Application of a Systems Approach to the Bottom-Up Assessment of Pharmacokinetics in Obese Patients

Ghobadi, Cyrus; Johnson, Trevor N.; Aarabi, Mohsen; Almond, Lisa; Allabi, Aurel Constant; Rowland‐Yeo, K; Jamei, Masoud; Rostami‐Hodjegan, Amin

doi:10.2165/11594420-000000000-00000

Cited by 77 publications

(92 citation statements)

References 91 publications

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“…Individual adult Q hepatic values for use in the PBPK model were determined using the relationship between cardiac output and body surface area (BSA) (Dubois and Dubois, 1989;Ghobadi et al, 2011). First, adult BSA (eq.…”

Section: Methodsmentioning

confidence: 99%

The Ontogeny and Population Variability of Human Hepatic NADPH Dehydrogenase Quinone Oxido-Reductase 1 (NQO1)

Rougée

Riches

Berman

et al. 2016

Drug Metabolism and Disposition

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The NADPH dehydrogenase quinone oxido-reductase 1 (NQO1) enzyme is an antioxidant and metabolic enzyme that performs two electron reduction of quinones and other chemicals. Based on the physiologic role(s) of NQO1, we hypothesized that expression and activity of this enzyme would vary with age and other demographic variables. Cytosols from 117 archived human livers were investigated for changes in NQO1 with age, sex, obesity, and ethnicity. Protein expression but not activity of NQO1 was weakly negatively correlated with age (Spearman r = -0.2, P = 0.03). No sex differences were observed for either protein expression or activity and for ethnicity; Caucasians had greater NQO1 activity than Asians (P < 0.05). Overweight children had statistically significantly higher NQO1 activity as compared with ideal weight children (P < 0.05) although this difference was not observed in adults. These findings establish that NQO1 is approximately as active in children as adults. However, modeled NQO1 clearance (both allometric and physiologically based pharmacokinetics) predicted maturation at 23 to 26 years. This is almost certainly an overestimate, with error in the model resulting from a small sample size and inability to scale for age-related changes in hepatic cellularity and/or cytosolic protein content, and indicates a delay in reaching maximum clearance through the NQO1 pathway that is affected by physiologic development as much, or more than, biochemical development. Obesity may increase hepatic NQO1 activity in children, which is likely a protective mechanism in oxidative stress, but may also have significant implications for drug and chemical disposition in obese children.

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Section: Methodsmentioning

confidence: 99%

The Ontogeny and Population Variability of Human Hepatic NADPH Dehydrogenase Quinone Oxido-Reductase 1 (NQO1)

Rougée

Riches

Berman

et al. 2016

Drug Metabolism and Disposition

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“…Narbro et al 's study demonstrates that 52% of the obese individuals were taking medications compared with only 36% of the randomly selected reference populations (89). Physiological changes such as increased muscle mass, connective tissue, and total body water in obese patients alter pharmacokinetics and pharmacodynamics of medications (90).…”

Section: Medicationmentioning

confidence: 99%

Morbidity and mortality associated with obesity

Abdelaal

Roux

Docherty

2017

Annals of Translational Medicine

769

459

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Obesity and its repercussions constitute an important source of morbidity, impaired quality of life and its complications can have a major bearing on life expectancy. The present article summarizes the most important co-morbidities of obesity and their prevalence. Furthermore, it describes classification and grading systems that can be used to assess the individual and combined impact of co-morbid conditions on mortality risk. The literature was screened for assessment tools that can be deployed in the quantification of morbidity and mortality risk in individual patients. Thirteen specific domains have been identified that account for morbidity and mortality in obesity. Cardiovascular disease (CVD) and cancer account for the greatest mortality risk associated with obesity. The King's Criteria and Edmonton Obesity Staging System (EOSS) were identified as useful tools for the detection and monitoring of individual patient mortality risk in obesity care. The stark facts on the complications of obesity should be capitalized on to improve patient management and knowledge and referred to in the wider dissemination of public health messages aimed at improving primary prevention.

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“…Oleh karena pada kelompok obesitas terdapat peningkatan curah jantung dan efektivitas fungsi ginjal, maka dapat menyebabkan nilai eLFG yang lebih tinggi jika dibandingkan kelompok non-obesitas. 31 Seperti yang telah diketahui, kreatinin merupakan hasil metabolisme protein otot, sehingga pada jumlah massa otot tinggi dapat menyebabkan kadar kreatinin yang lebih tinggi yang berakibat perolehan nilai eLFG yang lebih rendah terutama pada laki-laki. 32 Namun demikian dengan rumus perhitungan nilai eLFG yang digunakan pada penelitian ini, dengan memasukkan variabel yang berbeda untuk tiap kelompok jenis kelamin, telah diupayakan meminimalkan pengaruh perbedaan jenis kelamin.…”

Section: Pembahasanunclassified

Glycemic Control and Prevalence of Chronic Kidney Disease in Type‑2 Diabetes Mellitus Patients at Primary Healthcare Centers in Yogyakarta Province 2015

Ningrum

Ikawati

Sadewa

et al. 2017

Indones J Clin Pharm

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AbstrakPengendalian glikemik yang baik pada diabetes melitus tipe 2 (DMT2) terbukti dapat mencegah penyakit komplikasi akibat DMT2. Puskesmas sebagai sarana pelayanan kesehatan primer merupakan garda terdepan yang diharapkan dapat memberikan pelayanan pengelolaan DMT2 dengan baik untuk mencegah penyakit komplikasi seperti penyakit gagal ginjal kronik (GGK). Kejadian GGK yang seringkali tanpa gejala spesifik serta keterbatasan pemeriksaan diagnostik di puskesmas menyebabkan keterlambatan diagnosis GGK maupun pengelolaan terapi yang sub-optimal. Penelitian ini bertujuan menganalisis kontrol glikemik dan kejadian GGK pada pasien DMT2 di puskesmas serta faktor pasien yang memengaruhi kontrol glikemik dan kejadian GGK. Penelitian potong-lintang pada 6 puskesmas di Yogyakarta tahun 2015 ini melibatkan pasien DMT2 dewasa tanpa riwayat gagal hati kronik. Parameter kontrol glikemik menggunakan Glukosa-Darah-Puasa (GDP), Glycated-Albumin (GA), atau hemoglobin terglikasi (HbA1C), sedangkan nilai eLFG digunakan sebagai dasar klasifikasi GGK. Sebanyak 101 pasien dengan rata-rata usia 50,75±6,73 tahun terlibat dalam penelitian. Kontrol glikemik kategori baik ditemukan hanya pada 13,86% pasien, sedangkan 12,87% pasien mengalami GGK. Tidak ada faktor pasien yang memengaruhi kontrol glikemik. Sementara itu, usia dan durasi DMT2 berkorelasi dengan kejadian GGK (p<0,01). Berdasarkan penelitian ini, kontrol glikemik yang buruk dapat meningkatkan kemungkinan kejadian GGK sebesar 63,64%. Oleh karena itu, diperlukan strategi pengelolaan DMT2 maupun pencegahan GGK yang lebih baik termasuk penyediaan fasilitas pemeriksaan yang memadai untuk meminimalkan kejadian clinical inertia di puskesmas.Kata kunci: Faktor-pasien, gagal ginjal kronik, kontrol glikemik, puskesmas Glycemic Control and Prevalence of Chronic Kidney Disease in Type-2 Diabetes Mellitus Patients at Primary Healthcare Centers in Yogyakarta Province 2015 AbstractGood glycemic control in type-2 diabetes mellitus (T2DM) has proven to be able to prevent complications. Primary healthcare is at the forefront being expected to provide good services in T2DM management for preventing such complication as chronic kidney disease (CKD). The incidence of CKD that often shows no specific symptoms and the limitations in diagnostic examinations at primary healthcare centers has caused delay in diagnosis and suboptimal therapy management. This study aimed to determine glycemic controls and prevalence of CKD in patients with T2DM in primary healthcare centers as well as to assess patient's factors related to the glycemic controls and prevalence of CKD. This cross-sectional study in six primary healthcare centers in Yogyakarta in 2015 involved adult T2DM patients without a history of chronic liver disease. The glycemic control parameters comprised of Fasting-Blood-Glucose (FBG), Glycated-Albumin (GA), or glycated-hemoglobin (HbA1C), while the estimated GlomerularFiltration-Rate (eGFR) was used as the basis for CKD classification. A total of 101 patients with an average age of 50.75±6.73 years...

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Application of a Systems Approach to the Bottom-Up Assessment of Pharmacokinetics in Obese Patients

Cited by 77 publications

References 91 publications

The Ontogeny and Population Variability of Human Hepatic NADPH Dehydrogenase Quinone Oxido-Reductase 1 (NQO1)

The Ontogeny and Population Variability of Human Hepatic NADPH Dehydrogenase Quinone Oxido-Reductase 1 (NQO1)

Morbidity and mortality associated with obesity

Glycemic Control and Prevalence of Chronic Kidney Disease in Type‑2 Diabetes Mellitus Patients at Primary Healthcare Centers in Yogyakarta Province 2015

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