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Population-Pharmacokinetic Modeling of Tildrakizumab (MK-3222), an Anti-Interleukin-23-p19 Monoclonal Antibody, in Healthy Volunteers and Subjects with Psoriasis

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Abstract

Background

Tildrakizumab is an anti-interleukin-23p19 monoclonal antibody recently approved for the treatment of chronic plaque psoriasis.

Methods

This analysis characterizes the population pharmacokinetics of subcutaneous tildrakizumab and identifies covariates influencing exposure in 2098 healthy volunteers and subjects with psoriasis. Tested covariates included body weight, formulation type, sex, age, race, serum albumin, creatinine clearance, Japanese origin, prior treatment with a biologic agent, subject status (subjects with psoriasis vs. healthy volunteers), and ethnicity.

Results

The pharmacokinetics was described by a one-compartment model with first-order absorption and elimination kinetics, and inter-individual variability on clearance, volume of distribution, and absorption rate constant. The pharmacokinetics was characterized by low clearance and limited volume of distribution. In subjects with psoriasis, the geometric mean clearance (coefficient of variation) was 0.32 L/day (38%), volume of distribution was 10.8 L (24%), and absorption and elimination half-life were 1.5 days (18%) and 23.4 days (23%), respectively, with an absorption lag time of 1.2 h. For the 100-mg dose, steady-state area under the plasma concentration vs. time curve for one dosing interval and maximum plasma concentration were 305 µg*day/mL (41%) and 8.1 µg/mL (34%), respectively. Steady state was achieved by 16 weeks with the clinical regimen (dosing on week 0 and week 4 and every 12 weeks thereafter) with 1.1-fold accumulation in maximum plasma concentration. Healthy subjects had 31% higher bioavailability than subjects with psoriasis. Subjects with increased body weight had a lower area under the plasma concentration-time curve at steady state vs. those with lower body weight. The modeled exposures were contained within clinical comparability bounds for all covariates including body weight.

Conclusions

The pharmacokinetics of tildrakizumab behaves like a typical monoclonal antibody without requiring dosage adjustment.

Trial Registration

NCT01729754, NCT01225731, NCT01722331.

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Acknowledgements

The authors gratefully acknowledge the writing and editorial assistance of Amy O. Johnson-Levonas, Ph.D. and Anish Mehta (both of Merck & Co., Inc., Kenilworth, NJ, USA). The authors also acknowledge the assistance of Diana Montgomery (Merck & Co., Inc., Kenilworth, NJ, USA) in summarizing the immunogenicity data, and of Michele McColgan (Merck & Co., Inc., Kenilworth, NJ, USA) in formatting and preparing this article for publication.

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Authors and Affiliations

  1. Certara USA, Inc., Princeton, NJ, USA

    Petra Jauslin, Pooja Kulkarni, Hanbin Li, Suresh Vatakuti & Thomas Kerbusch

  2. Merck & Co., Inc., Kenilworth, USA

    Azher Hussain & Larissa Wenning

  3. Merck & Co., Inc., UG4D-48, 351 North Sumneytown Pike, North Wales, PA, 19454-2505, USA

    Larissa Wenning

Authors
  1. Petra Jauslin
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  7. Thomas Kerbusch
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Corresponding author

Correspondence to Larissa Wenning.

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Funding

This analysis was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and conducted by Certara USA Inc.

Conflict of interest

Petra Jauslin, Pooja Kulkarni, Hanbin Li, Suresh Vatakuti, and Thomas Kerbusch are employees of Certara USA, Inc. or its subsidiaries, who conducted analysis or provided consulting services for Merck & Co., Inc. Azher Hussain and Larissa Wenning are employees of Merck & Co., Inc., Kenilworth, NJ, USA, and hold stock and/or stock options in the company. Thomas Kerbusch is a former employee of Merck & Co., Inc., Kenilworth, NJ, USA, who was an employee of Certara USA, Inc. at the time of the analysis covered in this article.

Ethics approval

The studies used in this work were conducted in compliance with the Declaration of Helsinki, International Conference on Harmonization Guidelines for Good Clinical Practice, and applicable local regulations. The study protocols were approved by ethics committees of all participating centers.

Consent to participate

All patients provided written informed consent before study entry and the initiation of any study tests/procedures.

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Jauslin, P., Kulkarni, P., Li, H. et al. Population-Pharmacokinetic Modeling of Tildrakizumab (MK-3222), an Anti-Interleukin-23-p19 Monoclonal Antibody, in Healthy Volunteers and Subjects with Psoriasis. Clin Pharmacokinet 58, 1059–1068 (2019). https://doi.org/10.1007/s40262-019-00743-7

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  • DOI: https://doi.org/10.1007/s40262-019-00743-7

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