Quantitative systems toxicology (QST) reproduces species differences in PF-04895162 liver safety due to combined mitochondrial and bile acid toxicity
Grant Generaux, Vinal V Lakhani, Yuching Yang, Sashi Nadanaciva, Luping Qiu, Keith Riccardi, Li Di, Brett A Howell, Scott Q Siler, Paul B Watkins, Hugh A Barton, Michael D Aleo, Lisl K M Shoda, Grant Generaux, Vinal V Lakhani, Yuching Yang, Sashi Nadanaciva, Luping Qiu, Keith Riccardi, Li Di, Brett A Howell, Scott Q Siler, Paul B Watkins, Hugh A Barton, Michael D Aleo, Lisl K M Shoda
Abstract
Many compounds that appear promising in preclinical species, fail in human clinical trials due to safety concerns. The FDA has strongly encouraged the application of modeling in drug development to improve product safety. This study illustrates how DILIsym, a computational representation of liver injury, was able to reproduce species differences in liver toxicity due to PF-04895162 (ICA-105665). PF-04895162, a drug in development for the treatment of epilepsy, was terminated after transaminase elevations were observed in healthy volunteers (NCT01691274). Liver safety concerns had not been raised in preclinical safety studies. DILIsym, which integrates in vitro data on mechanisms of hepatotoxicity with predicted in vivo liver exposure, reproduced clinical hepatotoxicity and the absence of hepatotoxicity observed in the rat. Simulated differences were multifactorial. Simulated liver exposure was greater in humans than rats. The simulated human hepatotoxicity was demonstrated to be due to the interaction between mitochondrial toxicity and bile acid transporter inhibition; elimination of either mechanism from the simulations abrogated injury. The bile acid contribution occurred despite the fact that the IC50 for bile salt export pump (BSEP) inhibition by PF-04895162 was higher (311 µmol/L) than that has been generally thought to contribute to hepatotoxicity. Modeling even higher PF-04895162 liver exposures than were measured in the rat safety studies aggravated mitochondrial toxicity but did not result in rat hepatotoxicity due to insufficient accumulation of cytotoxic bile acid species. This investigative study highlights the potential for combined in vitro and computational screening methods to identify latent hepatotoxic risks and paves the way for similar and prospective studies.
Keywords: DILIsym; PBPK; PF‐04895162; QSP; QST; bile acid transporters; drug‐induced liver injury; mechanistic; mitochondria; species translation.
Conflict of interest statement
The authors report that this research did not receive external public or private foundation funding. The study was sponsored by Pfizer. Authors are former or current employees of Pfizer or DSS or an advisory board member of DSS (PBW) and may continue to hold stock or other equity positions with the companies.
© 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
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References
- Battista C, Howell BA, Siler SQ, Watkins PB. An introduction to DILIsym® software, a mechanistic mathematical representation of drug‐induced liver injury In: Chen M, Will Y, eds. Drug‐induced liver toxicity. New York, NY: Springer; 2018:101–121.
- Longo DM, Generaux GT, Howell BA, et al. Refining liver safety risk assessment: application of mechanistic modeling and serum biomarkers to cimaglermin alfa (GGF2) clinical trials. Clin Pharmacol Ther. 2017;102:961‐969.
- Longo DM, Woodhead JL, Walker P, et al. Quantitative systems toxicology analysis of in vitro mechanistic assays reveals importance of bile acid accumulation and mitochondrial dysfunction in TAK‐875‐induced liver injury. Toxicol Sci Off J Soc Toxicol. 2019;167:458‐467.
- Woodhead JL, Yang K, Oldach D, et al. Analyzing the mechanisms behind macrolide antibiotic‐induced liver injury using quantitative systems toxicology modeling. Pharm Res. 2019;36:48.
- Battista C, Yang K, Stahl SH, et al. Using quantitative systems toxicology to investigate observed species differences in CKA-mediated hepatotoxicity. Toxicol Sci Off J Soc Toxicol. 2018;166:123–130.
- Howell BA, Yang Y, Kumar R, et al. In vitro to in vivo extrapolation and species response comparisons for drug‐induced liver injury (DILI) using DILIsymTM: a mechanistic, mathematical model of DILI. J Pharmacokinet Pharmacodyn. 2012;39:527‐541.
- Yang K, Woodhead JL, Watkins PB, Howell BA, Brouwer K. Systems pharmacology modeling predicts delayed presentation and species differences in bile acid‐mediated troglitazone hepatotoxicity. Clin Pharmacol Ther. 2014;96:589‐598.
- Kasteleijn‐Nolst Trenité D, Biton V, French JA, et al. Kv7 potassium channel activation with ICA‐105665 reduces photoparoxysmal EEG responses in patients with epilepsy. Epilepsia. 2013;54:1437‐1443.
- Roeloffs R, Wickenden AD, Crean C, et al. In vivo profile of ICA‐27243 [N‐(6‐chloro‐pyridin‐3‐yl)‐3,4‐difluoro‐benzamide], a potent and selective KCNQ2/Q3 (Kv7.2/Kv7.3) activator in rodent anticonvulsant models. J Pharmacol Exp Ther. 2008;326:818‐828.
- Aleo MD, Aubrecht J, Bonin D, et al. Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis. Pharmacol Res Perspect. 2019;7:e00467.
- Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res. 2013;103:2‐30.
- Bhattacharya S, Shoda L, Zhang Q, et al. Modeling drug‐ and chemical‐induced hepatotoxicity with systems biology approaches. Front. Physiol. 2012;3:462.
- Shoda L, Woodhead JL, Siler SQ, Watkins PB, Howell BA. Linking physiology to toxicity using DILIsym®, a mechanistic mathematical model of drug‐induced liver injury. Biopharm Drug Dispos. 2014;35:33‐49.
- Watkins PB. The DILI‐sim initiative: insights into hepatotoxicity mechanisms and biomarker interpretation. Clin Transl Sci. 2019;12:122‐129.
- Woodhead JL, Howell BA, Yang Y, et al. An analysis of N‐acetylcysteine treatment for acetaminophen overdose using a systems model of drug‐induced liver injury. J Pharmacol Exp Ther. 2012;342:529‐540.
- Longo DM, Yang Y, Watkins PB, Howell BA, Siler SQ. Elucidating differences in the hepatotoxic potential of tolcapone and entacapone with DILIsym(®), a mechanistic model of drug‐induced liver injury. CPT Pharmacomet Syst Pharmacol. 2016;5:31‐39.
- Woodhead JL, Yang K, Siler SQ, et al. Exploring BSEP inhibition‐mediated toxicity with a mechanistic model of drug‐induced liver injury. Front Pharmacol. 2014;5:240.
- Woodhead JL, Brock WJ, Roth SE, et al. Application of a mechanistic model to evaluate putative mechanisms of tolvaptan drug‐induced liver injury and identify patient susceptibility factors. Toxicol Sci Off J Soc Toxicol. 2017;155:61‐74.
- Eakins J, Bauch C, Woodhouse H, et al. A combined in vitro approach to improve the prediction of mitochondrial toxicants. Toxicol Vitro Int J Publ Assoc BIBRA. 2016;34:161‐170.
- Nadanaciva S, Rana P, Beeson GC, et al. Assessment of drug‐induced mitochondrial dysfunction via altered cellular respiration and acidification measured in a 96‐well platform. J Bioenerg Biomembr. 2012;44:421‐437.
- Yang Y, Nadanaciva S, Will Y, et al. MITOsym®: a mechanistic, mathematical model of hepatocellular respiration and bioenergetics. Pharm Res. 2015;32:1975‐1992.
- Watkins PB, Desai M, Berkowitz SD, et al. Evaluation of drug‐induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery. Drug Saf. 2011;34:243‐252.
- Schulz S, Schmitt S, Wimmer R, et al. Progressive stages of mitochondrial destruction caused by cell toxic bile salts. Biochim Biophys Acta. 2013;1828:2121‐2133.
- Kenna JG, Taskar KS, Battista C, et al. Can bile salt export pump inhibition testing in drug discovery and development reduce liver injury risk? An international transporter consortium perspective. Clin Pharmacol Ther. 2018;104:916‐932.
- Aleo MD, Luo Y, Swiss R, Bonin PD, Potter DM, Will Y. Human drug‐induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump. Hepatology. 2014;60:1015‐1022.
- Kullak‐Ublick GA, Andrade RJ, Merz M, et al. Drug‐induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017;66:1154‐1164.
- Morgan RE, van Staden CJ, Chen Y, et al. A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci Off J Soc Toxicol. 2013;136:216‐241.
- Morgan RE, Trauner M, van Staden CJ, et al. Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci Off J SocToxicol. 2010;118:485‐500.
- Michel MC, Radziszewski P, Falconer C, Marschall‐Kehrel D, Blot K. Unexpected frequent hepatotoxicity of a prescription drug, flupirtine, marketed for about 30 years. Br J Clin Pharmacol 2012;73:821‐825.
- Han D, Ybanez MD, Johnson HS, et al. Dynamic adaptation of liver mitochondria to chronic alcohol feeding in mice: biogenesis, remodeling, and functional alterations. J Biol Chem 2012;287:42165‐42179.
Source: PubMed