The Impact of Paediatric Obesity on Drug Pharmacokinetics: A Virtual Clinical Trials Case Study with Amlodipine
Abstract
:1. Introduction
2. Materials and Methods
2.1. Step 1: Development of the Paediatric Obesity Population
2.1.1. Age, Weight, and Height Relationship
2.1.2. Haematocrit–Age Relationship
2.1.3. Protein-Binding-to-Age Relationship
2.1.4. Glomerular Filtration Rate (GFR)-to-Age Relationship
2.2. Step 2: Validation of a Paediatric Obesity Population with Metformin and Ceftazidime Compound Files
2.2.1. Step 2.1: Validation with Metformin
2.2.2. Step 2.2: Validation with Ceftazidime
2.3. Step 3: Verification with Amlodipine
Reference | Subjects | Age (Years) | Dose Regimen | PK Sampling Duration |
---|---|---|---|---|
Healthy subjects | ||||
[74] | Single dose: 12 healthy males Multiple doses: 56 healthy males | Single dose: 25.8 ± 3.8 Multiple dose: 26.1 ± 36 | Single-dose fasting: 10 mg intravenous (1 mg/min) in period 1, 34-day washout period, 10 mg oral dose (2–5 mg capsule) Multiple doses: 15 mg once daily (3 × 5 mg capsule) or placebo for 14 days | Single dose: Up to 144 h post-dose Multiple doses: Day 1: up to 24 h post-dose, Day 7: pre-dose and up to 14 h post-dose, Day 14: up to 168 h post-dose |
[67] | 12 healthy males | 23–34 | 2.5 mg single dose 5 mg single dose 10 mg single dose With 14-day washout period between each dose | Up to 144 h post-dose |
[66] | 13 patients with hypertension (10 males, 3 females) | 28–45 | 1st dose of 10 mg intravenously, after Day 4 of the intravenous dose followed by 2.5 mg oral once daily for 10 days | After 10 days of amlodipine dose, up to 24 h post-dose |
[75] | 12 healthy subjects (7 males, 5 females) | 46–76 | 5 mg oral once daily for 14 days | Up to 48 h post-dose after the 1st dose and after the last dose at 14 days |
[76] | 24 healthy subjects | Adult | 10 mg oral once | Up to 72 h post-dose |
[77] | 28 patients with hypertension (10 males, 18 females) BMI = 30.6 ± 1.3 | 22–50 | 5 mg oral once daily for 8 weeks | After the 1st dose, up to 24 h post-dose After the last dose, up to 240 h |
Obese subjects | ||||
[78] | 22 hypertensive patients: - 4 normal - 6 overweight - 12 obese - 27.3% male | 16 adults (<65 years old with majority 50–60 years old) 6 elderly (≥65 years old) | Fixed-dose combination of telmisartan and amlodipine once daily: 40/5 mg—8 subjects 80/5 mg—6 subjects 80/10 mg—8 subjects | Up to 72 h post-dose at steady state |
Paediatric subjects | ||||
[72] | 9 (6 males, 3 females) | 0.5–12 | 0.15 (0.10–0.22) a mg/kg/day (oral solution) | Sparse trough concentrations |
Mixture of paediatric with and without obesity | ||||
[73] | 73 (49 males, 24 females) - 43.2% obese children | 1.0–17.7 | 0.17 ± 0.13 (0.03–0.77) mg/kg/day - Absolute dose: 1.3–20 mg/day - Administered either once or twice daily (tablet and suspension) | Sparse samples |
2.4. Step 4: Influence of Obesity on Amlodipine Pharmacokinetic Parameters and Dose Adjustment in the Paediatric Obesity Population
2.5. Prediction Performance
2.6. Data and Statistical Analysis
3. Results
3.1. Step 1: Development of the Paediatric Obesity Population
3.2. Step 2: Validation of the Paediatric Obesity Population
3.2.1. Step 2.1: Validation with Metformin
3.2.2. Step 2.2: Validation with Ceftazidime
3.3. Step 3: Verification of the Amlodipine Model
3.4. Step 4: Impact of Paediatric Obesity on Amlodipine Pharmacokinetics
3.4.1. Comparison of Non-Obese and Obese Paediatrics
3.4.2. Dose Adjustments in Paediatric Obesity
4. Discussion
4.1. Step 1: Development of the Paediatric Obesity Population
4.2. Step 2: Validation of Paediatric Population with Metformin and Ceftazidime
4.3. Step 3: Validation of the Amlodipine Model
4.4. Step 4: Impact of Obesity on Amlodipine Pharmacokinetics and Dose Optimisation in Obese Paediatric Population
4.4.1. Influence of Obesity on Amlodipine Pharmacokinetics
4.4.2. Dose Adjustment in Paediatric Obesity
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- World Obesity Federation. World Obesity Atlas 2023; World Obesity Federation: London, UK, 2023. [Google Scholar]
- National Health Service Digital. National Child Measurement Programme, England, 2021/22 School Year; National Health Service Digital: Leeds, UK, 2022. [Google Scholar]
- National Health Service Digital. National Child Measurement Programme, England, 2020/21 School Year; National Health Service Digital: Leeds, UK, 2021. [Google Scholar]
- NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: A pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet 2017, 390, 2627–2642. [Google Scholar] [CrossRef] [PubMed]
- Benedek, I.H.; Fiske, W.D., 3rd; Griffen, W.O.; Bell, R.M.; Blouin, R.A.; McNamara, P.J. Serum alpha 1-acid glycoprotein and the binding of drugs in obesity. Br. J. Clin. Pharmacol. 1983, 16, 751–754. [Google Scholar] [CrossRef] [PubMed]
- Benedek, I.H.; Blouin, R.A.; McNamara, P.J. Serum protein binding and the role of increased alpha 1-acid glycoprotein in moderately obese male subjects. Br. J. Clin. Pharmacol. 1984, 18, 941–946. [Google Scholar] [CrossRef]
- Blouin, R.A.; Kolpek, J.H.; Mann, H.J. Influence of obesity on drug disposition. Clin. Pharm. 1987, 6, 706–714. [Google Scholar] [PubMed]
- Krogstad, V.; Peric, A.; Robertsen, I.; Kringen, M.K.; Vistnes, M.; Hjelmesaeth, J.; Sandbu, R.; Johnson, L.K.; Angeles, P.C.; Jansson-Lofmark, R.; et al. Correlation of Body Weight and Composition with Hepatic Activities of Cytochrome P450 Enzymes. J. Pharm. Sci. 2021, 110, 432–437. [Google Scholar] [CrossRef] [PubMed]
- van Rongen, A.; Brill, M.J.E.; Vaughns, J.D.; Valitalo, P.A.J.; van Dongen, E.P.A.; van Ramshorst, B.; Barrett, J.S.; van den Anker, J.N.; Knibbe, C.A.J. Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults. Clin. Pharmacokinet. 2018, 57, 601–611. [Google Scholar] [CrossRef] [PubMed]
- Correia-Costa, L.; Schaefer, F.; Afonso, A.C.; Bustorff, M.; Guimaraes, J.T.; Guerra, A.; Barros, H.; Azevedo, A. Normalization of glomerular filtration rate in obese children. Pediatr. Nephrol. 2016, 31, 1321–1328. [Google Scholar] [CrossRef]
- Gerhart, J.G.; Carreno, F.O.; Edginton, A.N.; Sinha, J.; Perrin, E.M.; Kumar, K.R.; Rikhi, A.; Hornik, C.P.; Harris, V.; Ganguly, S.; et al. Development and Evaluation of a Virtual Population of Children with Obesity for Physiologically Based Pharmacokinetic Modeling. Clin. Pharmacokinet. 2022, 61, 307–320. [Google Scholar] [CrossRef]
- World Health Organisation (WHO). Obesity and Overweight. Available online: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight (accessed on 18 January 2023).
- Centers for Disease Control and Prevention (CDC). Defining Childhood Weight Status. Available online: https://www.cdc.gov/obesity/basics/childhood-defining.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fobesity%2Fchildhood%2Fdefining.html (accessed on 18 January 2023).
- Clasey, J.L.; Easley, E.A.; Murphy, M.O.; Kiessling, S.G.; Stromberg, A.; Schadler, A.; Huang, H.; Bauer, J.A. Body mass index percentiles versus body composition assessments: Challenges for disease risk classifications in children. Front. Pediatr. 2023, 11, 1112920. [Google Scholar] [CrossRef]
- Marginean, C.O.; Melit, L.E.; Hutanu, A.; Ghiga, D.V.; Sasaran, M.O. The adipokines and inflammatory status in the era of pediatric obesity. Cytokine 2020, 126, 154925. [Google Scholar] [CrossRef]
- Goknar, N.; Oktem, F.; Ozgen, I.T.; Torun, E.; Kucukkoc, M.; Demir, A.D.; Cesur, Y. Determination of early urinary renal injury markers in obese children. Pediatr. Nephrol. 2015, 30, 139–144. [Google Scholar] [CrossRef] [PubMed]
- Harskamp-van Ginkel, M.W.; Hill, K.D.; Becker, K.C.; Testoni, D.; Cohen-Wolkowiez, M.; Gonzalez, D.; Barrett, J.S.; Benjamin, D.K., Jr.; Siegel, D.A.; Banks, P.; et al. Drug Dosing and Pharmacokinetics in Children with Obesity: A Systematic Review. JAMA Pediatr. 2015, 169, 678–685. [Google Scholar] [CrossRef] [PubMed]
- Kyler, K.E.; Wagner, J.; Hosey-Cojocari, C.; Watt, K.; Shakhnovich, V. Drug Dose Selection in Pediatric Obesity: Available Information for the Most Commonly Prescribed Drugs to Children. Paediatr. Drugs 2019, 21, 357–369. [Google Scholar] [CrossRef]
- Natale, S.; Bradley, J.; Nguyen, W.H.; Tran, T.; Ny, P.; La, K.; Vivian, E.; Le, J. Pediatric Obesity: Pharmacokinetic Alterations and Effects on Antimicrobial Dosing. Pharmacotherapy 2017, 37, 361–378. [Google Scholar] [CrossRef] [PubMed]
- Ross, E.L.; Jorgensen, J.; DeWitt, P.E.; Okada, C.; Porter, R.; Haemer, M.; Reiter, P.D. Comparison of 3 body size descriptors in critically ill obese children and adolescents: Implications for medication dosing. J. Pediatr. Pharmacol. Ther. 2014, 19, 103–110. [Google Scholar] [CrossRef] [PubMed]
- Ford, J.L.; Gerhart, J.G.; Edginton, A.N.; Yanovski, J.A.; Hon, Y.Y.; Gonzalez, D. Physiologically Based Pharmacokinetic Modeling of Metformin in Children and Adolescents with Obesity. J. Clin. Pharmacol. 2022, 62, 960–969. [Google Scholar] [CrossRef] [PubMed]
- Gerhart, J.G.; Carreno, F.O.; Ford, J.L.; Edginton, A.N.; Perrin, E.M.; Watt, K.M.; Muller, W.J.; Atz, A.M.; Al-Uzri, A.; Delmore, P.; et al. Use of physiologically-based pharmacokinetic modeling to inform dosing of the opioid analgesics fentanyl and methadone in children with obesity. CPT Pharmacomet. Syst. Pharmacol. 2022, 11, 778–791. [Google Scholar] [CrossRef]
- Flynn, J. The changing face of pediatric hypertension in the era of the childhood obesity epidemic. Pediatr. Nephrol. 2013, 28, 1059–1066. [Google Scholar] [CrossRef]
- Flynn, J.T.; Kaelber, D.C.; Baker-Smith, C.M.; Blowey, D.; Carroll, A.E.; Daniels, S.R.; de Ferranti, S.D.; Dionne, J.M.; Falkner, B.; Flinn, S.K.; et al. Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Pediatrics 2017, 140, e20171904. [Google Scholar] [CrossRef]
- Lurbe, E.; Agabiti-Rosei, E.; Cruickshank, J.K.; Dominiczak, A.; Erdine, S.; Hirth, A.; Invitti, C.; Litwin, M.; Mancia, G.; Pall, D.; et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J. Hypertens. 2016, 34, 1887–1920. [Google Scholar] [CrossRef]
- Hanafy, S.; Pinsk, M.; Jamali, F. Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease. Pediatr. Nephrol. 2009, 24, 815–821. [Google Scholar] [CrossRef]
- de Onis, M.; Lobstein, T. Defining obesity risk status in the general childhood population: Which cut-offs should we use? Int. J. Pediatr. Obes. 2010, 5, 458–460. [Google Scholar] [CrossRef]
- WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr. Suppl. 2006, 450, 76–85. [Google Scholar] [CrossRef]
- Styne, D.M.; Arslanian, S.A.; Connor, E.L.; Farooqi, I.S.; Murad, M.H.; Silverstein, J.H.; Yanovski, J.A. Pediatric Obesity-Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2017, 102, 709–757. [Google Scholar] [CrossRef]
- Centers for Disease Control and Prevention (CDC). Clinical Growth Charts. Available online: https://www.cdc.gov/growthcharts/clinical_charts.htm (accessed on 18 January 2023).
- Kilic, E.; Ozer, O.F.; Erek Toprak, A.; Erman, H.; Torun, E.; Kesgin Ayhan, S.; Caglar, H.G.; Selek, S.; Kocyigit, A. Oxidative Stress Status in Childhood Obesity: A Potential Risk Predictor. Med. Sci. Monit. 2016, 22, 3673–3679. [Google Scholar] [CrossRef]
- Panichsillaphakit, E.; Suteerojntrakool, O.; Pancharoen, C.; Nuchprayoon, I.; Chomtho, S. The Association between Hepcidin and Iron Status in Children and Adolescents with Obesity. J. Nutr. Metab. 2021, 2021, 9944035. [Google Scholar] [CrossRef]
- Cacciari, E.; Balsamo, A.; Palareti, G.; Cassio, A.; Argento, R.; Poggi, M.; Tassoni, P.; Cicognani, A.; Tacconi, M.; Pascucci, M.G.; et al. Haemorheologic and fibrinolytic evaluation in obese children and adolescents. Eur. J. Pediatr. 1988, 147, 381–384. [Google Scholar] [CrossRef]
- Oni, O.; Orekoya, O.; Bamji, M. Prevalence of Disease Conditions and Laboratory Findings in Obese Children: A Decade Analysis of National Health and Nutrition Examination Survey 2005-2014. Pediatrics 2021, 147, 183–184. [Google Scholar] [CrossRef]
- Jeong, H.R.; Shim, Y.S.; Lee, H.S.; Hwang, J.S. Hemoglobin and hematocrit levels are positively associated with blood pressure in children and adolescents 10 to 18 years old. Sci. Rep. 2021, 11, 19052. [Google Scholar] [CrossRef] [PubMed]
- Belo, L.; Nascimento, H.; Kohlova, M.; Bronze-da-Rocha, E.; Fernandes, J.; Costa, E.; Catarino, C.; Aires, L.; Mansilha, H.F.; Rocha-Pereira, P.; et al. Body fat percentage is a major determinant of total bilirubin independently of UGT1A1*28 polymorphism in young obese. PLoS ONE 2014, 9, e98467. [Google Scholar] [CrossRef] [PubMed]
- Yu, L.; Li, Y.; Zhang, Q.; Zhu, L.; Ding, N.; Zhang, B.; Zhang, J.; Liu, W.; Li, S.; Zhang, J. Association between dietary essential amino acids intake and metabolic biomarkers: Influence of obesity among Chinese children and adolescents. Amino Acids 2021, 53, 635–644. [Google Scholar] [CrossRef] [PubMed]
- Abitbol, C.L.; Chandar, J.; Rodriguez, M.M.; Berho, M.; Seeherunvong, W.; Freundlich, M.; Zilleruelo, G. Obesity and preterm birth: Additive risks in the progression of kidney disease in children. Pediatr. Nephrol. 2009, 24, 1363–1370. [Google Scholar] [CrossRef] [PubMed]
- Marginean, C.O.; Melit, L.E.; Ghiga, D.V.; Marginean, M.O. Early Inflammatory Status Related to Pediatric Obesity. Front. Pediatr. 2019, 7, 241. [Google Scholar] [CrossRef]
- Marginean, C.O.; Claudia, B.; Carmen, D.; Maria, P.A.; Septimiu, V.; Claudiu, M. The role of IL-6 572 C/G, 190 C/T, and 174 G/C gene polymorphisms in children’s obesity. Eur. J. Pediatr. 2014, 173, 1285–1296. [Google Scholar] [CrossRef]
- Marginean, C.O.; Marginean, C.; Voidazan, S.; Melit, L.; Crauciuc, A.; Duicu, C.; Banescu, C. Correlations Between Leptin Gene Polymorphisms 223 A/G, 1019 G/A, 492 G/C, 976 C/A, and Anthropometrical and Biochemical Parameters in Children with Obesity: A Prospective Case-Control Study in a Romanian Population-The Nutrichild Study. Medicine 2016, 95, e3115. [Google Scholar] [CrossRef]
- Sobieska, M.; Gajewska, E.; Kalmus, G.; Samborski, W. Obesity, physical fitness, and inflammatory markers in Polish children. Med. Sci. Monit. 2013, 19, 493–500. [Google Scholar] [CrossRef]
- Gibson, R.S.; Bailey, K.B.; Williams, S.; Houghton, L.; Costa-Ribeiro, H.C.; Mattos, A.P.; Barreto, D.L.; Lander, R.L. Tissue iron deficiency and adiposity-related inflammation in disadvantaged preschoolers from NE Brazil. Eur. J. Clin. Nutr. 2014, 68, 887–891. [Google Scholar] [CrossRef]
- Ferrari, M.; Cuenca-Garcia, M.; Valtuena, J.; Moreno, L.A.; Censi, L.; Gonzalez-Gross, M.; Androutsos, O.; Gilbert, C.C.; Huybrechts, I.; Dallongeville, J.; et al. Inflammation profile in overweight/obese adolescents in Europe: An analysis in relation to iron status. Eur. J. Clin. Nutr. 2015, 69, 247–255. [Google Scholar] [CrossRef]
- Duzova, A.; Yalcinkaya, F.; Baskin, E.; Bakkaloglu, A.; Soylemezoglu, O. Prevalence of hypertension and decreased glomerular filtration rate in obese children: Results of a population-based field study. Nephrol. Dial. Transplant. 2013, 28 (Suppl. 4), iv166–iv171. [Google Scholar] [CrossRef] [PubMed]
- Burt, H.J.; Neuhoff, S.; Almond, L.; Gaohua, L.; Harwood, M.D.; Jamei, M.; Rostami-Hodjegan, A.; Tucker, G.T.; Rowland-Yeo, K. Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug-drug interactions. Eur. J. Pharm. Sci. 2016, 88, 70–82. [Google Scholar] [CrossRef] [PubMed]
- Tucker, G.T.; Casey, C.; Phillips, P.J.; Connor, H.; Ward, J.D.; Woods, H.F. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br. J. Clin. Pharmacol. 1981, 12, 235–246. [Google Scholar] [CrossRef] [PubMed]
- Graham, G.G.; Punt, J.; Arora, M.; Day, R.O.; Doogue, M.P.; Duong, J.K.; Furlong, T.J.; Greenfield, J.R.; Greenup, L.C.; Kirkpatrick, C.M.; et al. Clinical pharmacokinetics of metformin. Clin. Pharmacokinet. 2011, 50, 81–98. [Google Scholar] [CrossRef] [PubMed]
- 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, 1259–1276. [Google Scholar] [CrossRef] [PubMed]
- 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, 1238–1257. [Google Scholar] [CrossRef] [PubMed]
- Jeong, Y.S.; Jusko, W.J. Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species. Pharmaceuticals 2021, 14, 545. [Google Scholar] [CrossRef] [PubMed]
- Gusler, G.; Gorsline, J.; Levy, G.; Zhang, S.Z.; Weston, I.E.; Naret, D.; Berner, B. Pharmacokinetics of metformin gastric-retentive tablets in healthy volunteers. J. Clin. Pharmacol. 2001, 41, 655–661. [Google Scholar] [CrossRef] [PubMed]
- Timmins, P.; Donahue, S.; Meeker, J.; Marathe, P. Steady-state pharmacokinetics of a novel extended-release metformin formulation. Clin. Pharmacokinet. 2005, 44, 721–729. [Google Scholar] [CrossRef] [PubMed]
- Padwal, R.S.; Gabr, R.Q.; Sharma, A.M.; Langkaas, L.A.; Birch, D.W.; Karmali, S.; Brocks, D.R. Effect of gastric bypass surgery on the absorption and bioavailability of metformin. Diabetes Care 2011, 34, 1295–1300. [Google Scholar] [CrossRef]
- Sanchez-Infantes, D.; Diaz, M.; Lopez-Bermejo, A.; Marcos, M.V.; de Zegher, F.; Ibanez, L. Pharmacokinetics of metformin in girls aged 9 years. Clin. Pharmacokinet. 2011, 50, 735–738. [Google Scholar] [CrossRef]
- van Rongen, A.; van der Aa, M.P.; Matic, M.; van Schaik, R.H.N.; Deneer, V.H.M.; van der Vorst, M.M.; Knibbe, C.A.J. Increased Metformin Clearance in Overweight and Obese Adolescents: A Pharmacokinetic Substudy of a Randomized Controlled Trial. Paediatr. Drugs 2018, 20, 365–374. [Google Scholar] [CrossRef]
- Sam, W.J.; Roza, O.; Hon, Y.Y.; Alfaro, R.M.; Calis, K.A.; Reynolds, J.C.; Yanovski, J.A. Effects of SLC22A1 Polymorphisms on Metformin-Induced Reductions in Adiposity and Metformin Pharmacokinetics in Obese Children with Insulin Resistance. J. Clin. Pharmacol. 2017, 57, 219–229. [Google Scholar] [CrossRef]
- Maharaj, A.R.; Wu, H.; Zimmerman, K.O.; Muller, W.J.; Sullivan, J.E.; Sherwin, C.M.T.; Autmizguine, J.; Rathore, M.H.; Hornik, C.D.; Al-Uzri, A.; et al. Pharmacokinetics of Ceftazidime in Children and Adolescents with Obesity. Paediatr. Drugs 2021, 23, 499–513. [Google Scholar] [CrossRef] [PubMed]
- Zhou, L.; Tong, X.; Sharma, P.; Xu, H.; Al-Huniti, N.; Zhou, D. Physiologically based pharmacokinetic modelling to predict exposure differences in healthy volunteers and subjects with renal impairment: Ceftazidime case study. Basic. Clin. Pharmacol. Toxicol. 2019, 125, 100–107. [Google Scholar] [CrossRef] [PubMed]
- Zhou, W.; Johnson, T.N.; Xu, H.; Cheung, S.; Bui, K.H.; Li, J.; Al-Huniti, N.; Zhou, D. Predictive Performance of Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling of Renally Cleared Drugs in Children. CPT Pharmacomet. Syst. Pharmacol. 2016, 5, 475–483. [Google Scholar] [CrossRef] [PubMed]
- Yao, X.; Liu, X.; Tu, S.; Li, X.; Lei, Z.; Hou, Z.; Yu, Z.; Cui, C.; Dong, Z.; Salem, F.; et al. Development of a Virtual Chinese Pediatric Population Physiological Model Targeting Specific Metabolism and Kidney Elimination Pathways. Front. Pharmacol. 2021, 12, 648697. [Google Scholar] [CrossRef] [PubMed]
- Coppola, P.; Kerwash, E.; Cole, S. The Use of Pregnancy Physiologically Based Pharmacokinetic Modeling for Renally Cleared Drugs. J. Clin. Pharmacol. 2022, 62 (Suppl. 1), S129–S139. [Google Scholar] [CrossRef]
- Zhou, D.; Bui, K.; Sostek, M.; Al-Huniti, N. Simulation and Prediction of the Drug-Drug Interaction Potential of Naloxegol by Physiologically Based Pharmacokinetic Modeling. CPT Pharmacomet. Syst. Pharmacol. 2016, 5, 250–257. [Google Scholar] [CrossRef] [PubMed]
- Rhee, S.J.; Lee, H.A.; Lee, S.; Kim, E.; Jeon, I.; Song, I.S.; Yu, K.S. Physiologically Based Pharmacokinetic Modeling of Fimasartan, Amlodipine, and Hydrochlorothiazide for the Investigation of Drug-Drug Interaction Potentials. Pharm. Res. 2018, 35, 236. [Google Scholar] [CrossRef] [PubMed]
- Mukherjee, D.; Zha, J.; Menon, R.M.; Shebley, M. Guiding dose adjustment of amlodipine after co-administration with ritonavir containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic model. J. Pharmacokinet. Pharmacodyn. 2018, 45, 443–456. [Google Scholar] [CrossRef]
- Abernethy, D.R.; Gutkowska, J.; Winterbottom, L.M. Effects of amlodipine, a long-acting dihydropyridine calcium antagonist in aging hypertension: Pharmacodynamics in relation to disposition. Clin. Pharmacol. Ther. 1990, 48, 76–86. [Google Scholar] [CrossRef]
- Williams, D.M.; Cubeddu, L.X. Amlodipine pharmacokinetics in healthy volunteers. J. Clin. Pharmacol. 1988, 28, 990–994. [Google Scholar] [CrossRef] [PubMed]
- Sun, H. Capture hydrolysis signals in the microsomal stability assay: Molecular mechanisms of the alkyl ester drug and prodrug metabolism. Bioorg. Med. Chem. Lett. 2012, 22, 989–995. [Google Scholar] [CrossRef]
- Kadono, K.; Akabane, T.; Tabata, K.; Gato, K.; Terashita, S.; Teramura, T. Quantitative prediction of intestinal metabolism in humans from a simplified intestinal availability model and empirical scaling factor. Drug Metab. Dispos. 2010, 38, 1230–1237. [Google Scholar] [CrossRef]
- Salem, F.; Small, B.G.; Johnson, T.N. Development and application of a pediatric mechanistic kidney model. CPT Pharmacomet. Syst. Pharmacol. 2022, 11, 854–866. [Google Scholar] [CrossRef] [PubMed]
- Ghobadi, C.; Johnson, T.N.; Aarabi, M.; Almond, L.M.; Allabi, A.C.; Rowland-Yeo, K.; Jamei, M.; Rostami-Hodjegan, A. Application of a systems approach to the bottom-up assessment of pharmacokinetics in obese patients: Expected variations in clearance. Clin. Pharmacokinet. 2011, 50, 809–822. [Google Scholar] [CrossRef] [PubMed]
- van der Vossen, A.C.; Cransberg, K.; de Winter, B.C.M.; Schreuder, M.F.; van Rooij-Kouwenhoven, R.W.G.; Vulto, A.G.; Hanff, L.M. Use of amlodipine oral solution for the treatment of hypertension in children. Int. J. Clin. Pharm. 2020, 42, 848–852. [Google Scholar] [CrossRef]
- Flynn, J.T.; Nahata, M.C.; Mahan, J.D.; Portman, R.J.; PATH-2 Investigators. Population pharmacokinetics of amlodipine in hypertensive children and adolescents. J. Clin. Pharmacol. 2006, 46, 905–916. [Google Scholar] [CrossRef]
- Faulkner, J.K.; McGibney, D.; Chasseaud, L.F.; Perry, J.L.; Taylor, I.W. The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily. Br. J. Clin. Pharmacol. 1986, 22, 21–25. [Google Scholar] [CrossRef]
- Bainbridge, A.D.; Herlihy, O.; Meredith, P.A.; Elliott, H.L. A comparative assessment of amlodipine and felodipine ER: Pharmacokinetic and pharmacodynamic indices. Eur. J. Clin. Pharmacol. 1993, 45, 425–430. [Google Scholar] [CrossRef]
- Rausl, D.; Fotaki, N.; Zanoski, R.; Vertzoni, M.; Cetina-Cizmek, B.; Khan, M.Z.; Reppas, C. Intestinal permeability and excretion into bile control the arrival of amlodipine into the systemic circulation after oral administration. J. Pharm. Pharmacol. 2006, 58, 827–836. [Google Scholar] [CrossRef]
- Leenen, F.H.; Coletta, E. Pharmacokinetic and antihypertensive profile of amlodipine and felodipine-ER in younger versus older patients with hypertension. J. Cardiovasc. Pharmacol. 2010, 56, 669–675. [Google Scholar] [CrossRef] [PubMed]
- Varga, A.; Briciu, C.; Vlase, L.; Primejdie, D.P.; Gheldiu, A.-M.; Caraşca, C.; Ţilea, I. Pharmacokinetics of different formulations of Telmisartan/Amlodipine fixed-dose combination in hypertensive patients. Acta Medica Transilv. 2015, 20, 45–50. [Google Scholar]
- Paediatric Formulary Committee. BNF for Children). Available online: https://bnfc.nice.org.uk/drugs/amlodipine/ (accessed on 2 August 2023).
- Drugs.com. Amlodipine Information from Drugs.com. Available online: https://www.drugs.com/pro/amlodipine.html (accessed on 2 August 2023).
- Linnet, K.; Lang, L.M.; Johansen, S.S. Postmortem femoral blood concentrations of amlodipine. J. Anal. Toxicol. 2011, 35, 227–231. [Google Scholar] [CrossRef]
- Spiller, H.A.; Milliner, B.A.; Bosse, G.M. Amlodipine fatality in an infant with postmortem blood levels. J. Med. Toxicol. 2012, 8, 179–182. [Google Scholar] [CrossRef]
- Adams, B.D.; Browne, W.T. Amlodipine overdose causes prolonged calcium channel blocker toxicity. Am. J. Emerg. Med. 1998, 16, 527–528. [Google Scholar] [CrossRef]
- The United States Food and Drug Administration. Summary Minutes of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology; The United States Food and Drug Administration: Silver Spring, MD, USA, 2012.
- Zakaria, Z.H.; Fong, A.Y.Y.; Badhan, R.K.S. Clopidogrel Pharmacokinetics in Malaysian Population Groups: The Impact of Inter-Ethnic Variability. Pharmaceuticals 2018, 11, 74. [Google Scholar] [CrossRef]
- Yu, H.; Singh Badhan, R.K. The Pharmacokinetics of Gefitinib in a Chinese Cancer Population Group: A Virtual Clinical Trials Population Study. J. Pharm. Sci. 2021, 110, 3507–3519. [Google Scholar] [CrossRef] [PubMed]
- Edginton, A.N.; Schmitt, W.; Willmann, S. Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin. Pharmacokinet. 2006, 45, 1013–1034. [Google Scholar] [CrossRef]
- Ginsberg, G.; Hattis, D.; Russ, A.; Sonawane, B. Physiologically based pharmacokinetic (PBPK) modeling of caffeine and theophylline in neonates and adults: Implications for assessing children’s risks from environmental agents. J. Toxicol. Environ. Health A 2004, 67, 297–329. [Google Scholar] [CrossRef]
- Burhanuddin, K.; Badhan, R. Optimising Fluvoxamine Maternal/Fetal Exposure during Gestation: A Pharmacokinetic Virtual Clinical Trials Study. Metabolites 2022, 12, 1281. [Google Scholar] [CrossRef]
- Wuhl, E. Hypertension in childhood obesity. Acta Paediatr. 2019, 108, 37–43. [Google Scholar] [CrossRef] [PubMed]
- Thomas, J.; Stonebrook, E.; Kallash, M. Pediatric hypertension: Review of the definition, diagnosis, and initial management. Int. J. Pediatr. Adolesc. Med. 2022, 9, 1–6. [Google Scholar] [CrossRef]
- Flynn, J.T.; Smoyer, W.E.; Bunchman, T.E. Treatment of hypertensive children with amlodipine. Am. J. Hypertens. 2000, 13, 1061–1066. [Google Scholar] [CrossRef] [PubMed]
- Flynn, J.T. Efficacy and safety of prolonged amlodipine treatment in hypertensive children. Pediatr. Nephrol. 2005, 20, 631–635. [Google Scholar] [CrossRef]
- Gerhart, J.G.; Balevic, S.; Sinha, J.; Perrin, E.M.; Wang, J.; Edginton, A.N.; Gonzalez, D. Characterizing Pharmacokinetics in Children with Obesity-Physiological, Drug, Patient, and Methodological Considerations. Front. Pharmacol. 2022, 13, 818726. [Google Scholar] [CrossRef] [PubMed]
- Machado, T.R.; Honorio, T.; Souza Domingos, T.F.; Candido de Paula, D.D.S.; Cabral, L.M.; Rodrigues, C.R.; Abrahim-Vieira, B.A.; Teles de Souza, A.M. Physiologically based pharmacokinetic modelling of semaglutide in children and adolescents with healthy and obese body weights. Br. J. Clin. Pharmacol. 2023, 89, 3175–3194. [Google Scholar] [CrossRef]
- Elhag, W.; El Ansari, W.; Abdulrazzaq, S.; Abdullah, A.; Elsherif, M.; Elgenaied, I. Evolution of 29 Anthropometric, Nutritional, and Cardiometabolic Parameters Among Morbidly Obese Adolescents 2 Years Post Sleeve Gastrectomy. Obes. Surg. 2018, 28, 474–482. [Google Scholar] [CrossRef]
- Zhou, X.; Dun, J.; Chen, X.; Xiang, B.; Dang, Y.; Cao, D. Predicting the correct dose in children: Role of computational Pediatric Physiological-based pharmacokinetics modeling tools. CPT Pharmacomet. Syst. Pharmacol. 2023, 12, 13–26. [Google Scholar] [CrossRef]
- Ezuruike, U.; Zhang, M.; Pansari, A.; De Sousa Mendes, M.; Pan, X.; Neuhoff, S.; Gardner, I. Guide to development of compound files for PBPK modeling in the Simcyp population-based simulator. CPT Pharmacomet. Syst. Pharmacol. 2022, 11, 805–821. [Google Scholar] [CrossRef]
- van der Heijden, J.E.M.; Freriksen, J.J.M.; de Hoop-Sommen, M.A.; Greupink, R.; de Wildt, S.N. Physiologically-Based Pharmacokinetic Modeling for Drug Dosing in Pediatric Patients: A Tutorial for a Pragmatic Approach in Clinical Care. Clin. Pharmacol. Ther. 2023, 114, 960–971. [Google Scholar] [CrossRef]
- European Medicines Agency. Guideline on the Investigation of Bioequivalence. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf (accessed on 26 November 2011).
- Noe, D.A. Criteria for reporting noncompartmental estimates of half-life and area under the curve extrapolated to infinity. Pharm. Stat. 2020, 19, 101–112. [Google Scholar] [CrossRef]
- von Vigier, R.O.; Franscini, L.M.; Bianda, N.D.; Pfister, R.; Casaulta Aebischer, C.; Bianchetti, M.G. Antihypertensive efficacy of amlodipine in children with chronic kidney diseases. J. Hum. Hypertens. 2001, 15, 387–391. [Google Scholar] [CrossRef] [PubMed]
- Stopher, D.A.; Beresford, A.P.; Macrae, P.V.; Humphrey, M.J. The metabolism and pharmacokinetics of amlodipine in humans and animals. J. Cardiovasc. Pharmacol. 1988, 12 (Suppl. 7), S55–S59. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Y.; Wang, F.; Li, Q.; Zhu, M.; Du, A.; Tang, W.; Chen, W. Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation. Drug Metab. Dispos. 2014, 42, 245–249. [Google Scholar] [CrossRef]
- Pynnonen, S.; Sillanpaa, M.; Frey, H.; Iisalo, E. Carbamazepine and its 10,11-epoxide in children and adults with epilepsy. Eur. J. Clin. Pharmacol. 1977, 11, 129–133. [Google Scholar] [CrossRef] [PubMed]
- Riva, R.; Contin, M.; Albani, F.; Perucca, E.; Procaccianti, G.; Baruzzi, A. Free concentration of carbamazepine and carbamazepine-10,11-epoxide in children and adults. Influence of age and phenobarbitone co-medication. Clin. Pharmacokinet. 1985, 10, 524–531. [Google Scholar] [CrossRef] [PubMed]
- de Wildt, S.N.; Kearns, G.L.; Leeder, J.S.; van den Anker, J.N. Cytochrome P450 3A: Ontogeny and drug disposition. Clin. Pharmacokinet. 1999, 37, 485–505. [Google Scholar] [CrossRef] [PubMed]
- Mansoor, A.; Mahabadi, N. Volume of Distribution. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2023. [Google Scholar]
- van Rongen, A.; Vaughns, J.D.; Moorthy, G.S.; Barrett, J.S.; Knibbe, C.A.; van den Anker, J.N. Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents. Br. J. Clin. Pharmacol. 2015, 80, 1185–1196. [Google Scholar] [CrossRef]
- Gade, C.; Sverrisdottir, E.; Dalhoff, K.; Sonne, J.; Johansen, M.O.; Christensen, H.R.; Burhenne, J.; Mikus, G.; Holm, J.C.; Lund, T.M.; et al. Midazolam Pharmacokinetics in Obese and Non-obese Children and Adolescents. Clin. Pharmacokinet. 2020, 59, 643–654. [Google Scholar] [CrossRef]
- Hanafy, S.; Dagenais, N.J.; Dryden, W.F.; Jamali, F. Effects of angiotensin II blockade on inflammation-induced alterations of pharmacokinetics and pharmacodynamics of calcium channel blockers. Br. J. Pharmacol. 2008, 153, 90–99. [Google Scholar] [CrossRef]
- Sattari, S.; Dryden, W.F.; Eliot, L.A.; Jamali, F. Despite increased plasma concentration, inflammation reduces potency of calcium channel antagonists due to lower binding to the rat heart. Br. J. Pharmacol. 2003, 139, 945–954. [Google Scholar] [CrossRef] [PubMed]
- Abernethy, D.R.; Schwartz, J.B. Verapamil pharmacodynamics and disposition in obese hypertensive patients. J. Cardiovasc. Pharmacol. 1988, 11, 209–215. [Google Scholar] [CrossRef] [PubMed]
- Mayo, P.R.; Skeith, K.; Russell, A.S.; Jamali, F. Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis. Br. J. Clin. Pharmacol. 2000, 50, 605–613. [Google Scholar] [CrossRef] [PubMed]
- Ross, E.L.; Heizer, J.; Mixon, M.A.; Jorgensen, J.; Valdez, C.A.; Czaja, A.S.; Reiter, P.D. Development of recommendations for dosing of commonly prescribed medications in critically ill obese children. Am. J. Health Syst. Pharm. 2015, 72, 542–556. [Google Scholar] [CrossRef] [PubMed]
- Avataneo, V.; De Nicolo, A.; Rabbia, F.; Perlo, E.; Burrello, J.; Berra, E.; Pappaccogli, M.; Cusato, J.; D’Avolio, A.; Di Perri, G.; et al. Therapeutic drug monitoring-guided definition of adherence profiles in resistant hypertension and identification of predictors of poor adherence. Br. J. Clin. Pharmacol. 2018, 84, 2535–2543. [Google Scholar] [CrossRef]
- Alessandrini, E.; Brako, F.; Scarpa, M.; Lupo, M.; Bonifazi, D.; Pignataro, V.; Cavallo, M.; Cullufe, O.; Enache, C.; Nafria, B.; et al. Children’s Preferences for Oral Dosage Forms and Their Involvement in Formulation Research via EPTRI (European Paediatric Translational Research Infrastructure). Pharmaceutics 2021, 13, 730. [Google Scholar] [CrossRef]
Parameters | Values | Notes |
---|---|---|
Physical chemistry and blood binding | ||
Compound type | Monoprotic base | |
Molecular weight (g/mol) | 129.16 | |
Log P | −1.43 | |
pKa 1 | 11.8 | |
fu | 1 | |
B/P | 1 | |
Absorption | ||
Model | 1st order | |
fa | 0.45 | Fitted based on reported values [47,48]. |
ka (1/h) | 0.27 | |
Lag time (h) | 0.29 | |
Distribution | ||
Model | Full PBPK | |
Vss(L/kg) | 1.0172 | Predicted using Rodgers and Rowland method [49,50]. |
Kp scalar | 1 | Fitted based on observed profiles [47,52]. |
Elimination (enzyme kinetics) | ||
Pathway 1 | CYP3A4 | |
CLint (µL/min/pmol—isoform) | 0.334 | |
fumic | 1 | |
Renal clearance (L/h) | 32.3 | |
Drug transport | ||
Pathway 1 (Liver) | SLC22A1 (OCT1) | |
CLint,T (µL/min/million—cells) | 0.316 | |
fuinc | 1 | |
RAF/REF | 1.84 | |
CLPD (mL/min/million hepatocytes) | 0.0000588 | |
Pathway 2 (Kidney) | SLC22A2 (OCT2) | |
CLint,T (µL/min/million—cells) | 14.21 | |
Jmax | 21084 | |
Km (µmol) | 1483 | |
Pathway 3 (Kidney) | SLC47As (MATEs) | |
CLint,T (µL/min/million—cells) | 16.64 | |
RAF/REF | 0.128 | |
JOCT2 (pmol/min/millivolt/million cells) | 1.155 |
Reference | Subjects | Age (Years) | Dose Regimen | PK Sampling |
---|---|---|---|---|
Metformin | ||||
Healthy adult subjects | ||||
[47] | 4 males | 30–36 | Single-dose 500 mg—fed state (oral) | Up to 24 h post-dose |
[52] | 14 (7 males, 8 females) | 37.0 ± 7.7 | Single-dose 500 mg—fed state (oral) | Up to 24 h post-dose |
[53] | 15 (9 males, 7 females) | 19–40 | 1000 mg twice daily (oral) | Up to 24 h post-dose at steady state |
Obese adults | ||||
[54] | 16 (3 males, 13 females) BMI: 40.5 ± 6.9 | 43.5 ± 11.7 | Single-dose 1000 mg—fast state (oral) | Up to 24 h post-dose |
Paediatric subjects | ||||
[55] | 4 females | 9 | 850 mg once daily—fed state (oral) | Up to 24 h post-dose at steady state |
Paediatric obesity subjects | ||||
[56] | 22 (6 males, 16 females) (5 overweight, 17 obese) | 11.1–17.5 | 1000 mg twice daily (oral) | Up to 8 h post-dose at steady state |
[57] | 28 obese paediatrics | 7.7–13.5 | 1000 mg twice daily (oral) | Up to 12 h post-dose at steady state |
Ceftazidime | ||||
[58] | 29 (17 males, 12 females) (82.80% obese) | 2.3–20.6 | Median: 33.8 mg/kg/dose, Lowest–highest: 16.5–92.9 mg/kg/dose, maximum dose: 2 g/dose (intravenous every 8 h) | Post-dose sparse sampling after at least 8 doses |
Parameters | Values | Notes |
---|---|---|
Physical chemistry and blood binding | ||
Compound type | Diprotic acid | |
Molecular weight (g/mol) | 546.58 | |
Log P | −3.75 | |
pKa (1/2) | 2.43, 2.89 | |
fu | 0.85 | |
B/P | 0.55 | |
Distribution (full PBPK) | ||
Vss(L/kg) | 0.22 | Predicted using Rodgers and Rowland method [49,50]. |
Kp scalar | 1.03 | |
Elimination | ||
Renal clearance (L/h) | 6 | |
Additional systemic clearance (L/h) | 0.9 |
Parameters | Values | Notes |
---|---|---|
Physical chemistry and blood binding | ||
Compound type | Diprotic base | |
Molecular weight (g/mol) | 408.88 | |
Log P | 3.43 | [63] |
pKa 1 | 9.40 | [63] |
pKa 2 | 1.90 | [63] |
fu | 0.07 | [63] |
B/P | 0.71 | Predicted by Simcyp®. |
Absorption | ||
Model | ADAM | Permeability limited model. |
fuGut | 0.20 | [65] |
Peff in man (10−4 cm/s) | 0.289 | Predicted by Simcyp® from PSA/HBD. |
PSA (Å2) | 105.50 | [63] |
HBD | 3.00 | [63] |
Distribution | ||
Model | Full PBPK | |
Vss (L/kg) | 36.12 | Predicted using Rodgers and Rowland method [49,50]. |
Kp scalar | 22.70 | An estimate based on observed data [67]. |
Elimination (enzyme kinetics) | ||
HLM CLint by CYP3A4 (µL/min/mg—microsomal) | 42.40 | [68] |
Additional HIMel CLint (µL/min/mg—microsomal) | 22.00 | [69] |
Renal clearance (L/h) | 5.77 | [64] |
Study | Dosing | PK Parameters | Observed | Predicted | Predicted/ Observed |
---|---|---|---|---|---|
Healthy adults | |||||
[47] | 500 mg once | Cmax (mcg/L) | 1.02 ± 0.34 | 0.78 ± 0.28 | 0.77 |
AUC0–24 (h.mcg/mL) | 6.71 ± 1.82 | 6.70 ± 2.16 | 1.00 | ||
Tmax (h) | 2.20 ± 0.30 | 2.62 ± 0.70 | 1.19 | ||
[52] | 500 mg once | Cmax (ng/mL) | 741.00 ± 175.00 | 782.22 ± 277.48 | 1.06 |
AUC0–24 (h.ng/mL) | 5330.00 ± 1400.00 | 6696.68 ± 2158.24 | 1.25 | ||
Tmax (h) | 3.50 ± 0.70 | 2.62 ± 0.70 | 0.75 | ||
[53] | 1000 mg twice daily | Cmaxss (ng/mL) | 1321.00 ± 234.00 | 1898.97 ± 630.13 | 1.44 |
AUC0–24ss (h.ng/mL) | 20,544.00 ± 4445.00 | 28,806.57 ± 9843.03 | 1.40 | ||
Tmax (h) | 3.00 (1.50–6.00) | 2.32 (1.35–3.45) | 0.77 | ||
Obese adults | |||||
[54] | 1000 mg once | Cmax (mcg/mL) | 1.80 ± 0.61 | 1.37 ± 0.49 | 0.76 |
AUC0–24 (h.mcg/mL) | 11.10 ± 3.60 | 11.89 ± 4.15 | 1.07 | ||
Tmax (h) | 3.00 (1.5–3.0) | 2.75 (1.60–4.90) | 1.16 | ||
Paediatric subjects | |||||
[55] | 850 mg once daily | Cmaxss (mg/L) | 3.10 ± 0.30 | 3.40 ± 1.12 | 1.10 |
AUC0–12ss (h.mg/L) | 21.20 ± 1.50 | 24.18 ± 9.40 | 1.14 | ||
Tmax (h) | 2.40 ± 0.20 | 2.78 ± 0.56 | 1.16 | ||
Paediatric obesity subjects | |||||
[57] | 1000 mg twice daily | Cmaxss (mg/L) | 2.80 ± 0.98 | 2.44 ± 1.06 | 0.87 |
AUC0–12ss (h.mg/L) | 14.30 ± 5.00 | 18.64 ± 9.87 | 1.30 | ||
CL/F (mL/min) | 1007.00 ± 326.00 | 1108.83 ± 524.17 | 1.10 | ||
[56] | 1000 mg twice daily | Cmaxss (mg/L) | 1.80 (0.79–3.45) | 1.64 (0.68–4.95) | 0.91 |
AUC0–8ss (h.mg/L) | 10.06 (4.78–18.66) | 10.13 (3.59–33.83) | 1.01 | ||
Tmax (h) | 2.00 (1.00–4.00) | 2.50 (1.40–3.55) | 1.25 |
Study | Dosing | PK Parameters | Observed | Predicted | Predicted/ Observed |
---|---|---|---|---|---|
Adult populations | |||||
[74] | Single-dose 10 mg IV | AUC0-inf (h.ng/mL) | 371.00 ± 69.00 | 668.60 ± 197.38 | 1.80 |
Single-dose 10 mg oral | Cmax (ng/mL) | 5.90 ± 1.20 | 6.10 ± 2.45 | 1.03 | |
AUC0-inf (h.ng/mL) | 238.00 ± 53.00 | 373.21 ± 132.47 | 1.57 | ||
Tmax (h) | 7.60 ± 1.80 | 5.06 ± 0.93 | 0.67 | ||
15 mg oral daily for 14 days | Day 1: Cmax (ng/mL) | 6.90 ± 2.60 | 6.92 ± 1.60 | 1.00 | |
Day 1: Cmin (ng/mL) | 3.30 ± 1.20 | 3.36 ± 0.90 | 1.02 | ||
Day 1: Tmax (h) | 8.90 ± 3.70 | 5.50 ± 0.79 | 0.62 | ||
Day 14: Cmax (ng/mL) | 18.10 ± 7.10 | 23.55 ± 7.09 | 1.30 | ||
Day 14: Cmin (ng/mL) | 11.80 ± 5.30 | 8.17 ± 3.93 | 0.69 | ||
Day 14: Tmax (h) | 8.70 ± 1.90 | 4.92 ± 0.60 | 0.57 | ||
[67] | Single-dose 2.5 mg | Cmax (ng/mL) | 1.20 | 1.52 ± 0.61 | 1.27 |
AUC0–72 (h.ng/mL) | 41.00 | 46.51 ± 17.13 | 1.13 | ||
Tmax (h) | 5.40 | 5.06 ± 0.93 | 0.94 | ||
Single-dose 5 mg | Cmax (ng/mL) | 2.66 | 3.05 ± 1.23 | 1.15 | |
AUC0–72 (h.ng/mL) | 94.00 | 93.10 ± 34.30 | 0.99 | ||
Tmax (h) | 6.30 | 5.06 ± 0.93 | 0.80 | ||
Single-dose 10 mg | Cmax (ng/mL) | 5.49 | 6.10 ± 2.45 | 1.11 | |
AUC0–72 (h.ng/mL) | 200.00 | 186.52 ± 68.78 | 0.93 | ||
Tmax (h) | 6.4 | 5.06 ± 0.93 | 0.79 | ||
[66] | 2.5 mg once daily | Cmaxss (ng/mL) | 4.20 ± 1.10 | 3.90 ± 1.32 | 0.93 |
AUC0–24ss (h.ng/mL) | 81.00 ± 22.00 | 77.49 ± 26.36 | 0.96 | ||
Tmaxss (h) | 7.00 ± 2.00 | 4.54 ± 0.72 | 0.65 | ||
[75] | Single-dose 5 mg | Cmax (ng/mL) | 3.50 ± 0.80 | 3.05 ± 1.23 | 0.87 |
AUC0-inf (h.ng/mL) | 169.00 ± 53.00 | 145.60 ± 55.19 | 0.86 | ||
Tmax (h) | 6.80 ± 1.80 | 5.06 ± 0.93 | 0.74 | ||
5 mg once daily for 14 days | Cmaxss (ng/mL) | 10.50 ± 4.40 | 8.51 ± 2.82 | 0.81 | |
AUC0-infss (h.ng/mL) | 214.00 ± 78.00 | 885.10 ± 462.87 | 4.14 | ||
Tmaxss (h) | 7.00 ± 1.00 | 4.53 ± 0.71 | 0.65 | ||
[76] | Single-dose 10 mg | Cmax (ng/mL) | 4.30 ± 0.90 | 6.10 ± 2.45 | 1.42 |
AUC0–72 (h.ng/mL) | 163.00 | 186.52 ± 68.78 | 1.14 | ||
Tmax (h) a | 7.00 (5.00–12.00) | 4.98 (2.85–7.40) | 0.71 | ||
[77] | Single-dose 5 mg | Cmax (ng/mL) | 2.40 ± 0.20 | 3.05 ± 1.23 | 1.27 |
AUC0–24 (h.ng/mL) | 42.00 ± 3.40 | 49.54 ± 18.60 | 1.18 | ||
Tmax (h) | 6.90 ± 0.60 | 5.06 ± 0.93 | 0.73 | ||
5 mg once daily for 8 weeks | Cmaxss (ng/mL) | 8.10 ± 0.60 | 9.52 ± 3.25 | 1.18 | |
AUC0–24ss (h.ng/mL) | 162.90 ± 13.80 | 194.63 ± 71.84 | 1.20 | ||
AUC0–240ss (h.ng/mL) | 594.50 ± 58.20 | 949.43 ± 519.01 | 1.60 | ||
Tmaxss (h) | 6.40 ± 0.60 | 4.48 ± 0.69 | 0.70 | ||
Obese adult | |||||
[78] | 5 mg daily 10 mg daily | Cmaxss (ng/mL) | 24.88 ± 13.87 | 14.75 ± 6.68 | 0.59 |
AUC0–72ss (h.ng/mL) | 1176.38 ± 704.86 | 794.80 ± 383.20 | 0.68 | ||
AUC0-infss (h.ng/mL) | 2387.34 ± 1705.50 | 2270.93 ± 1474.58 | 0.95 | ||
Tmax (h) | 5.33 ± 1.97 | 5.01 ± 0.76 | 0.94 |
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Burhanuddin, K.; Mohammed, A.; Badhan, R.K.S. The Impact of Paediatric Obesity on Drug Pharmacokinetics: A Virtual Clinical Trials Case Study with Amlodipine. Pharmaceutics 2024, 16, 489. https://doi.org/10.3390/pharmaceutics16040489
Burhanuddin K, Mohammed A, Badhan RKS. The Impact of Paediatric Obesity on Drug Pharmacokinetics: A Virtual Clinical Trials Case Study with Amlodipine. Pharmaceutics. 2024; 16(4):489. https://doi.org/10.3390/pharmaceutics16040489
Chicago/Turabian StyleBurhanuddin, Khairulanwar, Afzal Mohammed, and Raj K. S. Badhan. 2024. "The Impact of Paediatric Obesity on Drug Pharmacokinetics: A Virtual Clinical Trials Case Study with Amlodipine" Pharmaceutics 16, no. 4: 489. https://doi.org/10.3390/pharmaceutics16040489