Population Pharmacokinetics of Abrocitinib in Healthy Individuals and Patients with Psoriasis or Atopic Dermatitis
Jessica Wojciechowski, Bimal K Malhotra, Xiaoxing Wang, Luke Fostvedt, Hernan Valdez, Timothy Nicholas, Jessica Wojciechowski, Bimal K Malhotra, Xiaoxing Wang, Luke Fostvedt, Hernan Valdez, Timothy Nicholas
Abstract
Background and objective: Abrocitinib is a Janus kinase 1 inhibitor in development for the treatment of atopic dermatitis (AD). This work characterized orally administered abrocitinib population pharmacokinetics in healthy individuals, patients with psoriasis, and patients with AD and the effects of covariates on abrocitinib exposure.
Methods: Abrocitinib concentration measurements (n = 6206) from 995 individuals from 11 clinical trials (seven phase I, two phase II, and two phase III) were analyzed, and a non-linear mixed-effects model was developed. Simulations of abrocitinib dose proportionality and steady-state accumulation of maximal plasma drug concentration (Cmax) and area under the curve (AUC) were conducted using the final model.
Results: A two-compartment model with parallel zero- and first-order absorption, time-dependent bioavailability, and time- and dose-dependent clearance best described abrocitinib pharmacokinetics. Abrocitinib coadministration with rifampin resulted in lower exposure, whereas Asian/other race coadministration with fluconazole and fluvoxamine, inflammatory skin conditions (psoriasis/AD), and hepatic impairment resulted in higher exposure. After differences in body weight are accounted for, Asian participants demonstrated a 1.43- and 1.48-fold increase in Cmax and AUC, respectively. The overall distribution of exposures (Cmax and AUC) was similar in adolescents and adults after accounting for differences in total body weight.
Conclusions: A population pharmacokinetics model was developed for abrocitinib that can be used to predict abrocitinib steady-state exposure in the presence of drug-drug interaction effects or intrinsic patient factors. Key covariates in the study population accounting for variability in abrocitinib exposures are Asian race and adolescent age, although these factors are not clinically meaningful.
Clinical trial numbers: NCT01835197, NCT02163161, NCT02201524, NCT02780167, NCT03349060, NCT03575871, NCT03634345, NCT03637790, NCT03626415, NCT03386279, NCT03937258.
Conflict of interest statement
Jessica Wojciechowski, Bimal K. Malhotra, Xiaoxing Wang, Luke Fostvedt, Hernan Valdez, and Timothy Nicholas are employees and shareholders of Pfizer Inc.
© 2022. The Author(s).
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References
- Vazquez ML, Kaila N, Strohbach JW, Trzupek JD, Brown MF, Flanagan ME, et al. Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfo namide (PF-04965842): a selective JAK1 clinical candidate for the treatment of autoimmune diseases. J Med Chem. 2018;61(3):1130–1152. doi: 10.1021/acs.jmedchem.7b01598.
- Gooderham MJ, Forman SB, Bissonnette R, Beebe JS, Zhang W, Banfield C, et al. Efficacy and safety of oral Janus kinase 1 inhibitor abrocitinib for patients with atopic dermatitis: a phase 2 randomized clinical trial. JAMA Dermatol. 2019;155(12):1371–1379. doi: 10.1001/jamadermatol.2019.2855.
- Silverberg JI, Simpson EL, Thyssen JP, Gooderham M, Chan G, Feeney C, et al. Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2020;156(8):863–873. doi: 10.1001/jamadermatol.2020.1406.
- Simpson EL, Sinclair R, Forman S, Wollenberg A, Aschoff R, Cork M, et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2020;396(10246):255–266. doi: 10.1016/S0140-6736(20)30732-7.
- European Medicines Agency. SmPC for Cibinqo 2021. . Accessed 5 Nov 2021.
- Pharmaceuticals and Medical Device Agency (PMDA) H.P. List of Approved Products in Reiwa 3rd-year October 27, 2021. . Accessed 5 Nov 2021.
- Schmieder GJ, Draelos ZD, Pariser DM, Banfield C, Cox L, Hodge M, et al. Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study. Br J Dermatol. 2018;179(1):54–62. doi: 10.1111/bjd.16004.
- Peeva E, Hodge MR, Kieras E, Vazquez ML, Goteti K, Tarabar SG, et al. Evaluation of a Janus kinase 1 inhibitor, PF-04965842, in healthy subjects: a phase 1, randomized, placebo-controlled, dose-escalation study. Br J Clin Pharmacol. 2018;84(8):1776–1788. doi: 10.1111/bcp.13612.
- Dowty M, Yang X, Lin J, Bauman J, Doran A, Goosen T, et al. P190—the effect of CYP2C9 and CYP2C19 genotype on the pharmacokinetics of PF 04965842, a JAK1 inhibitor in clinical development. Drug Metab Pharmacokinet. 2020;35(1 Suppl):S80. doi: 10.1016/j.dmpk.2020.04.191.
- Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacomet Syst Pharmacol. 2013;2:e38. doi: 10.1038/psp.2013.14.
- Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development. CPT Pharmacomet Syst Pharmacol. 2012;1(9):e6. doi: 10.1038/psp.2012.4.
- Beal SS, Boeckmann L, Sheiner LB. NONMEM User’s Guides. (1989–2009). Gaithersburg, MD: ICON Development Solutions; 2009. Corpus ID: 65385267. . Accessed 20 Jan 2021.
- R Core Team. R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing; 2019. Available at: . Accessed 20 Jan 2021.
- Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28(5):481–504. doi: 10.1023/A:1012299115260.
- Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol. 2004;44(10):1083–1105. doi: 10.1177/0091270004268128.
- Krekels EHJ, Rower JE, Constance JE, Knibbe CAJ, Sherwin CMT. Hepatic drug metabolism in pediatric patients. In: Xie W, editor. Drug metabolism in diseases. Boston: Academic Press; 2017. pp. 181–206.
- de Wildt SN, Tibboel D, Leeder JS. Drug metabolism for the paediatrician. Arch Dis Child. 2014;99(12):1137–1142. doi: 10.1136/archdischild-2013-305212.
- Kaye JL. Review of paediatric gastrointestinal physiology data relevant to oral drug delivery. Int J Clin Pharm. 2011;33(1):20–24. doi: 10.1007/s11096-010-9455-0.
- Morgan ET. Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther. 2009;85(4):434–438. doi: 10.1038/clpt.2008.302.
- Tanino T, Komada A, Ueda K, Bando T, Nojiri Y, Ueda Y, et al. Pharmacokinetics and differential regulation of cytochrome P450 enzymes in type 1 allergic mice. Drug Metab Dispos. 2016;44(12):1950–1957. doi: 10.1124/dmd.116.072462.
- Ma G, Xie R, Strober B, Langley R, Ito K, Krishnaswami S, et al. Pharmacokinetic characteristics of tofacitinib in adult patients with moderate to severe chronic plaque psoriasis. Clin Pharmacol Drug Dev. 2018;7(6):587–596. doi: 10.1002/cpdd.471.
- Nader A, Stodtmann S, Friedel A, Mohamed MF, Othman AA. Pharmacokinetics of upadacitinib in healthy subjects and subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, or atopic dermatitis: population analyses of phase 1 and 2 clinical trials. J Clin Pharmacol. 2020;60(4):528–539. doi: 10.1002/jcph.1550.
- Klunder B, Mohamed MF, Othman AA. Population pharmacokinetics of upadacitinib in healthy subjects and subjects with rheumatoid arthritis: analyses of phase I and II clinical trials. Clin Pharmacokinet. 2018;57(8):977–988. doi: 10.1007/s40262-017-0605-6.
Source: PubMed