Anne van Rongen1,2,3, Margreke J E Brill1,2,4, Janelle D Vaughns5,6, Pyry A J Välitalo2, Eric P A van Dongen7, Bert van Ramshorst8, Jeffrey S Barrett9, Johannes N van den Anker6,10,11, Catherijne A J Knibbe12,13. 1. Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands. 2. Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. 3. Department of Clinical Pharmacy, Reinier de Graaf Hospital, Delft, The Netherlands. 4. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. 5. Division of Anesthesiology and Pain Medicine, Children's National Health System, Washington, DC, USA. 6. Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA. 7. Department of Anesthesiology and Intensive Care, St. Antonius Hospital, Nieuwegein, The Netherlands. 8. Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands. 9. Laboratory for Applied PK/PD, Children's Hospital of Philadelphia, Philadelphia, USA. 10. Division of Pediatric Pharmacology and Pharmacometrics, University Children's Hospital, Basel, Switzerland. 11. Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands. 12. Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands. c.knibbe@antoniusziekenhuis.nl. 13. Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. c.knibbe@antoniusziekenhuis.nl.
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.
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.
Authors: Margreke J E Brill; Jeroen Diepstraten; Anne van Rongen; Simone van Kralingen; John N van den Anker; Catherijne A J Knibbe Journal: Clin Pharmacokinet Date: 2012-05-01 Impact factor: 6.447
Authors: K E Thummel; D O'Shea; M F Paine; D D Shen; K L Kunze; J D Perkins; G R Wilkinson Journal: Clin Pharmacol Ther Date: 1996-05 Impact factor: 6.875
Authors: Jang-Ik Lee; Diego Chaves-Gnecco; Janet A Amico; Patricia D Kroboth; John W Wilson; Reginald F Frye Journal: Clin Pharmacol Ther Date: 2002-12 Impact factor: 6.875
Authors: Marie Ng; Tom Fleming; Margaret Robinson; Blake Thomson; Nicholas Graetz; Christopher Margono; Erin C Mullany; Stan Biryukov; Cristiana Abbafati; Semaw Ferede Abera; Jerry P Abraham; Niveen M E Abu-Rmeileh; Tom Achoki; Fadia S AlBuhairan; Zewdie A Alemu; Rafael Alfonso; Mohammed K Ali; Raghib Ali; Nelson Alvis Guzman; Walid Ammar; Palwasha Anwari; Amitava Banerjee; Simon Barquera; Sanjay Basu; Derrick A Bennett; Zulfiqar Bhutta; Jed Blore; Norberto Cabral; Ismael Campos Nonato; Jung-Chen Chang; Rajiv Chowdhury; Karen J Courville; Michael H Criqui; David K Cundiff; Kaustubh C Dabhadkar; Lalit Dandona; Adrian Davis; Anand Dayama; Samath D Dharmaratne; Eric L Ding; Adnan M Durrani; Alireza Esteghamati; Farshad Farzadfar; Derek F J Fay; Valery L Feigin; Abraham Flaxman; Mohammad H Forouzanfar; Atsushi Goto; Mark A Green; Rajeev Gupta; Nima Hafezi-Nejad; Graeme J Hankey; Heather C Harewood; Rasmus Havmoeller; Simon Hay; Lucia Hernandez; Abdullatif Husseini; Bulat T Idrisov; Nayu Ikeda; Farhad Islami; Eiman Jahangir; Simerjot K Jassal; Sun Ha Jee; Mona Jeffreys; Jost B Jonas; Edmond K Kabagambe; Shams Eldin Ali Hassan Khalifa; Andre Pascal Kengne; Yousef Saleh Khader; Young-Ho Khang; Daniel Kim; Ruth W Kimokoti; Jonas M Kinge; Yoshihiro Kokubo; Soewarta Kosen; Gene Kwan; Taavi Lai; Mall Leinsalu; Yichong Li; Xiaofeng Liang; Shiwei Liu; Giancarlo Logroscino; Paulo A Lotufo; Yuan Lu; Jixiang Ma; Nana Kwaku Mainoo; George A Mensah; Tony R Merriman; Ali H Mokdad; Joanna Moschandreas; Mohsen Naghavi; Aliya Naheed; Devina Nand; K M Venkat Narayan; Erica Leigh Nelson; Marian L Neuhouser; Muhammad Imran Nisar; Takayoshi Ohkubo; Samuel O Oti; Andrea Pedroza; Dorairaj Prabhakaran; Nobhojit Roy; Uchechukwu Sampson; Hyeyoung Seo; Sadaf G Sepanlou; Kenji Shibuya; Rahman Shiri; Ivy Shiue; Gitanjali M Singh; Jasvinder A Singh; Vegard Skirbekk; Nicolas J C Stapelberg; Lela Sturua; Bryan L Sykes; Martin Tobias; Bach X Tran; Leonardo Trasande; Hideaki Toyoshima; Steven van de Vijver; Tommi J Vasankari; J Lennert Veerman; Gustavo Velasquez-Melendez; Vasiliy Victorovich Vlassov; Stein Emil Vollset; Theo Vos; Claire Wang; XiaoRong Wang; Elisabete Weiderpass; Andrea Werdecker; Jonathan L Wright; Y Claire Yang; Hiroshi Yatsuya; Jihyun Yoon; Seok-Jun Yoon; Yong Zhao; Maigeng Zhou; Shankuan Zhu; Alan D Lopez; Christopher J L Murray; Emmanuela Gakidou Journal: Lancet Date: 2014-05-29 Impact factor: 79.321
Authors: Kathryn E Kyler; Jonathan Wagner; Chelsea Hosey-Cojocari; Kevin Watt; Valentina Shakhnovich Journal: Paediatr Drugs Date: 2019-10 Impact factor: 3.022
Authors: Jacqueline G Gerhart; Fernando O Carreño; Andrea N Edginton; Jaydeep Sinha; Eliana M Perrin; Karan R Kumar; Aruna Rikhi; Christoph P Hornik; Vincent Harris; Samit Ganguly; Michael Cohen-Wolkowiez; Daniel Gonzalez Journal: Clin Pharmacokinet Date: 2021-10-07 Impact factor: 5.577
Authors: Anil R Maharaj; Huali Wu; Kanecia O Zimmerman; David G Speicher; Janice E Sullivan; Kevin Watt; Amira Al-Uzri; Elizabeth H Payne; Jinson Erinjeri; Susan Lin; Barrie Harper; Chiara Melloni; Christoph P Hornik Journal: J Clin Pharmacol Date: 2019-12-08 Impact factor: 2.860
Authors: Kayode Ogungbenro; Jonathan B Wagner; Susan Abdel-Rahman; J Steven Leeder; Aleksandra Galetin Journal: Eur J Clin Pharmacol Date: 2019-06-06 Impact factor: 2.953
Authors: Jacqueline G Gerhart; Stephen Balevic; Jaydeep Sinha; Eliana M Perrin; Jian Wang; Andrea N Edginton; Daniel Gonzalez Journal: Front Pharmacol Date: 2022-03-10 Impact factor: 5.810
Authors: Jose Rodríguez-Morató; Albert Goday; Klaus Langohr; Mitona Pujadas; Ester Civit; Clara Pérez-Mañá; Esther Papaseit; Jose Manuel Ramon; David Benaiges; Olga Castañer; Magí Farré; Rafael de la Torre Journal: Sci Rep Date: 2019-12-31 Impact factor: 4.379