Physiologically Based Pharmacokinetic Modelling to Identify Physiological and Drug Parameters Driving Pharmacokinetics in Obese Individuals.
Journal
Clinical pharmacokinetics
ISSN: 1179-1926
Titre abrégé: Clin Pharmacokinet
Pays: Switzerland
ID NLM: 7606849
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
accepted:
28
11
2022
pubmed:
27
12
2022
medline:
14
3
2023
entrez:
26
12
2022
Statut:
ppublish
Résumé
Obese individuals are often underrepresented in clinical trials, leading to a lack of dosing guidance. This study aimed to investigate which physiological parameters and drug properties determine drug disposition changes in obese using our physiologically based pharmacokinetic (PBPK) framework, informed with obese population characteristics. Simulations were performed for ten drugs with clinical data in obese (i.e., midazolam, triazolam, caffeine, chlorzoxazone, acetaminophen, lorazepam, propranolol, amikacin, tobramycin, and glimepiride). PBPK drug models were developed and verified first against clinical data in non-obese (body mass index (BMI) ≤ 30 kg/m Predicted pharmacokinetic parameters were within 1.25-fold (71.5%), 1.5-fold (21.5%) and twofold (7%) of clinical data. On average, clearance increased by 1.6% per BMI unit up to 64% for a BMI of 60 kg/m Both physiological changes and drug properties impact drug pharmacokinetics in obese subjects. Clearance increases due to enhanced hepatic and renal blood flows. Volume of distribution is higher for all drugs, with differences among drugs depending on their pK
Sections du résumé
BACKGROUND
Obese individuals are often underrepresented in clinical trials, leading to a lack of dosing guidance.
OBJECTIVE
This study aimed to investigate which physiological parameters and drug properties determine drug disposition changes in obese using our physiologically based pharmacokinetic (PBPK) framework, informed with obese population characteristics.
METHODS
Simulations were performed for ten drugs with clinical data in obese (i.e., midazolam, triazolam, caffeine, chlorzoxazone, acetaminophen, lorazepam, propranolol, amikacin, tobramycin, and glimepiride). PBPK drug models were developed and verified first against clinical data in non-obese (body mass index (BMI) ≤ 30 kg/m
RESULTS
Predicted pharmacokinetic parameters were within 1.25-fold (71.5%), 1.5-fold (21.5%) and twofold (7%) of clinical data. On average, clearance increased by 1.6% per BMI unit up to 64% for a BMI of 60 kg/m
CONCLUSION
Both physiological changes and drug properties impact drug pharmacokinetics in obese subjects. Clearance increases due to enhanced hepatic and renal blood flows. Volume of distribution is higher for all drugs, with differences among drugs depending on their pK
Identifiants
pubmed: 36571702
doi: 10.1007/s40262-022-01194-3
pii: 10.1007/s40262-022-01194-3
pmc: PMC9998327
doi:
Substances chimiques
Midazolam
R60L0SM5BC
Caffeine
3G6A5W338E
Propranolol
9Y8NXQ24VQ
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
277-295Informations de copyright
© 2022. The Author(s).
Références
World Health Organization. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight . Accessed 4 Nov 2021.
Collaborators GBDO, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377(1):13–27.
doi: 10.1056/NEJMoa1614362
Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766–81.
doi: 10.1016/S0140-6736(14)60460-8
pubmed: 24880830
pmcid: 4624264
Hruby A, Hu FB. The epidemiology of obesity: a big picture. Pharmacoeconomics. 2015;33(7):673–89.
doi: 10.1007/s40273-014-0243-x
pubmed: 25471927
pmcid: 4859313
Fruh SM. Obesity: risk factors, complications, and strategies for sustainable long-term weight management. J Am Assoc Nurse Pract. 2017;29(S1):S3–14.
doi: 10.1002/2327-6924.12510
pubmed: 29024553
pmcid: 6088226
Jain R, Chung SM, Jain L, Khurana M, Lau SW, Lee JE, et al. Implications of obesity for drug therapy: limitations and challenges. Clin Pharmacol Ther. 2011;90(1):77–89.
doi: 10.1038/clpt.2011.104
pubmed: 21633345
Smit C, De Hoogd S, Bruggemann RJM, Knibbe CAJ. Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters. Expert Opin Drug Metab Toxicol. 2018;14(3):275–85.
doi: 10.1080/17425255.2018.1440287
pubmed: 29431542
Berton M, Bettonte S, Stader F, Battegay M, Marzolini C. Repository describing the anatomical, physiological, and biological changes in an obese population to inform physiologically based pharmacokinetic models. Clin Pharmacokinet. 2022;61(9):1251–70.
doi: 10.1007/s40262-022-01132-3
pubmed: 35699913
pmcid: 9439993
Stader F, Penny MA, Siccardi M, Marzolini C. A comprehensive framework for physiologically based pharmacokinetic modelling in Matlab. CPT Pharmacomet Syst Pharmacol. 2019 Feb 18;8(7):444–59.
Rodgers T, Leahy D, Rowland M. Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci. 2005;94(6):1259–76.
doi: 10.1002/jps.20322
pubmed: 15858854
Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95(6):1238–57.
doi: 10.1002/jps.20502
pubmed: 16639716
Stader F, Siccardi M, Battegay M, Kinvig H, Penny MA, Marzolini C. Repository describing an aging population to inform physiologically based pharmacokinetic models considering anatomical, physiological, and biological age-dependent changes. Clin Pharmacokinet. 2019;58(4):483–501.
doi: 10.1007/s40262-018-0709-7
pubmed: 30128967
Berton M, Bettonte S, Stader F, Battegay M, Marzolini C. Repository describing the anatomical, physiological, and biological changes in an obese population to inform physiologically based pharmacokinetic models. Clin Pharmacokinet. 2022; (in press).
Rowland Yeo K, Walsky RL, Jamei M, Rostami-Hodjegan A, Tucker GT. Prediction of time-dependent CYP3A4 drug-drug interactions by physiologically based pharmacokinetic modelling: impact of inactivation parameters and enzyme turnover. Eur J Pharm Sci. 2011;43(3):160–73.
doi: 10.1016/j.ejps.2011.04.008
pubmed: 21540107
Chetty M, Rose RH, Abduljalil K, Patel N, Lu G, Cain T, et al. Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability. Front Pharmacol. 2014;5:258.
doi: 10.3389/fphar.2014.00258
pubmed: 25505415
pmcid: 4244809
Darakjian LI, Kaddoumi A. Physiologically based pharmacokinetic/pharmacodynamic model for caffeine disposition in pregnancy. Mol Pharm. 2019;16(3):1340–9.
doi: 10.1021/acs.molpharmaceut.8b01276
pubmed: 30689395
Li J, Guo HF, Liu C, Zhong Z, Liu L, Liu XD. Prediction of drug disposition in diabetic patients by means of a physiologically based pharmacokinetic model. Clin Pharmacokinet. 2015;54(2):179–93.
doi: 10.1007/s40262-014-0192-8
pubmed: 25316573
Jiang XL, Zhao P, Barrett JS, Lesko LJ, Schmidt S. Application of physiologically based pharmacokinetic modeling to predict acetaminophen metabolism and pharmacokinetics in children. CPT Pharmacomet Syst Pharmacol. 2013;16(2): e80.
doi: 10.1038/psp.2013.55
Maharaj AR, Barrett JS, Edginton AN. A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. AAPS J. 2013;15(2):455–64.
doi: 10.1208/s12248-013-9451-0
pubmed: 23344790
pmcid: 3675728
Rose RH, Turner DB, Neuhoff S, Jamei M. Incorporation of the time-varying postprandial increase in splanchnic blood flow into a PBPK model to predict the effect of food on the pharmacokinetics of orally administered high-extraction drugs. AAPS J. 2017;19(4):1205–17.
doi: 10.1208/s12248-017-0099-z
pubmed: 28526963
Ferreira A, Martins H, Oliveira JC, Lapa R, Vale N. PBPK Modeling and simulation of antibiotics amikacin, gentamicin, tobramycin, and vancomycin used in hospital practice. Life (Basel). 2021;11(11):1130.
Shebley M, Sandhu P, Emami Riedmaier A, Jamei M, Narayanan R, Patel A, et al. Physiologically based pharmacokinetic model qualification and reporting procedures for regulatory submissions: a consortium perspective. Clin Pharmacol Ther. 2018;104(1):88–110.
doi: 10.1002/cpt.1013
pubmed: 29315504
pmcid: 6032820
Berton M, Bettonte S, Decosterd L, Battegay M, Cavassini M, Stader F, et al. Pharmacokinetics of Dolutegravir And Bictegravir in Obese People Living With HIV [Poster-G01]. Conference on retroviruses and opportunistic infections. February 12–16, 2022.
U.S. Food and Drug Administration. Department of Health and Human Services. Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA Guidance for Industry. (2021)
European Medicines Agency. Committee for medicinal products for human use. Guideline on the investigation of bioequivalence. (2010)
Blanchard J, Sawers SJ. Comparative pharmacokinetics of caffeine in young and elderly men. J Pharmacokinet Biopharm. 1983;11(2):109–26.
doi: 10.1007/BF01061844
pubmed: 6886969
Peter R, Boecker R, Beaune PH, Iwasaki M, Guengerich FP, Yang CS. Hydroxylation of chlorzoxazone as a specific probe for human liver cytochrome P-450IIE1. Chem Res Toxicol. 1990;3(6):566–73.
doi: 10.1021/tx00018a012
pubmed: 2103328
van Rongen A, Välitalo PAJ, Peeters MYM, Boerma D, Huisman FW, van Ramshorst B, et al. Morbidly obese patients exhibit increased CYP2E1-mediated oxidation of acetaminophen. Clin Pharmacokinet. 2016;55(7):833–47.
doi: 10.1007/s40262-015-0357-0
pubmed: 26818482
pmcid: 4916199
Elliott HW. Metabolism of lorazepam. Br J Anaesth. 1976;48(10):1017–23.
doi: 10.1093/bja/48.10.1017
pubmed: 10938
U.S. Food and Drug Administration. Amikacin NDA. 1997. https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/64146AP.PDF . Accessed 11 Apr 2022.
U.S. Food and Drug Administration. Tobramycin NDA. 2003. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/050789s000_Tobramycin_PharmR.pdf . Accessed 11 Apr 2022.
Prescribing information. Amaryl (glimepiride). Bridgewater, NJ: Aventis Pharmaceutical Products. 2000; https://products.sanofi.us/amaryl/amaryl.pdf . Accessed 11 Apr 2022.
Abernethy DR, Greenblatt DJ. Drug disposition in obese humans. An update Clin Pharmacokinet. 1986;11(3):199–213.
doi: 10.2165/00003088-198611030-00002
pubmed: 3524955
Dave RA, Morris ME. A quantitative threshold for high/low extent of urinary excretion of compounds in humans. Biopharm Drug Dispos. 2016;37(5):287–309.
doi: 10.1002/bdd.2013
pubmed: 27122230
pmcid: 4956512
Benet LZ, Broccatelli F, Oprea TI. BDDCS applied to over 900 drugs. AAPS J. 2011;13(4):519–47.
doi: 10.1208/s12248-011-9290-9
pubmed: 21818695
pmcid: 3231854
Kokate A, Li X, Jasti B. Effect of drug lipophilicity and ionization on permeability across the buccal mucosa: a technical note. AAPS PharmSciTech. 2008;9(2):501–4.
doi: 10.1208/s12249-008-9071-7
pubmed: 18431653
pmcid: 2976956
Ulvestad M, Skottheim IB, Jakobsen GS, Bremer S, Molden E, Asberg A, et al. Impact of OATP1B1, MDR1, and CYP3A4 expression in liver and intestine on interpatient pharmacokinetic variability of atorvastatin in obese subjects. Clin Pharmacol Ther. 2013;93(3):275–82.
doi: 10.1038/clpt.2012.261
pubmed: 23361102
Krogstad V, Peric A, Robertsen I, Kringen MK, Vistnes M, Hjelmesaeth J, et al. Correlation of body weight and composition with hepatic activities of cytochrome P450 enzymes. J Pharm Sci. 2021;110(1):432–7.
doi: 10.1016/j.xphs.2020.10.027
pubmed: 33091408
Stader F, Kinvig H, Penny MA, Battegay M, Siccardi M, Marzolini C. Physiologically based pharmacokinetic modelling to identify pharmacokinetic parameters driving drug exposure changes in the elderly. Clin Pharmacokinet. 2020;59(3):383–401.
doi: 10.1007/s40262-019-00822-9
pubmed: 31583609
Eknoyan G. Obesity and chronic kidney disease. Nefrologia. 2011;31(4):397–403.
pubmed: 21623393
Carr RM, Oranu A, Khungar V. Nonalcoholic fatty liver disease: pathophysiology and management. Gastroenterol Clin North Am. 2016;45(4):639–52.
doi: 10.1016/j.gtc.2016.07.003
pubmed: 27837778
pmcid: 5127277
Abduljalil K, Pansari A, Jamei M. Prediction of maternal pharmacokinetics using physiologically based pharmacokinetic models: assessing the impact of the longitudinal changes in the activity of CYP1A2, CYP2D6 and CYP3A4 enzymes during pregnancy. J Pharmacokinet Pharmacodyn. 2020;47(4):361–83.
doi: 10.1007/s10928-020-09711-2
pubmed: 32840724
Heimbach T, Chen Y, Chen J, Dixit V, Parrott N, Peters SA, et al. Physiologically-based pharmacokinetic modeling in renal and hepatic impairment populations: a pharmaceutical industry perspective. Clin Pharmacol Ther. 2021;110(2):297–310.
doi: 10.1002/cpt.2125
pubmed: 33270249
Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology. 1984;61(1):27–35.
doi: 10.1097/00000542-198461010-00006
pubmed: 6742481
Lam YW, Alfaro CL, Ereshefsky L, Miller M. Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone. J Clin Pharmacol. 2003;43(11):1274–82.
doi: 10.1177/0091270003259216
pubmed: 14551182
Derry CL, Kroboth PD, Pittenger AL, Kroboth FJ, Corey SE, Smith RB. Pharmacokinetics and pharmacodynamics of triazolam after two intermittent doses in obese and normal-weight men. J Clin Psychopharmacol. 1995;15(3):197–205.
doi: 10.1097/00004714-199506000-00008
pubmed: 7635997
Abernethy DR, Greenblatt DJ, Divoll M, Smith RB, Shader RI. The influence of obesity on the pharmacokinetics of oral alprazolam and triazolam. Clin Pharmacokinet. 1984;9(2):177–83.
doi: 10.2165/00003088-198409020-00005
pubmed: 6143633
Abernethy DR, Todd EL, Schwartz JB. Caffeine disposition in obesity. Br J Clin Pharmacol. 1985;20(1):61–6.
doi: 10.1111/j.1365-2125.1985.tb02799.x
pubmed: 4027137
pmcid: 1400629
Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Cotreau MM, Harmatz JS, et al. Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans. J Clin Pharmacol. 1997;37(8):693–703.
doi: 10.1002/j.1552-4604.1997.tb04356.x
pubmed: 9378841
Cysneiros RM, Farkas D, Harmatz JS, von Moltke LL, Greenblatt DJ. Pharmacokinetic and pharmacodynamic interactions between zolpidem and caffeine. Clin Pharmacol Ther. 2007;82(1):54–62.
doi: 10.1038/sj.clpt.6100211
pubmed: 17443132
Wang Z, Hall SD, Maya JF, Li L, Asghar A, Gorski JC. Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans. Br J Clin Pharmacol. 2003;55(1):77–85.
doi: 10.1046/j.1365-2125.2003.01731.x
pubmed: 12534643
pmcid: 1884181
Hohmann N, Blank A, Burhenne J, Suzuki Y, Mikus G, Haefeli WE. Simultaneous phenotyping of CYP2E1 and CYP3A using oral chlorzoxazone and midazolam microdoses. Br J Clin Pharmacol. 2019;85(10):2310–20.
doi: 10.1111/bcp.14040
pubmed: 31222796
pmcid: 6783597
Abernethy DR, Divoll M, Greenblatt DJ, Ameer B. Obesity, sex, and acetaminophen disposition. Clin Pharmacol Ther. 1982;31(6):783–90.
doi: 10.1038/clpt.1982.111
pubmed: 7075126
Rawlins MD, Henderson DB, Hijab AR. Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration. Eur J Clin Pharmacol. 1977;11(4):283–6.
doi: 10.1007/BF00607678
pubmed: 862649
Kamali F, Edwards C, Rawlins MD. The effect of pirenzepine on gastric emptying and salivary flow rate: constraints on the use of saliva paracetamol concentrations for the determination of paracetamol pharmacokinetics. Br J Clin Pharmacol. 1992;33(3):309–12.
doi: 10.1111/j.1365-2125.1992.tb04041.x
pubmed: 1576053
pmcid: 1381281
Chen KF, Chan LN, Senn TD, Oelschlager BK, Flum DR, Shen DD, et al. The impact of Proximal Roux-en-Y gastric bypass surgery on acetaminophen absorption and metabolism. Pharmacotherapy. 2020;40(3):191–203.
doi: 10.1002/phar.2368
pubmed: 31960977
Abernethy DR, Greenblatt DJ, Divoll M, Shader RI. Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen. J Lab Clin Med. 1983;101(6):873–80.
pubmed: 6133901
Greenblatt DJ, Shader RI, Franke K, MacLaughlin DS, Harmatz JS, Allen MD, et al. Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans. J Pharm Sci. 1979;68(1):57–63.
doi: 10.1002/jps.2600680119
pubmed: 31453
Greenblatt DJ, Divoll M, Harmatz JS, Shader RI. Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam. J Pharm Sci. 1982;71(2):248–52.
doi: 10.1002/jps.2600710227
pubmed: 6121043
Wermeling DP, Miller JL, Archer SM, Manaligod JM, Rudy AC. Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration. J Clin Pharmacol. 2001;41(11):1225–31.
doi: 10.1177/00912700122012779
pubmed: 11697755
Bowman SL, Hudson SA, Simpson G, Munro JF, Clements JA. A comparison of the pharmacokinetics of propranolol in obese and normal volunteers. Br J Clin Pharmacol. 1986;21(5):529–32.
doi: 10.1111/j.1365-2125.1986.tb02837.x
pubmed: 3718810
pmcid: 1401028
Regardh CG, Johnsson G, Jordo L, Lungborg P, Persson BA, Ronn O. Plasma concentrations and beta-blocking effects in normal volunteers after intravenous doses of metoprolol and propranolol. J Cardiovasc Pharmacol. 1980;2(6):715–23.
doi: 10.1097/00005344-198011000-00002
pubmed: 6160322
Mould GP, Clough J, Morris BA, Stout G, Marks V. A propranolol radioimmunoassay and its use in the study of its pharmacokinetics following low doses. Biopharm Drug Dispos. 1981;2(1):49–57.
doi: 10.1002/bdd.2510020106
pubmed: 7236871
Walker JM, Wise R, Mitchard M. The pharmacokinetics of amikacin and gentamicin in volunteers: a comparison of individual differences. J Antimicrob Chemother. 1979;5(1):95–9.
doi: 10.1093/jac/5.1.95
pubmed: 762009
Bauer LA, Blouin RA, Griffen WO Jr, Record KE, Bell RM. Amikacin pharmacokinetics in morbidly obese patients. Am J Hosp Pharm. 1980;37(4):519–22.
pubmed: 7377215
Smit C, Wasmann RE, Wiezer MJ, van Dongen HPA, Mouton JW, Bruggemann RJM, et al. Tobramycin clearance is best described by renal function estimates in obese and non-obese individuals: results of a prospective rich sampling pharmacokinetic study. Pharm Res. 2019;36(8):112.
doi: 10.1007/s11095-019-2651-2
pubmed: 31147853
pmcid: 6542779
Shukla UA, Chi EM, Lehr KH. Glimepiride pharmacokinetics in obese versus non-obese diabetic patients. Ann Pharmacother. 2004;38(1):30–5.
doi: 10.1345/aph.1C397
pubmed: 14742789