Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 5/2018

Open Access 01-05-2018 | Original Research Article

Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults

Authors: Anne van Rongen, Margreke J. E. Brill, Janelle D. Vaughns, Pyry A. J. Välitalo, Eric P. A. van Dongen, Bert van Ramshorst, Jeffrey S. Barrett, Johannes N. van den Anker, Catherijne A. J. Knibbe

Published in: Clinical Pharmacokinetics | Issue 5/2018

Login to get access

Abstract

Background

The clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults.

Methods

Data from 19 obese adolescents [102.7 kg (62–149.5 kg)] and 20 morbidly obese adults [144 kg (112–186 kg)] receiving intravenous midazolam were analysed, using population pharmacokinetic modelling (NONMEM 7.2). In the covariate analysis, the influence of study group, age, total body weight (TBW), developmental weight (WTfor age and length) and excess body weight (WTexcess = TBW − WTfor age and length) was evaluated.

Results

The population mean midazolam clearance was significantly higher in obese adolescents than in morbidly obese adults [0.71 (7%) vs. 0.44 (11%) L/min; p < 0.01]. Moreover, clearance in obese adolescents increased with TBW (p < 0.01), which seemed mainly explained by WTexcess, and for which a so-called ‘excess weight’ model scaling WTfor age and length to the power of 0.75 and a separate function for WTexcess was proposed.

Discussion

We hypothesise that higher midazolam clearance in obese adolescents is explained by less obesity-induced suppression of CYP3A activity, while the increase with WTexcess is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents.
Appendix
Available only for authorised users
Literature
1.
Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(10):103–41.CrossRefPubMed
2.
Kotlyar M, Carson SW. Effects of obesity on the cytochrome P450 enzyme system. Int J Clin Pharmacol Ther. 1999;37(132):8–19.PubMed
3.
Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van den Anker JN, Knibbe CA. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet. 2012;51(71):277–304.CrossRefPubMed
4.
Vet NJ, Brussee JM, de Hoog M, Mooij MG, Verlaat CW, Jerchel IS, et al. Inflammation and organ failure severely affect midazolam clearance in critically ill children. Am J Respir Crit Care Med. 2016;194(1):58–66.CrossRefPubMed
5.
Carcillo JA, Doughty L, Kofos D, Frye RF, Kaplan SS, Sasser H, et al. Cytochrome P450 mediated-drug metabolism is reduced in children with sepsis-induced multiple organ failure. Intensive Care Med. 2003;29(6):980–4.CrossRefPubMed
6.
Ince I, Knibbe CA, Danhof M, de Wildt SN. Developmental changes in the expression and function of cytochrome P450 3A isoforms: evidence from in vitro and in vivo investigations. Clin Pharmacokinet. 2013;52(5):333–45.CrossRefPubMed
7.
de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet. 1999;37(6):485–505.CrossRefPubMed
8.
Thummel KE, Shen DD, Podoll TD, Kunze KL, Trager WF, Hartwell PS, et al. Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients. J Pharmacol Exp Ther. 1994;271(1):549–56.PubMed
9.
Fuhr U, Jetter A, Kirchheiner J. Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the “cocktail” approach. Clin Pharmacol Ther. 2007;81(12):270–83.CrossRefPubMed
10.
Kolwankar D, Vuppalanchi R, Ethell B, Jones DR, Wrighton SA, Hall SD, et al. Association between nonalcoholic hepatic steatosis and hepatic cytochrome P-450 3A activity. Clin Gastroenterol Hepatol. 2007;5(3):388–93.CrossRefPubMed
11.
Yoshinari K, Takagi S, Yoshimasa T, Sugatani J, Miwa M. Hepatic CYP3A expression is attenuated in obese mice fed a high-fat diet. Pharm Res. 2006;23(6):1188–200.CrossRefPubMed
12.
Ghose R, Omoluabi O, Gandhi A, Shah P, Strohacker K, Carpenter KC, et al. Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters. Life Sci. 2011;89(1–2):57–64.CrossRefPubMedPubMedCentral
13.
Woolsey SJ, Mansell SE, Kim RB, Tirona RG, Beaton MD. CYP3A activity and expression in nonalcoholic fatty liver disease. Drug Metab Dispos. 2015;43(10):1484–90.CrossRefPubMed
14.
Brill MJ, van Rongen A, Houwink AP, Burggraaf J, van Ramshorst B, Wiezer RJ, et al. Midazolam pharmacokinetics in morbidly obese patients following semi-simultaneous oral and intravenous administration: a comparison with healthy volunteers. Clin Pharmacokinet. 2014;53(12):931–41.CrossRefPubMedPubMedCentral
15.
Brill MJ, van Rongen A, van Dongen EP, van Ramshorst B, Hazebroek EJ, Darwich AS, et al. The pharmacokinetics of the CYP3A substrate midazolam in morbidly obese patients before and one year after bariatric surgery. Pharm Res. 2015;32(12):3927–36.CrossRefPubMedPubMedCentral
16.
Brill M, Valitalo P, Darwich AS, van Ramshorst B, van Dongen H, Rostami-Hodjegan A, et al. Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1-OH-midazolam in morbidly obese and weight loss surgery patients. CPT Pharmacomet Syst Pharmacol. 2016;5(1):20–30.CrossRef
17.
Tandra S, Chalasani N, Jones DR, Mattar S, Hall SD, Vuppalanchi R. Pharmacokinetic and pharmacodynamic alterations in the Roux-en-Y gastric bypass recipients. Ann Surg. 2013;258(2):262–9.CrossRefPubMed
18.
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.CrossRefPubMedPubMedCentral
19.
Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet. 1997;33(5):313–27.CrossRefPubMed
20.
Momper JD, Mulugeta Y, Green DJ, Karesh A, Krudys KM, Sachs HC, et al. Adolescent dosing and labeling since the Food and Drug Administration Amendments Act of 2007. JAMA Pediatr. 2013;167(10):926–32.CrossRefPubMed
21.
Mahmood I. Dosing in children: a critical review of the pharmacokinetic allometric scaling and modelling approaches in paediatric drug development and clinical settings. Clin Pharmacokinet. 2014;53(15):327–46.CrossRefPubMed
22.
US Food and Drug Administration Center for Drug Evaluation and Research. Advisory Committee for Pharmaceutical Science and Clinical Pharmacology (ACPS-CP) meeting: summary minutes and FDA transcript. 14 March 2012.
23.
Calvier EA, Krekels EH, Valitalo PA, Rostami-Hodjegan A, Tibboel D, Danhof M, et al. Allometric scaling of clearance in paediatric patients: when does the magic of 0.75 fade? Clin Pharmacokinet. 2017;56(3):273–85.CrossRefPubMed
24.
Knibbe CA, Brill MJ, van Rongen A, Diepstraten J, van der Graaf PH, Danhof M. Drug disposition in obesity: toward evidence-based dosing. Annu Rev Pharmacol Toxicol. 2015;55(1):149–67.CrossRefPubMed
25.
Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132(6):2169–80.CrossRefPubMed
26.
Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol. 2005;115(16):911–9 (quiz 920).CrossRefPubMed
27.
van Rongen A, Vaughns JD, Moorthy GS, Barrett JS, Knibbe CA, van den Anker JN. Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents. Br J Clin Pharmacol. 2015;80(5):1185–96.CrossRefPubMedPubMedCentral
28.
Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM user’s guides. (1989–2009). Ellicott City: Icon Development Solutions; 2009.
29.
Keizer RJ, Karlsson MO, Hooker A. Modeling and simulation workbench for NONMEM: tutorial on Pirana, PsN, and Xpose. CPT Pharmacomet Syst Pharmacol. 2013;2(43):e50.CrossRef
30.
R Development Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statatistical Computing; 2008.
31.
Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean bodyweight. Clin Pharmacokinet. 2005;44(31):1051–65.CrossRefPubMed
32.
33.
Renton KW. Regulation of drug metabolism and disposition during inflammation and infection. Expert Opin Drug Metab Toxicol. 2005;1(17):629–40.CrossRefPubMed
34.
Alexander JK, Dennis EW, Smith WG, Amad KH, Duncan WC, Austin RC. Blood volume, cardiac output, and distribution of systemic blood flow in extreme obesity. Cardiovasc Res Cent Bull. 1962;1(48):39–44.PubMed
35.
Lewis MC, Phillips ML, Slavotinek JP, Kow L, Thompson CH, Toouli J. Change in liver size and fat content after treatment with Optifast very low calorie diet. Obes Surg. 2006;16(6):697–701.CrossRefPubMed
36.
Diepstraten J, Chidambaran V, Sadhasivam S, Esslinger HR, Cox SL, Inge TH, et al. Propofol clearance in morbidly obese children and adolescents: influence of age and body size. Clin Pharmacokinet. 2012;51(27):543–51.CrossRefPubMed
37.
Bartelink IH, van Kesteren C, Boelens JJ, Egberts TC, Bierings MB, Cuvelier GD, et al. Predictive performance of a busulfan pharmacokinetic model in children and young adults. Ther Drug Monit. 2012;34(307):574–83.CrossRefPubMed
38.
Diepstraten J, Chidambaran V, Sadhasivam S, Blusse van Oud-Alblas HJ, Inge T, van Ramshorst B, et al. An integrated population pharmacokinetic meta-analysis of propofol in morbidly obese and nonobese adults, adolescents, and children. CPT Pharmacomet Syst Pharmacol. 2013;2(8):e73.CrossRef
39.
Mulla H, Johnson TN. Dosing dilemmas in obese children. Arch Dis Child Educ Pract Ed. 2010;95(6):112–7.CrossRefPubMed
40.
Kendrick JG, Carr RR, Ensom MH. Pharmacokinetics and drug dosing in obese children. J Pediatr Pharmacol Ther. 2010;15(7):94–109.PubMedPubMedCentral
41.
Kendrick JG, Carr RR, Ensom MH. Pediatric obesity: pharmacokinetics and implications for drug dosing. Clin Ther. 2015;37(9):1897–923.CrossRefPubMed
42.
Rowe S, Siegel D, Benjamin DK Jr. Best Pharmaceuticals for Children Act—Pediatric Trials Network Administrative Core Committee. Gaps in drug dosing for obese children: a systematic review of commonly prescribed emergency care medications. Clin Ther. 2015;37(9):1924–32.CrossRefPubMedPubMedCentral
43.
Xie R, Tan LH, Polasek EC, Hong C, Teillol-Foo M, Gordi T, et al. CYP3A and P-glycoprotein activity induction with St. John’s Wort in healthy volunteers from 6 ethnic populations. J Clin Pharmacol. 2005;45(3):352–6.CrossRefPubMed
44.
Wandel C, Witte JS, Hall JM, Stein CM, Wood AJ, Wilkinson GR. CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4*1B5′-promoter region polymorphism. Clin Pharmacol Ther. 2000;68(1):82–91.CrossRefPubMed
45.
Sowunmi A, Rashid TJ, Akinyinka OO, Renwick AG. Ethnic differences in nifedipine kinetics: comparisons between Nigerians, Caucasians and South Asians. Br J Clin Pharmacol. 1995;40(5):489–93.PubMedPubMedCentral
46.
Xie HG, Kim RB, Wood AJ, Stein CM. Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol. 2001;41:815–50.CrossRefPubMed
47.
Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology. 1984;61(13):27–35.CrossRefPubMed
48.
Thummel KE, O’Shea D, Paine MF, Shen DD, Kunze KL, Perkins JD, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther. 1996;59(10):491–502.CrossRefPubMed
49.
Lee JI, Chaves-Gnecco D, Amico JA, Kroboth PD, Wilson JW, Frye RF. Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping. Clin Pharmacol Ther. 2002;72(8):718–28.CrossRefPubMed
50.
Mandema JW, Tuk B, van Steveninck AL, Breimer DD, Cohen AF, Danhof M. Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite alpha-hydroxymidazolam in healthy volunteers. Clin Pharmacol Ther. 1992;51(24):715–28.CrossRefPubMed
51.
Gorski JC, Hall SD, Jones DR, VandenBranden M, Wrighton SA. Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily. Biochem Pharmacol. 1994;47(9):1643–53.CrossRefPubMed
52.
Shord SS, Chan LN, Camp JR, Vasquez EM, Jeong HY, Molokie RE, et al. Effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam. Br J Clin Pharmacol. 2010;69(2):160–6.CrossRefPubMedPubMedCentral
53.
van Gerven JM, Roncari G, Schoemaker RC, Massarella J, Keesmaat P, Kooyman H, et al. Integrated pharmacokinetics and pharmacodynamics of Ro 48-8684, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects. Br J Clin Pharmacol. 1997;44(5):487–93.CrossRefPubMedPubMedCentral
Metadata
Title
Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults
Authors
Anne van Rongen
Margreke J. E. Brill
Janelle D. Vaughns
Pyry A. J. Välitalo
Eric P. A. van Dongen
Bert van Ramshorst
Jeffrey S. Barrett
Johannes N. van den Anker
Catherijne A. J. Knibbe
Publication date
01-05-2018
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 5/2018
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-017-0579-4

Other articles of this Issue 5/2018

Clinical Pharmacokinetics 5/2018 Go to the issue

Original Research Article

Population Pharmacokinetics and Optimal Sampling Strategy for Model-Based Precision Dosing of Melphalan in Patients Undergoing Hematopoietic Stem Cell Transplantation

Author Correction

Author Correction: Exogenous Cannabinoid Efficacy: Merely a Pharmacokinetic Interaction?

Original Research Article

Pharmacokinetics of ABT-122, a TNF-α- and IL-17A-Targeted Dual-Variable Domain Immunoglobulin, in Healthy Subjects and Patients with Rheumatoid Arthritis: Results from Three Phase I Trials

Review Article

Clinical Pharmacokinetics and Pharmacodynamics of Oxazolidinones

Current Opinion

Exogenous Cannabinoid Efficacy: Merely a Pharmacokinetic Interaction?

Original Research Article

Pharmacokinetic Optimization of Everolimus Dosing in Oncology: A Randomized Crossover Trial