Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study

Abstract

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (E_max ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes.

Figure 1

Visual predictive check for ustekinumab pharmacokinetic model (left), and pharmacodynamic mixture model (right). The 95% prediction intervals are shown for predicted data in grey (97.5th and 2.5th percentiles top and bottom, respectively) and blue (50th percentile) bands with corresponding observed percentiles shown as broken black (97.5th and 2.5th percentiles top and bottom, respectively) and solid black (50th percentile) lines. PASI, Psoriasis Area Severity Index; USK, ustekinumab.

Figure 2

Distribution of random effects (ETA) of EC50 in the single population model. Solid blue line: density of the distribution. EC50, concentration of ustekinumab giving 50% of the maximum IL‐12/IL‐23 inhibition.

Figure 3

Simulated profiles using the mixture model of the probability of achieving PASI75 after 8 weekly, 12 weekly, and 16 weekly ustekinumab injections in the patient group on 45 mg (top), on 90 mg (middle), and simulating a 90 mg dose using parameters from the patient group on 45 mg (bottom) (Group 1: using parameters from mixture group 1, Group 2: using parameters from the mixture group 2). PASI, Psoriasis Area Severity Index.

Figure 4

Individual predicted 4‐week PASI change from baseline vs. 4‐week ustekinumab trough concentration. (a) Predicted 4‐week trough concentration by responder category; (b) predicted 4‐week PASI decrease from baseline (%) by responder category; (c) predicted 4‐week PASI decrease from baseline (%) vs. predicted 4‐week trough concentration. In c, open circles represent patients who were full‐responders at 6 months, triangles are partial‐responders, and filled circles are nonresponders. Horizontal and vertical lines represent 4‐week PASI cutoff of 25% decrease and 4‐week trough concentration of 1.4 μg/mL, respectively. The numbers in each quadrant represent the percentage of 6‐month full‐responder, partial‐responder, and nonresponders in each quadrant, respectively. PASI, Psoriasis Area Severity Index.