Clinical Pharmacokinetics & Pharmacotherapeutics Drug Monitoring Concepts

FIRST EDITION 2021

BHUPINDER BHYAN Assistant Professor Department of Pharmaceutics Teerthanker Mahaveer College of Pharmacy Teerthanker Mahaveer University Moradabad, UP, 244001

SARITA JANGRA Assistant Professor Department of Pharmacy Practice Teerthanker Mahaveer College of Pharmacy Teerthanker Mahaveer University Moradabad, UP, 244001

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Clinical Pharmacokinetics & Pharmacotherapeutics Drug Monitoring Concepts

BHUPINDER BHYAN & SARITA JANGRA

NOTION PRESS Notion Press, Inc. 800, West El Camino Real #180, California USA 94040

NOTION PRESS India. Singapore. Malaysia. ISBN 9781685236021 This book has been published with all reasonable efforts taken to make the material error-free after the consent of the author. No part of this book shall be used, reproduced in any manner whatsoever without written permission from the author, except in the case of brief quotations embodied in critical articles and reviews. The Author of this book is solely responsible and liable for its content including but not limited to the views, representations, descriptions, statements, information, opinions and references [“Content”]. The Content of this book shall not constitute or be construed or deemed to reflect the opinion or expression of the Publisher or Editor. Neither the Publisher nor Editor endorse or approve the Content of this book or guarantee the reliability, accuracy or completeness of the Content published herein and do not make any representations or warranties of any kind, express or implied, including but not limited to the implied warranties of merchantability, fitness for a particular purpose. The Publisher and Editor shall not be liable whatsoever for any errors, omissions, whether such errors or omissions result from negligence, accident, or any other cause or claims for loss or damages of any kind, including without limitation, indirect or consequential loss or damage arising out of use, inability to use, or about the reliability, accuracy or sufficiency of the information contained in this book.

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Dedicated to our Parents and Family Members

Contents Foreword ....................................................................... xi Preface ......................................................................... xiii Acknowledgments ........................................................ xv 1. INTRODUCTION TO CLINICAL PHARMACOKINETICS 1 Pharmacokinetics........................................................ 1 Clinical Pharmacokinetics .......................................... 2 Pharmacodynamics ..................................................... 2 Population Pharmacokinetics ..................................... 3 Application of Pharmacokinetics ............................... 3 Study of Pharmacokinetics ......................................... 3 Linear Pharmcokinetics .............................................. 4 Non-Linear Pharmacokinetics .................................... 4 Order of Process in Pharmacokinetics ........................ 5 Clinically Important Pharmacokinetic Parameters ..... 6 2. DESIGN OF DOSAGE REGIMENS ......................... 9 Dosage Regimen......................................................... 9 Design of Dosage Regimen ........................................ 9 Approches in Designing of Dosage Regimen ............ 9 Nomograms and Tabulations ................................... 12 Conversion from Intravenous to Oral Dosing .......... 14 Determination of Dose and Dosing Frequency ........ 15 Drug Dosing in Elderly Patients ............................... 16

Dosing in Pediatrics ................................................. 18 Dosing in Obese ....................................................... 21 3. PHARMACOKINETIC DRUG INTERACTIONS . 25 Mechanism of Drug-Drug Interaction ...................... 26 Classification of Drug-Drug Interactions ................. 27 Pharmacokinetic Drug-Drug Interactions................. 27 Inhibition of Drug Metabolism................................. 30 Induction of Drug Metabolism ................................. 31 Inhibition of Biliary Excretion ................................. 31 4. THERAPEUTIC DRUG MONITORING ................ 33 Indications for TDM................................................. 34 Protocol for TDM ..................................................... 35 Limitations of TDM ................................................. 37 Clinical Situations in TDM ...................................... 37 TDM of Digoxin....................................................... 39 5. DOSAGE ADJUSTMENT IN RENAL AND HEPATIC DISEASE ...................................................................................... 41 Renal Impairment ..................................................... 41 Dosage Adjustment in Renal Disease ...................... 43 Measurement of GFR ............................................... 46 Determination of Creatinine Clearance .................... 48 Extracorporeal Removal of the Drugs ...................... 50 Dose Adjustment in Hepatic Disease ....................... 52 6. POPULATION PHARMACOKINETICS ............... 55 Adaptive Method or Dosing with Feedback............. 56 Bayesian Theory....................................................... 56 Data Analysis of PopulationPharamcokinetics ........ 59 7. PHARMACOGENETICS ........................................ 61

Basics terms used in Genetics .................................. 62 Genetic Variations/Polymorphism ........................... 62 Nomenclature of Alleles ........................................... 63 Genetic Polymophism in CYP450 Enzymes ............ 64 Genetic Polymorphism in TPMT ............................. 66 Genetic polymorphism in N-acetyltransferase ......... 66 Polymorphism in Membrane Transporter ................ 66 8. DOSE DEPENDENT PHARMACOKINETICS ..... 69 Causes of Non-Linearity .......................................... 70 Michaelis-Menten Equation ..................................... 72 Determination of Km and Vmax .............................. 72 9. ADVERSE EVENT REPORTING IN CLINICAL SETTINGS ...................................................................................... 75 Reasons of Reporting Adverse Events ..................... 75 What Should be Recorded in AEs ............................ 76 Types of Adverse Event ........................................... 78 Detection of Adverse Event ..................................... 79 Collecting and Recording of AE Data ...................... 80 Adverse Event Follow-up ......................................... 80 Adverse Event Grading ............................................ 81 Reporting of Adverse Events ................................... 82 10. THERAPEUTICS AND PHARMACOKINETICS 85 Phenytoin .................................................................. 85 Cyclosporine............................................................. 90 Theophylline............................................................. 95 Digoxin ................................................................... 103

Foreword

The introduction of Doctor of Pharmacy programme in India by PCI in 2008 have generated tremendous scope of clinical pharmacy practice at various level of the pharmacy profession. In last decade the role of pharmacist has also broaden and become more specific in terms of suggesting treatment protocols, detection and management of ADRs, drug interactions, optimization of therapy, dose adjustment in renal/hepatic impairment and in some special patient population. This book is designed to prepare the pharmacists for the above mentioned expanded role in the healthcare system. The title of the book “Clinical Pharmacokinetics & Pharmacotherapeutic Drug Monitoring Concepts” emerge from the course syllabus as recommended by PCI for Pharm.D. programme. This book is the outcome of collaborative contributions of the expertise from the Department of Pharmaceutics and Pharmacy Practice to ensure better clarity of the concepts. It is my great pleasure to commend this book, as it will strengthen the knowledge of pharmacy aspirants and pharmacists already engaged in clinical pharmacy services.

Professor Parminder Nain HOD, Pharmacy Practice MMU, Maullana

Preface

This book was initiated to fulfil the students need, who felt that there was a requirement of a textbook which consolidate the whole syllabus of the Doctor of Pharmacy 5th year subject “Clinical Pharmacokinetics & Pharmacotherapeutics Drug Monitoring” as laid by PCI. It was written with a student friendly approach which will be particularly helpful for students who have found clinical pharmacokinetic and therapeutic drug monitoring difficult and unapproachable. The main objective of this book is to bring forward the basic concepts of clinical pharmacokinetics and therapeutic drug monitoring to the students with minimal skill in practical clinical therapeutic management. The discussions along with related mathematical equations made under the different chapter of this book, help to clarify the fundamental concepts of pharmacokinetics and therapeutics in a very simple manner. This book utilizes the short approaches which suits learner from different scientific background for quick understanding of pharmacokinetics and TDM concepts. Pharmacokinetics involves a quantitative explanation of absorption, distribution, metabolism and excretion of drugs, the process that govern the drug concentration time profile in the systemic circulation and different organs and tissues. This discipline has been of great interest to scientists involved in the drug discovery and development, preclinical and clinical evaluation of the drug and physician involved in clinical use of drug. The book was written to achieve following learning objectives. Students after reading this book should be able to

PREFACE

1. Design and implement pharmacokinetic services such as Intravenous to oral conversion of dosage regimens and therapeutic drug monitoring services 2. Explain the significance of altered pharmacokinetics, pharmacogenetics and pharmacometrics in therapy 3. Practice to adjust the dosage regimen for patients with renal / hepatic impairments and to assess the drug interaction issues in the clinical settings 4. Detect and report adverse drug reactions in clinical settings. We hope learner find this book helpful in understanding the concepts.

Bhupinder Bhyan Sarita Jangra

Acknowledgments

I am greatly indebted to Almighty, for showering his infinite graces and mercies on me, without which this work was impossible. I would like to express my gratitude to many people who saw me through this book; to all those who provided support and assisted in editing, proofreading and design. First of all, I would like to thank my mentor, my father Shri. Mohinder Singh, GI (Retd Govt. Offical) for enabling me to publish this book. Education commences at the mother’s knee, my Mother Smt. Rajbala, her blessings have always leaded me towards achieving my goals. I also would like to mention my source of energy Evan and Yuvika. I must not fail to express my special thanks and sincere love to my dear sister Bhawna & brother in law Karmvir Singh Kularia (In. Income Tax) who always inspired, encouraged and supported me morally and filled in me rocking determination to accomplish the task. The word “Thanks” seems to be too small to express my feelings for my wife & the co-author of this book Sarita Jangra. Who have been an inseparably important part of what I have tried to achieve. Speaking of encouragement and inspiration I must mention my guide Dean & Professor D.C. Bhatt, who always provided insightful feedback enable me to polish my work. I am thankful to Principal, Dr. Anurag Verma, for trusting me and providing the resource towards completion of this task.