Modèle PBPK

Année universitaire 2019-2020                Université Claude Bernard Lyon 1

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DEPARTEMENT DE BIOLOGIE HUMAINE

MASTER SANTE PUBLIQUE

BIBLIOGRAPHIC REPORT

Phuong Linh PHAM, p1716373

Master 2 Pharmacology, Modelling and Clinical Trials

Master’s Supervisors : Pr. François GUEYFFIER and Pr. Michel TOD

Internship Supervisor: Dr. Kim-An Huu NGUYEN

Table of contents

I. Introduction………………………………………………………………………………………...5

1.1. Background………………………………………………………………………………………..5

1.2 Objectives of the research project………………………………………………………………….6

II. PARACETAMOL…………………………………………………………………………………7

2.1. General…………………………………………………………………………………………….7

2.2. Pharmacokinetics………………………………………………………………………………….7

2.3. Pharmacodynamic ………………………………………………………………………………...8

2.4. Hepatotoxicity and overdose………………………………………………………………………9

III. Model PBPK…………………………………………………………………………………….10

3.1. Definition and characteristic……………………………………………………………………..10

3.2. Building PBPK models…………………………………………………………………………..11

3.3. Lumping………………………………………………………………………………………….11

3.4. Applications and limitations…………………………………………………………………….12
3.5. Model PBPK applied for APAP………………………………………………………………….13

IV. Develop model PBPK for APAP (in this study) ………………………………………………14

4.1. Modeling process…………………………………………………………………………………14

4.2. Bayesian population approach……………………………………………………………………16

V. Conclusion………………………………………………………………………………………...18

List of tables

Table 1. Factors influencing APAP-hepatotoxicity……………………………………………9

Table 2. PBPK models for APAP and its metabolites………………………………………. 13

Table 3. System of differential equations PBPK APAP Model………………………………15

List of figures

Figure 1. Chemical structure of Paracetamol (Pub Chem) …………………………………....7

Figure 2. Metabolism of paracetamol………………………………………………………….8

Figure 3. Mechanism of action of APAP in analgesic activity after an oral treatment………. 9

Figure 4. Example of a typical PBPK model………………………………………………....10

Figure 5. Necessary elements for building PBPK model……………………………………..11

Figure 6. A PBPK structure model applied for APAP………………………………………..14

Figure 7.  Schematic illustration of the presented Bayesian population PBPK approach……16

Figure 8. Analysis framework using Bayesian inference…………………………………….17

Abbreviations

APAP              Acetaminophen, Paracetamol

CNS                Central Nervous System

GSH                Glutathion

EtOH               Ethanol

PBPK model   Physiologically Based Pharmacokinetic Model

PK                   Pharmacokinetic

PKPD              Pharmacokinetic – Pharmacodynamic

PIC                  Poison Information Centers

I. INTRODUCTION

1.1. Background

During the past 10 years, the trend in children having obesity is relatively stable yet it is still highly prevalent nowadays [1]. The proportion of global prevalence of childhood overweight and obesity rose to 6,7% in 2010 (95% CI: 5.6%, 7.7%), compared to 4,2%
(95% CI: 3.2%, 5.2%) in 1990. In 2020, it is forecasted to reach 9,1%
(95% CI: 7.3%, 10.9%). In Africa, the figure in 2010 was 8.5% (95% CI: 7.4%, 9.5%) and it is expected to reach 12,7% (95% CI: 10.6%, 14.8%) after a decade. In comparison with Asia, while its prevalence is lower than that of Africa (4.9% in 2010), more children (18 million) are suffered from obesity [2].

According to the number of studies, pharmacokinetic and pharmacodynamic parameters in obese children are attributed to the changes in body composition and the physiology [3]. Some researchers proposed that these PKPD alterations may lead to the increase in vulnerability of obese children to overdose [4]. Some methods were suggested for adjusting the dosing in obese children [5], [6].

Nevertheless, the current data addressing the prediction of the potential toxic dosing in poisoned children is rather restricted. The PBPK model considering PK parameter changes in obese children would be useful for predicting toxic dosing in this special population. Known as the most common medication referring to toxic circumstance for all age groups, paracetamol is chosen as a model drug for this study. A further overview of assessing other drugs in overdose obese children would also be proposed.

1.2. Objectives of the research project

The aim of this study is to develop a PBPK model for predicting paracetamol pharmacokinetic parameters and liver toxicity in overdose obese children.

The secondary objectives of the research project are:

• To determine the optimal time for blood sampling to minimize the error in a dose estimate in different overdose circumstances
• To quantify the potential role of inclusion of metabolite concentration on
  dose estimates
• To predict paracetamol toxic dose in obese children and compare them with patient data collected in overdose obese children in literature and from database of 2 Poison information centers (PICs)
• To predict the risk of severe liver toxicity in obese children and compare them with patient data collected in overdose obese children in 2 PICs

II. PARACETAMOL

2.1. General

Paracetamol (Acetaminophen, N-acetyl-p-aminophenol, 4-hydroxyacetanilide, APAP),
a p-aminophenol derivative, is placed on the WHO’s list of essentials drugs. With the analgesic and antipyretic properties and weak anti-inflammatory activity, it is used for the relief of mild to moderate pain. [7], [8]

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Figure 1. Chemical structure of Paracetamol (Pub Chem)

2.2. Pharmacokinetics

Absorption and Distribution

Paracetamol taken orally is rapidly absorbed from the gastrointestinal tract by passive transport. The first pass effect is weak (about 25%). The maximum plasma concentrations are reached: in 10-15 minutes after intravenous infusion, in 15 min with effervescent tablets, in 30 to 60 min after oral administration, in 2 to 3 h after intrarectal administration. The bioavailability after oral intake is 63 to 69%. [7], [8]

Paracetamol is rapidly and uniformly distributed in the tissues. The ratio of binding to plasma proteins is low (10%). The volume of distribution of paracetamol is approximately 1 L/ kg. [7], [8]

Metabolism and elimination

Paracetamol is mainly bio transformed in the liver by sulphate and glucuronide conjugates, under the action of Sulfotransferase and Uridine 5’-diphospho (UDP) glucuronyltransferase respectively. About 4% of paracetamol is transformed by cytochrome P450 into N-acetyl benzoquinone imine (NAPQI). NAPQI, an hepatoxic intermediate metabolite, is rapidly detoxified by glutathione and eliminated by the kidney in urine, after conjugation with cysteine ​​or mercapturic acid. In children, glucuronide conjugation is deficient, the biotransformation is therefore essentially by sulfoconjugation. [7], [8]