Publication Cover
Xenobiotica
the fate of foreign compounds in biological systems
Volume 52, 2022 - Issue 3
318
Views
1
CrossRef citations to date
0
Altmetric
Clinical Pharmacokinetics and Metabolism

Pharmacokinetics, mass balance, metabolism, and excretion of the liver-targeted acetyl-CoA carboxylase inhibitor PF-05221304 (clesacostat) in humans

, , , ORCID Icon, , & ORCID Icon show all
Pages 240-253 | Received 18 Mar 2022, Accepted 01 Apr 2022, Published online: 13 Apr 2022

References

  • Alkhouri N, Lawitz E, Noureddin M, DeFronzo R, Shulman GI. 2020. GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 29(2):135–141.
  • Bai A, Shanmugasundaram V, Selkirk JV, Surapaneni S, Dalvie D. 2021. Investigation into MAO B-mediated formation of CC112273, a major circulating metabolite of ozanimod, in humans and preclinical species: stereospecific oxidative deamination of (S)-enantiomer of indaneamine (RP101075) by MAO B. Drug Metab Dispos. 49(8):601–609.
  • Bergman A, Carvajal-Gonzalez S, Tarabar S, Saxena AR, Esler WP, Amin NB. 2020. Safety, tolerability, pharmacokinetics, and pharmacodynamics of a liver-targeting acetyl-CoA carboxylase inhibitor (PF-05221304): a three-part randomized phase 1 study. Clin Pharmacol Drug Dev. 9(4):514–526.
  • Calle RA, Amin NB, Carvajal-Gonzalez S, Ross TT, Bergman A, Aggarwal S, Crowley C, Rinaldi A, Mancuso J, Aggarwal N, Somayaji V, Inglot M, et al. 2021. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials. Nat Med. 27(10):1836–1848.
  • Eng H, Bi YA, West MA, Ryu S, Yamaguchi E, Kosa RE, Tess DA, Griffith DA, Litchfield J, Kalgutkar AS, et al. 2021. Organic anion-transporting polypeptide 1B1/1B3-mediated hepatic uptake determines the pharmacokinetics of large lipophilic acids: in vitro-in vivo evaluation in cynomolgus monkey. J Pharmacol Exp Ther. 377(1):169–180.
  • El-Kattan AF, Varma MVS. 2018. Navigating transporter sciences in pharmacokinetics characterization using the extended clearance classification system. Drug Metab Dispos. 46(5):729–739.
  • Esler WP, Bence KK. 2019. Metabolic targets in nonalcoholic fatty liver disease. Cell Mol Gastroenterol Hepatol. 8(2):247–267.
  • Griffith DA, Kung DW, Esler WP, Amor PA, Bagley SW, Beysen C, Carvajal-Gonzalez S, Doran SD, Limberakis C, Mathiowetz AM, McPherson K, Price DA, et al. 2014. Decreasing the rate of metabolic ketone reduction in the discovery of a clinical acetyl-CoA carboxylase inhibitor for the treatment of diabetes. J Med Chem. 57(24):10512–10526.
  • Hamilton RA, Garnett WR, Kline BJ. 1981. Determination of mean valproic acid serum level by assay of a single pooled sample. Clin Pharmacol Ther. 29(3):408–413.
  • Harriman G, Greenwood J, Bhat S, Huang X, Wang R, Paul D, Tong L, Saha A, Westlin WF, Kapeller R, et al. 2016. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc Natl Acad Sci USA. 113(13):E1796–E1805.
  • Harwood HJ, Jr, Petras SF, Shelly LD, Zaccaro LM, Perry DA, Makowski MR, Hargrove DM, Martin KA, Tracey WR, Chapman JG, et al. 2003. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J Biol Chem. 278(39):37099–37111.
  • Huard K, Smith AC, Cappon G, Dow RL, Edmonds DJ, El-Kattan A, Esler WP, Fernando DP, Griffith DA, Kalgutkar AS, et al. 2020. Optimizing the benefit/risk of acetyl-CoA carboxylase inhibitors through liver targeting. J Med Chem. 63(19):10879–10896.
  • Kelly KL, Reagan WJ, Sonnenberg GE, Clasquin M, Hales K, Asano S, Amor PA, Carvajal-Gonzalez S, Shirai N, Matthews MD, et al. 2020. De novo lipogenesis is essential for platelet production in humans. Nat Metab. 2(10):1163–1178.
  • Kim CW, Addy C, Kusunoki J, Anderson NN, Deja S, Fu X, Burgess SC, Li C, Ruddy M, Chakravarthy M, et al. 2017. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metab. 26(3):309–406.
  • Kirby BJ, Lutz JD, Yue MS, Garrison KL, Qin AR, Ampaw L, Beysen C, Myers RP, Kearney BP, Mathias A. 2021. Organic anion transporting polypeptide inhibition dramatically increases plasma exposure but not pharmacodynamic effect nor inferred hepatic intracellular exposure of firsocostat. Clin Pharmacol Ther. 109(5):1334–1341.
  • Lau YY, Huang Y, Frassetto L, Benet LZ. 2007. Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 81(2):194–204.
  • Lawitz EJ, Coste A, Poordad F, Alkhouri N, Loo N, McColgan BJ, Tarrant JM, Nguyen T, Han L, Chung C, et al. 2018. Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 16(12):1983–1991.
  • Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, Wang L, Harting E, Tarrant JM, McColgan BJ, et al. 2018. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology. 155(5):1463–1473.
  • McGarry JD, Mannaerts GP, Foster DW. 1977. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest. 60(1):265–270.
  • Mori D, Kimoto E, Rago B, Kondo Y, King-Ahmad A, Ramanathan R, Wood LS, Johnson JG, Le VH, Vourvahis M, et al. 2020. Dose-dependent inhibition of OATP1B by rifampicin in healthy volunteers: comprehensive evaluation of candidate biomarkers and OATP1B probe drugs. Clin Pharmacol Ther. 107(4):1004–1013.
  • Romero FA, Jones CT, Xu Y, Fenaux M, Halcomb RL. 2020. The race to bash NASH: emerging targets and drug development in a complex liver disease. J Med Chem. 63(10):5031–5073.
  • Roth M, Obaidat A, Hagenbuch B. 2012. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol. 165(5):1260–1287.
  • Saggerson D. 2008. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu Rev Nutr. 28:253–272.
  • Savage DB, Choi CS, Samuel VT, Liu ZX, Zhang D, Wang A, Zhang XM, Cline GW, Yu XX, Geisler JG, et al. 2006. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest. 116(3):817–824.
  • Schadt S, Bister B, Chowdhury SK, Funk C, Hop CECA, Humphreys WG, Igarashi F, James AD, Kagan M, Khojasteh SC, Nedderman ANR, et al. 2018. A decade in the MIST: Learnings from investigations of drug metabolites in drug development under the “metabolites in safety testing” regulatory guidance. Drug Metab Dispos. 46(6):865–878.
  • Shitara Y, Maeda K, Ikejiri K, Yoshida K, Horie T, Sugiyama Y. 2013. Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos. 34(1):45–78.
  • Stiede K, Miao W, Blanchette HS, Beysen C, Harriman G, Harwood HJ, Jr, Kelley H, Kapeller R, Schmalbach T, Westlin WF. 2017. Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study. Hepatology. 66(2):324–334.
  • Tess DA, Eng H, Kalgutkar AS, Litchfield J, Edmonds DJ, Griffith DA, Varma MVS. 2020. Predicting the human hepatic clearance of acidic and zwitterionic drugs. J Med Chem. 63(20):11831–11844.
  • Tyndale RF, Kalow W, Inaba T. 1991. Oxidation of reduced haloperidol to haloperidol: involvement of human P450IID6 (sparteine/debrisoquine monooxygenase). Br J Clin Pharmacol. 31(6):655–660.
  • Varma MV, Kimoto E, Scialis R, Bi Y, Lin J, Eng H, Kalgutkar AS, El-Kattan AF, Rodrigues AD, Tremaine LM. 2017. Transporter-mediated hepatic uptake plays an important role in the pharmacokinetics and drug-drug interactions of montelukast. Clin Pharmacol Ther. 101(3):406–415.
  • Waite M, Wakil SJ. 1962. Studies on the mechanism of fatty acid synthesis. XII. Acetyl coenzyme A carboxylase. J Biol Chem. 237:2750–2757.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.