A population pharmacokinetic-pharmacodynamic model of navtemadlin, its glucuronide metabolite (M1) and serum macrophage inhibitory cykokine-1 (MIC-1)

References

• Al-Ali HK, Delgado RG, Lange A, Pluta A, McLornan DP, Vachhani P, Damaj GL, Jost PJ, Rejto L, Hus M, et al. 2020. KRT‑232, a first‑in‑class, murine double minute 2 inhibitor (MDM2i), for myelofibrosis (MF) relapsed or refractory (R/R) to Janus‑associated kinase inhibitor (JAKi) treatment (TX). HemaSphere. 4 (S1):65.
   Google Scholar
• Allard M, Wada D, Krejsa C, Greg Slatter J. 2020. Exposure-macrophage inhibitory cytokine-1 (MIC-1) response analysis of the MDM2 antagonist KRT-232 in patients with advanced solid tumors, multiple myeloma, or acute myeloid leukemia. HemaSphere. 4:212.
   Google Scholar
• Canon J, Osgood T, Olson SH, Saiki AY, Robertson R, Yu D, Eksterowicz J, Ye Q, Jin L, Chen A, et al. 2015. The MDM2 inhibitor AMG 232 demonstrates robust antitumor efficacy and potentiates the activity of p53-inducing cytotoxic agents. Mol Cancer Ther. 14 (3):649–658.
   PubMed Web of Science ®Google Scholar
• ClinicalTrials.gov. 2022. KRT-232 versus best available therapy for the treatment of subjects with myelofibrosis who are relapsed or refractory to JAK inhibitor treatment (BOREAS). ClinicalTrials.gov identifier: NCT03662126 [updated 2022 Jul 14. accessed July 27]. https://clinicaltrials.gov/show/NCT03662126.
   Google Scholar
• Craver BM, El Alaoui K, Scherber RM, Fleischman AG. 2018. The critical role of inflammation in the pathogenesis and progression of myeloid malignancies. Cancers (Basel). 10 (4):104.
   Web of Science ®Google Scholar
• Data on file. Kartos Therapeutics.
   Google Scholar
• Erba HP, Becker PS, Shami PJ, Grunwald MR, Flesher DL, Zhu M, Rasmussen E, Henary HA, Anderson AA, Wang ES. 2019. Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. Blood Adv. 3 (13):1939–1949.
   PubMed Web of Science ®Google Scholar
• Ezzet F, Krishna G, Wexler DB, Statkevich P, Kosoglou T, Batra VK. 2001. A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe. Clin Ther. 23 (6):871–885.
   PubMed Web of Science ®Google Scholar
• Gluck WL, Gounder MM, Frank R, Eskens F, Blay JY, Cassier PA, Soria JC, Chawla S, de Weger V, Wagner AJ, et al. 2020. Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced p53 wild-type solid tumors or multiple myeloma. Invest New Drugs. 38 (3):831–843.
   PubMed Web of Science ®Google Scholar
• Guiastrennec B, Sonne DP, Bergstrand M, Vilsboll T, Knop FK, Karlsson MO. 2018. Model-based prediction of plasma concentration and enterohepatic circulation of total bile acids in humans. CPT Pharmacometrics Syst Pharmacol. 7 (9):603–612.
   PubMedGoogle Scholar
• Guiastrennec B, Sonne DP, Hansen M, Bagger JI, Lund A, Rehfeld JF, Alskar O, Karlsson MO, Vilsboll T, Knop FK, et al. 2016. Mechanism-based modeling of gastric emptying rate and gallbladder emptying in response to caloric intake. CPT Pharmacometrics Syst Pharmacol. 5 (12):692–700.
   PubMedGoogle Scholar
• Italiano A, Miller WH, Jr., Blay JY, Gietema JA, Bang YJ, Mileshkin LR, Hirte HW, Higgins B, Blotner S, Nichols GL, et al. 2021. Phase I study of daily and weekly regimens of the orally administered MDM2 antagonist idasanutlin in patients with advanced tumors. Invest New Drugs. 39(6):1587–1597.
   PubMed Web of Science ®Google Scholar
• Jamois C, Anders D, Beckermann BM, Genevray M, Mundt K, Petry C, Yang J, Kassir N, Schmitt C. 2020. Contribution of idasanutlin exposure to safety, pharmacodynamics and clinical response of patients with acute myeloid leukemia treated with idasanutlin + cytarabine in phase I and III studies. Blood. 136 (Supplement 1):7–8.
   Web of Science ®Google Scholar
• Jeay S, Ferretti S, Holzer P, Fuchs J, Chapeau EA, Wartmann M, Sterker D, Romanet V, Murakami M, Kerr G, et al. 2018. Dose and schedule determine distinct molecular mechanisms underlying the efficacy of the p53-MDM2 inhibitor HDM201. Cancer Res. 78 (21):6257–6267.
   PubMed Web of Science ®Google Scholar
• Ma SC, Wada R, Allard M, Slatter G. 2019. Population pharmacokinetic analysis of the MDM2 inhibitor KRT-232 (formerly AMG 232) in subjects with advanced solid tumors, multiple myeloma or acute myeloid leukemia. Blood. 134 (Supplement_1):5766–5766.
   Web of Science ®Google Scholar
• Nemunaitis J, Young A, Ejadi S, Miller W, Chen LC, Nichols G, Blotner S, Vazvaei F, Zhi J, Razak A. 2018. Effects of posaconazole (a strong CYP3A4 inhibitor), two new tablet formulations, and food on the pharmacokinetics of idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 81 (3):529–537.
   PubMed Web of Science ®Google Scholar
• Sam WJ, Akhlaghi F, Rosenbaum SE. 2009. Population pharmacokinetics of mycophenolic acid and its 2 glucuronidated metabolites in kidney transplant recipients. J Clin Pharmacol. 49 (2):185–195.
   PubMed Web of Science ®Google Scholar
• Sharma R, Sharma S. 2022. Physiology, blood volume. Treasure Island (FL): StatPearls.
   Google Scholar
• Shou M, Lu W, Kari PH, Xiang C, Liang Y, Lu P, Cui D, Emary WB, Michel KB, Adelsberger JK, et al. 2005. Population pharmacokinetic modeling for enterohepatic recirculation in Rhesus monkey. Eur J Pharm Sci. 26 (2):151–161.
   PubMed Web of Science ®Google Scholar
• Soulele K, Karalis V. 2019. Development of a joint population pharmacokinetic model of ezetimibe and its conjugated metabolite. Eur J Pharm Sci. 128:18–26.
   PubMed Web of Science ®Google Scholar
• Stein EM, DeAngelo DJ, Chromik J, Chatterjee M, Bauer S, Lin CC, Suarez C, de Vos F, Steeghs N, Cassier PA, et al. 2022. Results from a first-in-human phase I study of siremadlin (HDM201) in patients with advanced wild-type TP53 solid tumors and acute leukemia. Clin Cancer Res. 28 (5):870–881.
   PubMed Web of Science ®Google Scholar
• Sun D, Li Z, Rew Y, Gribble M, Bartberger MD, Beck HP, Canon J, Chen A, Chen X, Chow D, et al. 2014. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem. 57 (4):1454–1472.
   PubMed Web of Science ®Google Scholar
• Sun K, Welty D. 2021. Elucidation of metabolic and disposition pathways for maribavir in nonhuman primates through mass balance and semi-physiologically based modeling approaches. Drug Metab Dispos. 49 (11):1025–1037.
   PubMed Web of Science ®Google Scholar
• Takahashi S, Fujiwara Y, Nakano K, Shimizu T, Tomomatsu J, Koyama T, Ogura M, Tachibana M, Kakurai Y, Yamashita T, et al. 2021. Safety and pharmacokinetics of milademetan, a MDM2 inhibitor, in Japanese patients with solid tumors: a phase I study. Cancer Sci. 112 (6):2361–2370.
   PubMed Web of Science ®Google Scholar
• Tan M, Wang Y, Guan K, Sun Y. 2000. PTGF-beta, a type beta transforming growth factor (TGF-beta) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-beta signaling pathway. Proc Natl Acad Sci USA. 97 (1):109–114.
   PubMed Web of Science ®Google Scholar
• Taylor A, Lee D, Allard M, Poland B, Greg Slatter J. 2021. Phase 1 concentration-QTc and cardiac safety analysis of the MDM2 antagonist KRT-232 in patients with advanced solid tumors, multiple myeloma, or acute myeloid leukemia. Clin Pharmacol Drug Dev. 10 (8):918–926.
   PubMed Web of Science ®Google Scholar
• Uchiyama T, Kawabata H, Miura Y, Yoshioka S, Iwasa M, Yao H, Sakamoto S, Fujimoto M, Haga H, Kadowaki N, et al. 2015. The role of growth differentiation factor 15 in the pathogenesis of primary myelofibrosis. Cancer Med. 4 (10):1558–1572.
   PubMed Web of Science ®Google Scholar
• Wischhusen J, Melero I, Fridman WH. 2020. Growth/differentiation factor-15 (GDF-15): from biomarker to novel targetable immune checkpoint. Front Immunol. 11:951.
   PubMed Web of Science ®Google Scholar
• Wong MKK, Burgess MA, Chandra S, Schadendorf D, Silk AW, Olszanski AJ, Grob J-J, Jang S, Grewal JS, Lewis K, et al. 2022. Navtemadlin (KRT-232) activity after failure of anti-PD-1/L1 therapy in patients with TP53WT Merkel cell carcinoma. Presented at American Society of Clinical Oncology Meeting; June 5, Chicago, IL.
   Google Scholar
• Wong MKK, Kelly CM, Burgess MA, Lewis K, Grewal JS, Olszanski AJ, McGreivy J, Rothbaum W, Qamoos H, DeCaprio JA. 2020. KRT-232, a first-in-class, murine double minute 2 inhibitor (MDM2i), for TP53 wild-type (p53WT) Merkel cell carcinoma (MCC) after anti–PD-1/L1 immunotherapy. JCO. 38 (15_suppl):10072–10072.
   Web of Science ®Google Scholar
• Wong S, Krejsa C, Lee D, Harris A, Simard E, Wang X, Allard M, Podoll T, O'Reilly T, Slatter JG. 2022. Pharmacokinetics and macrophage inhibitory cytokine-1 (MIC-1) pharmacodynamics of the murine double minute 2 (MDM2) inhibitor, KRT-232 in fed and fasted healthy subjects. Clin Pharmacol Drug Dev. 11 (5):640–653.
   PubMed Web of Science ®Google Scholar
• Yang G, Ge S, Singh R, Basu S, Shatzer K, Zen M, Liu J, Tu Y, Zhang C, Wei J, et al. 2017. Glucuronidation: driving factors and their impact on glucuronide disposition. Drug Metab Rev. 49 (2):105–138.
   PubMed Web of Science ®Google Scholar
• Yau WP, Vathsala A, Lou HX, Zhou S, Chan E. 2009. Mechanism-based enterohepatic circulation model of mycophenolic acid and its glucuronide metabolite: assessment of impact of cyclosporine dose in Asian renal transplant patients. J Clin Pharmacol. 49 (6):684–699.
   PubMed Web of Science ®Google Scholar
• Ye Q, Jiang M, Huang WT, Ling Y, Olson SH, Sun D, Xu G, Yan X, Wong BK, Jin L. 2015. Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo correlation. Xenobiotica. 45 (8):681–692.
   PubMed Web of Science ®Google Scholar
• Yoshimura K, Yano I, Yamamoto T, Kawanishi M, Isomoto Y, Yonezawa A, Kondo T, Takaori-Kondo A, Matsubara K. 2018. Population pharmacokinetics and pharmacodynamics of mycophenolic acid using the prospective data in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 53 (1):44–51.
   PubMed Web of Science ®Google Scholar
• Zhang L, Beal SL, Sheinerz LB. 2003. Simultaneous vs. sequential analysis for population PK/PD data II: robustness of methods. J Pharmacokinet Pharmacodyn. 30(6):405–416.
   PubMed Web of Science ®Google Scholar