Population Pharmacokinetics of Risankizumab in Healthy Volunteers and Subjects with Moderate to Severe Plaque Psoriasis: Integrated Analyses of Phase I-III Clinical Trials.

Abstract

BACKGROUND AND OBJECTIVE:

Risankizumab is an anti-interleukin (IL)-23 monoclonal antibody being developed for treatment of moderate to severe plaque psoriasis. This study provided a comprehensive analysis of risankizumab pharmacokinetics in healthy subjects and patients with plaque psoriasis using data across phase I-III clinical trials.

METHODS:

Plasma pharmacokinetic data from 1899 subjects, including 13,123 observations, who received single or multiple intravenous or subcutaneous doses of risankizumab (0.01-5 mg/kg intravenous [IV], 200-1200 mg IV, 0.25-1 mg/kg subcutaneous [SC], and 18-300 mg SC) across the phase I-III clinical program were analyzed using a non-linear mixed-effects modeling approach. The developed model was qualified and the clinical relevance of covariates statistically correlated with risankizumab clearance (CL) was evaluated using simulation analyses.

RESULTS:

Risankizumab pharmacokinetics were best described using a two-compartment model with first-order absorption and elimination. Risankizumab CL, volume of distribution at steady state (Vss), and terminal-phase elimination half-life (t½) were estimated to be approximately 0.31 L/day, 11.2 L, and 28 days, respectively, for a typical 90 kg psoriatic subject, approaching steady-state plasma exposures by week 16 of dosing. Absolute SC bioavailability (F) was 89%. Bodyweight, anti-drug antibody (ADA) titers ≥ 128 (detected in only 1% of ADA-evaluable subjects in phase III studies), baseline serum albumin, high-sensitivity C-reactive protein (hs-CRP), and serum creatinine were statistically correlated with risankizumab CL; however, they had no clinically relevant impact on exposure.

CONCLUSION:

Risankizumab is characterized by dose-proportional, bi-exponential disposition with no difference in exposure between healthy subjects and patients with psoriasis. None of the covariates identified as being statistically correlated with risankizumab CL has a clinically meaningful impact on its exposure with the proposed psoriasis clinical regimen of 150 mg administered SC at weeks 0 and 4, and every 12 weeks thereafter. CLINICALTRIALS.

GOV IDENTIFIERS:

NCT01577550, NCT02054481, NCT02596217, NCT02684370, NCT02672852, NCT02684357, NCT02694523.

• Authors: Ahmed A Suleiman, Mukul Minocha, Amit Khatri, Yinuo Pang, Ahmed A Othman
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 58 Issue 10 Pg. 1309-1321 (10 2019) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 31054118 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• C-Reactive Protein
• risankizumab
• Creatinine
• Serum Albumin, Human

Topics

• Administration, Intravenous
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (blood, pharmacokinetics)
• C-Reactive Protein (analysis)
• Creatinine (blood)
• Female
• Healthy Volunteers
• Humans
• Injections, Subcutaneous
• Male
• Middle Aged
• Models, Biological
• Psoriasis (blood, metabolism)
• Serum Albumin, Human (analysis)
• Young Adult