Nina Scherer (1), Christiane Dings (1), Michael Böhm (2), Ulrich Laufs (2) and Thorsten Lehr (1)
(1) Clinical Pharmacy, Saarland University, Saarbruecken, Germany, (2) Clinic of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Saarland University, Homburg/Saar, Germany
Objectives: Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a soluble protein that enhances low density lipoprotein cholesterol (LDLc) receptor degradation and thus lowers LDLc uptake by liver cells [1]. Alirocumab and Evolocumab are two human monoclonal antibodies inhibiting PCSK9. Aim of this analysis was to develop a pharmacokinetic and pharmacodynamic (PK/PD) model for Alirocumab and Evolocumab.
Methods: Data was digitized from different published studies describing Alirocumab and Evolocumab PK as well as the resulting LDLc levels in humans for various doses (single and multiple doses between 75mg and 300mg for Alirocumab [2–6]; single dose and multiple doses between 7mg and 420mg for Evolocumab [7–9]). The dataset consisted of 112 and 100 mean plasma concentrations for Alirocumab and Evolocumab, respectively and 86 and 209 mean LDLc measurements as changes from baseline with different mean LDLc baseline levels for each mean curve. The PK/PD model was developed stepwise: first, a PK model for each compound was developed and second, the PK models were linked to the PD model to describe the change in LDLc from baseline. Model parameters were estimated using NONMEM (version 7.3).
Results: A two-compartment model with a first-order absorption and a saturable elimination described the PK of both antibodies best. LDLc levels were described by a turn over model with a zero-order synthesis rate and first-order degradation rate. At time point zero the degradation rate were determined by the baseline LDLc level. Antibody concentrations in the central compartment increased the LDLc degradation rate and decreased the LDLc synthesis rate using an Emax function. Regarding the lack of individual data, no covariates affecting the PK/PD of PCSK9 antibodies were investigated.
Conclusion: A PK/PD model describing the link between Alirocumab and Evolocumab pharmacokinetics and LDLc levels was presented for the first time. The model may serve as an excellent tool to simulate different dosing regimens and the impact of different LDLc baseline levels on the response.
References:
[1] W. R. H. Brendan M. Everett, Robert J. Smith, “Reducing LDL with PCSK9 Inhibitors – The Clinical Benefit of Lipid Drugs,” N. Engl. J. Med., 2015.
[2] M. Farnier, “PCSK9: From discovery to therapeutic applications,” Arch. Cardiovasc. Dis., vol. 107, no. 1, pp. 58–66, 2014.
[3] M. James P. Smith, MD, “Food and Drug Administration Center for Drug Evaluation and Research. Briefing Document: Praluent (alirocumab) injection,” The Endocrinologic and Metabolic Drugs Advisory Committee Meeting, 2015. [Online]. Available: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM449865.pdf.
[4] A. Kumar, D. D. Jones, M. A. Hanna, B. Soediono, and A. C. Bartocci, “Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol,” J. Chem. Inf. Model., vol. 53, no. 3, pp. 556–581, 2009.
[5] C. Lunven, T. Paehler, F. Poitiers, A. Brunet, J. Rey, C. Hanotin, and W. J. Sasiela, “A randomized study of the relative pharmacokinetics, pharmacodynamics, and safety of alirocumab, a fully human monoclonal antibody to PCSK9, after single subcutaneous administration at three different injection sites in healthy subjects,” Cardiovasc. Ther., vol. 32, no. 6, pp. 297–301, 2014.
[6] J. E. Sang M. Chung, “Center for Drug Evaluation and Clinical Pharmacology and Biopharmaceutics Review,” 2014. [Online]. Available: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125559Orig1s000ClinPharmR.pdf.
[7] C. S. Dias, A. J. Shaywitz, S. M. Wasserm an, B. P. Smith, B. Gao, D. S. Stolman, C. P. Crispino, K. V. Smirnakis, M. G. Emery, A. Colbert, J. P. Gibbs, M. W. Retter, B. P. Cooke, S. T. Uy, M. Matson, and E. A. Stein, “Effects of AMG 145 on low-density lipoprotein cholesterol levels: Results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins,” J. Am. Coll. Cardiol., vol. 60, no. 19, pp. 1888–1898, 2012.
[8] J. V. Suryanarayana Sista, Justin Earp, Nitin Mehrotra, “Center for Drug Evaluation and Clinical Pharmacology and Biopharmaceutics Review,” 2014. [Online]. Available: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125522Orig1s000ClinPharmR.pdf.
[9] Amgen Inc, “Background Information for Endocrinologic and Metabolic Drugs Advisory Commitee,” 2015. [Online]. Available: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM450072.pdf.
Reference: PAGE 25 (2016) Abstr 5763 [www.page-meeting.org/?abstract=5763]
Poster: Drug/Disease modeling - Other topics