The Safety of Ustekinumab in Psoriasis
August 2012 | Volume 11 | Issue 8 | Original Article | 907 | Copyright © 2012
Ustekinumab is effective in the treatment of a variety of autoimmune conditions including psoriasis. As a relatively new therapeutic agent, its long-term effects are still under investigation. Short-term studies, however, have revealed ustekinumab to be generally well tolerated and safe. This article provides a comprehensive review of the pharmacokinetics of ustekinumab, its safety profile, adverse effects, and use in pregnancy. The effect of diabetes and prior immunosuppressant therapy is also addressed.
J Drugs Dermatol. 2012;11(8):907-910.
Purchase Original Article
Purchase a single fully formatted PDF of the original manuscript as it was published in the JDD.
Download the original manuscript as it was published in the JDD.
Contact a member of the JDD Sales Team to request a quote or purchase bulk reprints, e-prints or international translation requests.
To get access to JDD's full-text articles and archives, upgrade here.
Save an unformatted copy of this article for on-screen viewing.
Print the full-text of article as it appears on the JDD site.→ proceed | ↑ close
The efficacy of ustekinumab in treating psoriasis has been demonstrated in Phase I through Phase III trials.1-6 Ustekinumab is a human monoclonal antibody that binds to the shared p40 subunit of IL-12 and IL-237 which prevents the binding of these cytokines to receptors present on immune cells, consequently generating downregulation of the inflammatory cytokines produced by these cells.8 Literature has elucidated a role of these inflammatory cytokines in the pathogenesis of psoriasis and other diseases.9,10
Data obtained from the serum concentrations of the patients enrolled in the PHOENIX 1 and PHOENIX 2 trials have been analyzed to determine the pharmacokinetics of the drug. The apparent clearance, volume of distribution, and absorption rate constant have been 0.465 L per day (20%), 8.9 L, and 0.354 per day (16.2%), respectively.11 One study showed that injection of single dose of subcutaneous ustekinumab 0.27-2.7 mg per kg results in mean peak serum concentration (Cmax) of 3.1-14.1 µg per mL in approximately 12 days (tmax).12 In another study, a tmax of 8.5 days was found post treatment with one dose of ustekinumab 90 mg.13 In phase III trials, it was observed that steady-state concentrations are reached by week 28 subsequent to subcutaneous injections at weeks 0,4, and then every 12 weeks. The median steady-state trough concentrations (Ctrough) in these studies were measured to be from 0.21 to 0.26 µg per mL for the 45 mg dose and 0.47 to 0.49 µg per mL for the 90 mg dose.12 Bioavailability is 57.2% for a subcutaneous administration. The median half life has been measured to be 21.6 days.11 This value is consistent with those reported in phase I studies of patients and similar to values for other human immunoglobulin G1 therapeutic monoclonal antibodies (IgG1 therapeutic mAbs).13 The half life of endogenous IgG has been measured to be approximately 23 days and longer than other immunoglobulin isotypes, which provides the benefit of a less frequent dosage regimen.14 Although ustekinumab's metabolic pathway is not yet completely clear, studies have demonstrated a substantial dose-response relationship.12,15
Patient weight was shown to have the greatest effect on clearance and volume of distribution.11,16 Body weight has also been shown to effect the clearance of other IgG-based antibodies.17 For patients weighing less than 100 kg, apparent clearance (CL/F) and apparent volume of distribution (V/F) have been measured to be 0.44 L per day and 14.0 L, respectively. In patients weighing more than 100 kg, however, these values increase to 0.68 L per day and 19.5 L. Subsequent to a fixed dose administration, mean steady-state concentrations have been determined to be 30% lower in patients who weigh over 100 kg as compared to patients weighing less than 100 kg.12 Reduced drug concentration has been shown to result in clinically suboptimal response. In fact, in patients who weigh more than 100 kg, a greater proportion are able to achieve PASI75 when treated with 90 mg ustekinumab as compared to 45 mg ustekinumab.18 Thus, physicians should be cognizant that when their patients are over 100 kg, a higher dose may be considered.
In the PHOENIX 1 and PHOENIX 2 trials, patients with diabetes demonstrated enhanced clearance and volume of distribution of ustekinumab, resulting in reduced drug exposure with a fixed dose.11 Because diabetes and obesity tend to be concomitant conditions, the effects were analyzed to be independently additive. This may be due to changes in lymphatic flow, increased glycation of the antibody resulting in increased clearance, greater interstitial volume space, and increased capillary permeability in diabetic patients.19-22 However, the reduction in drug serum concentration was not shown to necessarily translate to decreased drug efficacy. Thus, the difference has not been significant to warrant dosing modification. Also, the formation of antibodies has been reported to influence drug clearance. In a study, CL/F was found to be 35.5% higher in patients who experienced a positive immune response, which would consequently be expected to decrease the efficacy of the drug at the same drug concentration.12 Age, gender, and ethnicity have not been shown to affect drug clearance.11,12 Also, no correlation has been shown between drug clearance and ustekinumab dose