Population Pharmacokinetic Modeling of Secukinumab in Patients With Moderate to Severe Psoriasis

Abstract

Secukinumab is a human monoclonal antibody with demonstrated efficacy for moderate to severe psoriasis; it binds to and neutralizes interleukin (IL)-17A. The pharmacokinetic (PK) parameters of secukinumab were best described by a 2-compartment model. Only weight was included in the final model, as other covariates did not affect clinical relevance. The estimated serum clearance of secukinumab was 0.19 L/day, with interindividual variability (IIV) of 32% coefficient of variation (CV), and low total volume of distribution (central compartment volume, 3.61 L with IIV of 30% CV; peripheral compartment volume, 2.87 L with IIV of 18% CV). The bioavailability of secukinumab after subcutaneous dosing was approximately 73%, with an absorption rate of 0.18/day with IIV of 35% CV. The PK profile of secukinumab was linear, with no evidence of a dose dependence of clearance. Clearance and volume of secukinumab varied with body weight in an allometric relationship. The time to maximum serum concentration at steady state occurred approximately 6 days after dosing for both secukinumab 300 mg and secukinumab 150 mg. Overall, the PK properties of secukinumab were typical of a 150-kDa human IgG1 antibody interacting with a soluble target.

Keywords: IL-17A; monoclonal antibody; pharmacodynamics; population pharmacokinetics; psoriasis; secukinumab.

Figure 1

Goodness‐of‐fit diagnostics for the simulated pharmacokinetic model. (A) Observed secukinumab concentration versus population‐predicted secukinumab concentration. (B) Observed secukinumab concentration versus individual‐predicted secukinumab concentration. (C) Conditional weighted residual versus population‐predicted secukinumab concentration. (D) Conditional weighted residual versus time.

Figure 2

External validation of goodness‐of‐fit diagnostics for the simulated pharmacokinetic model. (A) Observed secukinumab concentration versus population‐predicted secukinumab concentration. (B) Observed secukinumab concentration versus individual‐predicted secukinumab concentration. (C) Conditional weighted residual versus population predicted secukinumab concentration. (D) Conditional weighted residual versus time.

Figure 3

Simulated concentration profiles of secukinumab 300 and 150 mg with subcutaneous dosing regimens derived from phase 3 trials. Patients were simulated to receive secukinumab at baseline; weeks 1, 2, and 3; and then every 4 weeks from week 4 to week 48.

Figure 4

Observed serum secukinumab concentrations. Each line represents serum secukinumab concentrations from an individual patient in the phase 3 ERASURE trial.9 Secukinumab was administered at baseline; weeks 1, 2, and 3; and then every 4 weeks from week 4 to week 48. The last dose of secukinumab was given at week 48. Patients receiving placebo who did not achieve PASI 75 at week 12 were rerandomized to secukinumab 300 or 150 mg. Pharmacokinetic analysis was performed at baseline; weeks 4, 12, 24, 52, and 60; and during unscheduled visits.

Figure 5

Observed serum total I‐17A concentrations. Secukinumab was administered at baseline; weeks 1, 2, and 3; and then every 4 weeks from week 4 to week 48. Pharmacodynamic analysis was performed at baseline and weeks 4, 12, 16, 24, and 52. Results represent median total IL‐17A concentrations from patients in the phase 3 JUNCTURE trial.13