C_avg12), stratified by concentration decile. The blue lines (stair‐steps) represent the cumulative distribution of pharmacokinetic values and the location of each decile. The multicolour points represent individual subject response with (PASI response = yes; top) and without (PASI response = no; bottom) an event. The red line represents the model fit, with shading indicating 95% CIs

FIGURE 3

Goodness‐of‐fit plots for the final pharmacokinetic–pharmacodynamic model. Circles are individual observed values; solid red lines are either lines of unity (left panels) or zero horizon lines (right panels). Blue dashed lines at the right panels indicate conditional weighted residuals (CWRES) equal to −5 and + 5. Observed, individual, and population prediction Psoriasis Area and Severity Index (PASI) scores shown in the plots were transformed as PASI/(100 − PASI)

FIGURE 4

Risk–benefit analysis of the week 28 PASI75 response. PASI, Psoriasis Area and Severity Index