Population Pharmacokinetic Modeling of Inebilizumab in Subjects with Neuromyelitis Optica Spectrum Disorders, Systemic Sclerosis, or Relapsing Multiple Sclerosis
Tóm tắt
Inebilizumab is a humanized, affinity-optimized, afucosylated immunoglobulin (Ig)-G1κ monoclonal antibody that binds to CD19, resulting in effective depletion of peripheral B cells. It is being developed to treat various autoimmune diseases, including neuromyelitis optica spectrum disorders (NMOSD), systemic sclerosis (SSc), and relapsing multiple sclerosis (MS). Pharmacokinetic data from a pivotal study in adult subjects with NMOSD and two early-stage studies in subjects with SSc or relapsing MS were pooled and simultaneously analyzed using a population approach. Upon intravenous administration, the pharmacokinetics of inebilizumab were adequately described by a two-compartment model with parallel first-order and time-dependent nonlinear elimination pathways. An asymptotic nonlinear elimination suggests that inebilizumab undergoes receptor (CD19)-mediated clearance. The estimated systemic clearance (CL) of the first-order elimination pathway (0.188 L/day) and the volume of distribution (Vd) (5.52 L) were typical for therapeutic immunoglobulins. The elimination half-life was approximately 18 days. The maximum velocity (Vmax) of the nonlinear elimination pathway decreased with time, presumably due to the depletion of B cells upon inebilizumab administration. As for other therapeutic monoclonal antibodies, the CL and Vd of inebilizumab increased with body weight. The presence of antidrug antibodies, status of hepatic or renal function, and use of small-molecule drugs commonly used by subjects with NMOSD had no clinically relevant impact on the pharmacokinetics of inebilizumab. The nonlinear elimination pathway at the 300 mg therapeutic dose level is not considered clinically relevant.
Tài liệu tham khảo
Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6(9):810–5.
Jarius S, Wildemann B. AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol. 2010;6(7):383–92.
Chihara N, Aranami T, Sato W, Miyazaki Y, Miyake S, Okamoto T, et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Nat Acad Sci USA. 2010;108(9):3701–6.
Cree BAC, Bennett J, Kim HJ, Weinshenker BG, Pittock SJ, Wingerchuk DM, et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019;394(10206):1352–63.
SAS Software version 9.3, SAS Institute Inc, Cary, NC, United States. 2020.
Byon W, Smith MK, Chan P, Tortorici MA, Riley S, Dai H, et al. Establishing best practices and guidance in population modeling: an experience with an internal population pharmacokinetic analysis guidance. CPT Pharmacometrics Syst Pharmacol. 2013;2(7):e51.
Beal S, Boeckmann A, Bauer R, Sheiner LB. NONMEM User's Guides. (1989–2009) Icon Development Solutions, Ellicott City, MD, USA. 2009
Jonsson EN, Karlsson MO (1999) Xpose—an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed. 58(1):51–64
Lindbom L, Ribbing J, Jonsson EN. Perl-speaks-NONMEM (PsN)–a Perl module for NONMEM related programming. Comput Methods Programs Biomed. 2004;75(2):85–94.
Yan L, Wang B, Chia YL, Roskos LK. Population pharmacokinetic modeling of benralizumab in adult and adolescent patients with asthma. Clin Pharmacokinet. 2019;58:943–58.
Rozman S, Grabnar I, Novaković S, Mrhar A, Jezeršek NB. Population pharmacokinetics of rituximab in patients with diffuse large B-cell lymphoma and association with clinical outcome. Br J Clin Pharmacol. 2017;83:1782–90.
Schober P, Boer C, Schwarte LA. Correlation coefficients: appropriate use and interpretation. Anesth Analg. 2018;126(5):1763–8.
Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13(2):143–51.
Herbst R, Wang Y, Gallagher S, Mittereder N, Kuta E, et al. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther. 2010;335(1):213–22.
Gallagher S, Turman S, Yusuf I, Akhgar A, Wu Y, et al. Pharmacological profile of MEDI-551, a novel anti-CD19 antibody, in human CD19 transgenic mice. Int Immunopharmacol. 2016;36:205–12.
Yan X, Mager DE, Krzyzanski W. Selection between Michaelis-Menten and target-mediated drug disposition pharmacokinetic models. J Pharmacokinet Pharmacodyn. 2010;37(1):25–47.
Li J, Zhi J, Wenger M, Valente N, Dmoszynska A, Robak T, et al. Population pharmacokinetics of rituximab in patients with chronic lymphocytic leukemia. J Clin Pharmacol. 2012;52(12):1918–26.
Rituximab [package insert]. San Francisco, CA: Biogen Idec Inc. and Genentech, Inc.; 2012.
Ocrelizumab [package insert]. South San Francisco, CA: Genetech, Inc.; 2020.
Wang B, Arends R, Roskos LK. A preliminary population pharmacokinetic analysis of panitumumab, a fully human IgG2 anti-EGFR monoclonal antibody. AAPS J. 2004;6(1):2375.
Baverel PG, Jain M, Stelmach I, She D, Agoram B, Sandbach S, et al. Pharmacokinetics of tralokinumab in adolescents with asthma: implications for future dosing. Br J Clin Pharmacol. 2015;80(6):1337–49.
Oh CK, Faggioni R, Jin F, Roskos LK, Wang B, Birrell C, et al. An open-label, single-dose bioavailability study of the pharmacokinetics of CAT-354 after subcutaneous and intravenous administration in healthy males. Br J Clin Pharmacol. 2010;69(6):645–55.
Wang B, Wu CY, Jin D, Vicini P, Roskos L. Model-based discovery and development of biopharmaceuticals: a case study of mavrilimumab, DModel based discovery and development of biopharmaceuticals: a case study of mavrilimumab. CPT Pharmacometrics Syst Pharmacol. 2018;7(1):5–15.
Zheng Y, Narwal R, Jin C, Baverel PG, Jin X, Gupta A, et al. Population modeling of tumor kinetics and overall survival to identify prognostic and predictive biomarkers of efficacy for durvalumab in patients with urothelial carcinoma. Clin Pharmacol Ther. 2018;103(4):643–52.
US Food and Drug Administration. Guidance for industry: population pharmacokinetics. Rockville, MD: US FDA; 1999.
European Medicines Agency. Guideline on reporting the results of population pharmacokinetic analyses. London: EMA. 2007. https://www.ema.europa.eu/en/reporting-results-population-pharmacokinetic-analyses.