THERAPEUTIC DRUG MONITORING SERVICE

IN MALAYSIA: CURRENT PRACTICE AND

COST EVALUATION

by

HISHAM ELHAG AHMED ABDELRAHIM

Thesis submitted in fulfillment of the requirements for the degree of Master of

Science

September 2008
 DEDICATION

To

This thesis is dedicated to my Parents

(Elhag Ahmed and Batool Osman), sisters (Hanadi and Halla)
and brothers (Imad, Haitham and Hani) Their unconditional support of love,
encouragement and duaa never seized to lift me during hard times. To my
smaller family: my wife Hiba and children; Marwa, Nada and Mohamed
who made every single moment worthwhile and where with me
every step of the way. I can only say
Allah grant you al-Janna.

Hisham
May 2008

ii
 ACKNOWLEDGEMENTS

First and foremost I would like to show my thanks and appreciation to my supervisor

A/P Dr Ab Fatah Ab Rahman for his guidance and experience. Without his valuable

comments and recommendations I could not be able to complete this study. My

thanks also goes to my co-supervisor A/P Dr. Mohamed Izham Mohamed Ibrahim

although, he is very busy due to his many responsibilities in the university, yet he

offered me a lot of his valuable time. Then I would like to thank Dr Mohamed Azmi

Hassali, Dr. Asrul Akmal Shafie and En. Norshimi in the Department of Social and

Administrative Pharmacy (DSAP), USM Penang for their help, support and

continuous encouragement to complete my study. I will never forget the continuous

help and encouragement from my best friends, the post graduate colleagues; in the

DSAP I wish them the best and great success for them all. Many thanks go to brother

Abdallah Aldahbali for his help during the data analyses period.

My thanks extend to the director of HUSM who gave me the chance to perform my

study. A special thank you note goes to the chief pharmacist in HUSM Pn. Rasuna

Zakey Mohammad Zakey for her help in providing me with all necessary

information from the pharmacy department. I would like to show my gratitude to

thank Hj. Azman bin Mat chief of the Out-Patient Pharmacy Services, Pn. Noor Aini

Abu Samah the chief of the In-Patient Pharmacy Services and Pn. Zalina Zahari in

the Drug Information Unit, En. Dellemin Che Abdullah the head of the TDM unit

and En. Juhary Omar senior lab. assistant, Pn. Zaini Mohd Noor in the Unit rekod

Perubatan, and En. Ab. Ghani Abdullah in Unit Kewangan

iii
Also I would like to thank the director of Hospital Kulim and other staff in hospital

who helped me to accomplish my research in the hospital. Especially the pharmacists

in the pharmacy department, above all the chief pharmacist Pn. Salbiah Mohd Salleh

and the pharmacists in the TDM unit Chik. Norma Ramli And Chik. Nurzita Ahmad

Nasir. To the chief of the record office Pn. Suzana as well as Mr. Yeoh Loh Chin and

the other staff to offer me all the facilities in the unit. Many thanks to Hj Ismail the

chief of the medical assistant in the hospital.

There are many other people whose support, encouragement and prayers helped me a

lot in finishing this study. They include: My best friend Khalid Soghayroon for his

great assistant and continuous encouragement, although he is so far away but he was

with me all the time. I wish all the best for him and may Allah bless him. And for my

best friend Abdelgader Mohamed Salih who really was a good partner in

expatriation. I hope he can accomplish his studies successfully. All Sudanese

students and their families in USM where we have been one big family here. I wish

them all the best. Allah blesses them all. My thanks go To Sudan as well to Dr.

Marwan the director of the training department and Dr. Isam Ali the director of the

directorate of pharmacy, Ministry of Health, Khartoum State to offer me this

scholarship.

Finally, I would like to show my gratitude and appreciation for everybody who

helped me to complete this work directly or indirectly; thank you.

iv
 TABLE OF CONTENTS

Title Page

DEDICATION ii

ACKNOWLEDGEMENTS iii

TABLE OF CONTENTS v

LIST OF TABLES xiii

LIST OF FIGURES xvi

LIST OF ABBREVIATIONS xvii

ABSTRAK xx

ABSTRACT xii

CHAPTER ONE: GENERAL INTRODUCTION 1

1.0 GENERAL INTRODUCTION 2

CHAPTER TWO: CURRENT PRACTICE OF THERAPEUTIC 4

DRUG MONITORING SERVICE IN MALAYSIA

2.1 INTRODUCTION 5

2.1.1 Therapeutic Drug Monitoring (TDM) service 5

2.1.1(a) Principles of TDM 5

2.1.1(b) Clinical applications of TDM 6

2.1.1(c) TDM process 7

2.1.1(d) Sample matrices 9

2.1.1(e) Analytical techniques used in TDM 12

2.1.1(f) Drugs monitored and sampling time 14

2.1.2 Literature review of TDM service 19

v
 Title Page

2.1.2(a) TDM service in developed countries 19

2.1.2(b) TDM service in developing countries 22

2.1.2(c) TDM service in Malaysia 23

2.1.3 Study problems and rationale 25

2.1.4 Study objectives 25

i. General objective 25

ii. Specific objectives 25

2.1.5 Significance of the study 26

2.2 METHODOLOGY 27

2.2.1 Research design 27

2.2.2 Study population and sample size 30

2.2.3 Mailing of the questionnaire 30

2.2.4 Data analysis 31

2.3 RESULTS 32

2.3.1 General description of respondents 32

2.3.1(a) Survey response rate 32

2.3.1(b) General characteristics of respondents 32

2.3.1(c) Distribution of respondents 33

2.3.2 Hospitals with TDM service 36

2.3.2(a) Hospitals’ characteristics 36

2.3.2(b) Duration of TDM service 38

2.3.2(c) TDM service working hours 38

vi
Title Page

2.3.2(d) TDM staff 39

2.3.2(e) Drugs monitored by TDM service 40

2.3.2(f) Drug therapeutic range reference 42

2.3.2(g) Source and number of samples 42

2.3.2(h) Patients monitored 45

2.3.2(i) Biological fluids used in drug monitoring 46

2.3.2(j) Time taken to dispatch assay result to wards or clinics 47

2.3.2(k) Clinical pharmacokinetic activities 47

2.3.2(l) Intervention and recommendation to doctors 49

2.3.2(m) Methods of reporting 50

2.3.2(n) Training and educational programs 51

2.3.2(o) Payment for TDM service 53

2.3.2(p) Problems associated with TDM service 53

2.3.2(q) Evaluation studies on TDM service 55

2.3.3 TDM laboratory activities 56

2.3.3(a) Standard guideline for TDM laboratory procedure 56

2.3.3(b) Location of TDM laboratories in the hospital 56

2.3.3(c) Budget and source of funding 56

2.3.3(d) TDM techniques and machines 57

2.3.3(e) Quality control samples 58

2.3.3(f) Time taken to perform the assay 59

2.3.3(g) Quality assurance program (QA) 59

2.3.4 Hospitals with no TDM service 61

vii
 Title Page

2.3.4(a) Distribution of hospitals according to states 61

2.3.4(b) Hospitals characteristics 62

2.3.4(c) Reasons for not providing TDM service 63

2.4 DISCUSSION 64

2.5 CONCLUSIONS 87

2.6 RECOMMENDATIONS 89

2.7 LIMITATIONS 91

CHAPTER THREE: COST AND OUTCOME ANALYSES OF 92

PROVIDING TDM SERVICE OF GENTAMICIN IN

HOSPITALIZED PATIENTS WITH BRONCHOPNEUMONIA

3.1 INTRODUCTION 93

3.1.1 Aminoglycosides 93

3.1.1(a) Safety profile of aminoglycosides 94

3.1.1(b) Clinical applications of aminoglycosides 96

3.1.2 Pneumonia 97

3.1.3 Literature review 102

A. Evaluation of therapeutic drug monitoring service 102

B. Pharmacoeconomic studies on therapeutic drug monitoring 105

i. Cost-benefit analysis 106

ii. Cost-effectiveness analysis 108

iii. Cost-utility analysis 108

iv. Cost-minimization analysis 109

v. Cost of illness 110

viii
 Title Page

3.1.4 Study problems and rationale 111

3.1.5 Significance of the study 112

3.1.6 Study objectives 113

i. General objectives 113

ii. Specific objectives 113

3.2 METHODOLOGY 114

3.2.1 Hospital Universiti Sains Malaysia (HUSM) 114

3.2.1(a) Research design 114

3.2.1(b) Study time and location 114

3.2.1(c) Study population 115

i. Inclusion criteria 115

ii. Exclusion criteria 116

3.2.1(d) Sample size and sampling procedure 116

3.2.1(e) Data collection procedure 117

A. Cost calculation 118

B. Outcome measurement 122

3.2.2 Hospital Kulim 123

3.2.2(a) Research design 123

3.2.2(b) Study time and location 123

3.2.2(c) Study population 124

i. Inclusion criteria 124

ii. Exclusion criteria 124

3.2.2(d) Sample size and sampling procedure 125

ix
 Title Page

3.2.2(e) Data collection procedure 125

A. Cost calculation 125

B. Outcome measurement 127

3.2.3 Data analysis 127

3.3 RESULTS 129

3.3.1 Hospital Universiti Sains Malaysia (HUSM) 129

3.3.1(a) Demographic characteristics 130

3.3.1(b) Concomitant diseases during gentamicin therapy 131

3.3.1(c) Vital signs measurements 131

3.3.1(d) Laboratory investigations during gentamicin therapy 132

3.3.1(e) Length of stay and treatment 134

3.3.1(f) Pharmacoeconomic analysis 135

1. Cost of laboratory and clinical investigations 135

2. Cost of gentamicin dose 135

3. Cost of providing TDM service 136

i. Cost of TDM laboratory space 136

ii. Cost of laboratory equipments 136

iii. Cost of TDM reagents and consumables 138

iv. TDM team cost 138

v. Distribution of TDM costs 139

4. Cost of ward staff 140

5. Cost of hospital stay 140

6. Total hospitalization costs 140

x
 Title Page

3.3.2 Hospital Kulim 143

3.3.2(a) Demographic characteristics of the Non-TDM group 144

and TDM group
3.3.2(b) Concomitant diseases during gentamicin therapy 145

3.3.2(c) Vital signs 146

3.3.2(d) Laboratory investigations during gentamicin therapy 147

3.3.2(e) Length of stay and treatment 150

3.3.2(f) Pharmacoeconomic analysis 151

1. Cost of laboratory and clinical investigations 151

2. Cost of gentamicin dose 152

3. Cost of providing TDM service 152

i. Cost of laboratory space 152

ii. Cost of laboratory equipments 152

iii. Cost of TDM reagents and consumables 153

iv. TDM team cost 154

v. Distribution of TDM costs 155

4. Cost of ward staff 155

5. Cost of hospital stay 156

6. Cost comparison between the two groups in total costs 156

7. Comparison of TDM service cost between HUSM and 160

Hospital Kulim

3.4 DISCUSSION 161

3.4.1 HUSM 161

3.4.2 Hospital Kulim 171

3.5 CONCLUSION 182

xi
 Title Page

3.6 RECOMMENDATIONS 184

3.7 LIMITATIONS 185

CHAPTER FOUR: OVERALL CONCLUSIONS 186

4.0 OVERALL CONCLUSION 187

REFERENCES 188

APPENDICES 202

PUBLICATIONS 235

xii
 LIST OF TABLES

Title Page

Table 2.3.1 General characteristics of all respondents 32

Table 2.3.2 Distribution of respondents according to states 34

Table 2.3.3 Distribution of types of specialties in hospitals 35

Table 2.3.4 General descriptions of hospitals that provide the 37

TDM service

Table 2.3.5 Duration of providing TDM service 38

Table 2.3.6 TDM service working hours 39

Table 2.3.7 TDM staff included in the TDM service 40

Table 2.3.8 Drugs monitored by TDM service 41

Table 2.3.9 Distribution of different sources of samples 42

Table 2.3.10 Distribution of source of samples from hospital 44

departments

Table 2.3.11 Distribution of patients monitored 45

Table 2.3.12 Distribution of biological fluids used 46

Table 2.3.13 Distribution of time needed to dispatch assay results 47

Table 2.3.14 Clinical pharmacokinetic activities 48

Table 2.3.15 Types of interventions provided to doctors 49

Table 2.3.16 Methods of reporting 51

Table 2.3.17 Frequency of TDM staff educational activities 52

Table 2.3.18 Problems in TDM service 54

Table 2.3.19 Evaluation of TDM service 55

Table 2.3.20 Types of FPIA machines used 58

Table 2.3.21 Time taken to process one TDM assay 59

Table 2.3.22 General characteristics of respondents 62

xiii
 Title Page

Table 2.3.23 Reasons for not providing TDM service 63

Table 3.1.1 Ranking of the respiratory tract infections in 98

Malaysia

Table 3.3.1 Distribution of patients included in the study in 129

HUSM

Table 3.3.2 Demographic characteristics of the study patients 130

Table 3.3.3 Concomitant diseases with bronchopneumonia 131

Table 3.3.4 Vital signs measurements pre/post gentamicin 132

therapy

Table 3.3.5 Frequencies of laboratory investigations results 133

Table 3.3.6 Length of hospital stay and treatments 134

Table 3.3.7 Types of concurrent antibiotics given to patients 135

during gentamicin therapy

Table 3.3.8 Cost of gentamicin dose 136

Table 3.3.9 Cost of TDM laboratory equipments needed to 137

conduct gentamicin monitoring

Table 3.3.10 Cost of TDM reagents and consumables that 138

associated with gentamicin assay in the year 2005

Table 3.3.11 TDM team cost 138

Table 3.3.12 TDM materials costs 139

Table 3.3.13 Ward staff cost 140

Table 3.3.14 Distribution of different hospitalization costs 141

Table 3.3.15 Distribution of patients included in the study in 143

Hospital Kulim

Table 3.3.16 Comparison of the demographic characteristics of the 144

two groups

Table 3.3.17 Concomitant diseases with bronchopneumonia 145

Table 3.3.18 Vital signs measurements during gentamicin therapy 146

xiv
 Title Page

Table 3.3.19a Comparison of the laboratory investigations (WBC 148

and renal function tests)

Table 3.3.19b Comparison of the laboratory investigations 149

Table 3.3.20 Length of hospital stay and treatments 150

Table 3.3.21 Concurrent antibiotics during gentamicin dose 151

Table 3.3.22 Cost of gentamicin dose 152

Table 3.3.23 TDM laboratory equipments needed to run 153

gentamicin monitoring in the year 2005

Table 3.3.24 Cost of TDM reagents and consumables that were 154
needed to run gentamicin assay for the year 2005

Table 3.3.25 TDM team cost 154

Table 3.3.26 TDM materials costs 155

Table 3.3.27 Ward staff cost 156

Table 3.3.28 Cost distribution between Non-TDM and TDM group 157

Table 3.3.29 Distribution of hospitalization costs 158

Table 3.3.30 TDM service cost of HUSM and Hospital Kulim 160

xv
 LIST OF FIGURES

Title Page

Figure 2.1.1 TDM process 8

Figure 2.3.1 Distributions of respondents according to the 33

availability of TDM service and TDM laboratory

Figure 2.3.2 Annual budget to run TDM service 57

Figure 2.3.3 Agencies that run quality assurance program 60

Figure 2.3.4 Hospitals that do not provide TDM service 61

xvi
 LIST OF ABBREVIATIONS

AFB Acid fast bacilli

ASHP American Society of Health-System Pharmacists

BSc Bachelor of Science

0
C Degree Celsius

CAP Community acquired pneumonia

CCU Critical care unit

cm Centimeter

CME Continuous Medical Education

CNS Central nervous system

CPS Clinical Pharmacokinetic Service

CsA Cyclosporine-A

CSF Cerebrospinal fluid

C&S Culture and sensitivity

D5% Dextrose 5%

ELISA Enzyme-Linked Immunosorbent Assay technique

EMIT Enzyme Multiplied Immunoassay Techniques

FPIA Fluorescence Polarization Immunoassay

GLC Gas-Liquid Chromatography

HKL Hospital Kuala Lumpur

HPLC High Pressure Liquid Chromatography

HUKM Hospital Universiti Kebangsaan Malaysia

HUSM Hospital Universiti Sains Malaysia

IC Identity card

ICU Intensive care unit

xvii
I.V. Intravenous route

IU International unit

Kg Kilogram

LOS Length of hospital stay

m Meter

mg/dl Milligram per deciliter

μg/ml Microgram per milliliter

MIC Minimum inhibitory concentration

mmol/liter Millimole per liter

μmol/liter Micromole per liter

MOH Ministry of Health

MPharm Master of Clinical Pharmacy

MSc Master of Science

NS Normal saline

ORL Otolaryngology

pH Measure of the acidity or alkalinity of a solution.

PharmD Doctor of pharmacy

PhD Doctor of Philosophy

pKa The negative log of the acid ionization constant

QA Quality assurance

QC Quality control

RCPA The Royal College of Pathologists of Australia

RIA Radioimmunoassay

RIQAS International External Quality Assessment

RM Ringget Malaysia

xviii
RN Registration number

SPSS Statistical Package for Social Sciences

TDM Therapeutic drug monitoring

TFC Turbulent Flow Chromatography

TR Therapeutic range

UMMC Universiti Malaya Medical Centre

UKNEQAS United Kingdom National External Quality Assessment

Service

WBC White blood cells

xix
 PERKHIDMATAN PEMANTAUAN DRUG TERAPEUTIK DI MALAYSIA:

PRAKTIS SEMASA DAN PENILAIAN KOS

ABSTRAK

Pemantauan drug terapeutik (TDM) telah dikenalpasti sebagai satu alat klinikal yang

berguna dalam terapi drug. Walaupun ia telah bermula sejak tahun 1980an lagi di

negara ini, hanya sedikit sahaja kajian yang telah dilakukan mengenainya. Oleh yang

demikian, kajian ini bertujuan untuk menilai amalan perkhidmatan TDM di hospital-

hospital di Malaysia dan mengenalpasti kos dan hasilan klinikal perkhidmatan ini

dalam pesakit yang dimasukkan ke hospital. Kajian ini terdiri dari dua bahagian yang

berkait rapat. Bahagian pertama mengenalpasti amalan semasa perkhidmatan TDM

dalam hospital-hospital di Malaysia menggunakan borang soal-selidik. Soal-selidik

dihantar kepada 128 hospital di Malaysia. Data yang dikumpulkan termasuk ciri-ciri

umum hospital, aktiviti-aktiviti pentadbiran, klinikal dan makmal berkaitan

perkhidmatan TDM. Dari 121 hospital yang memberikan respon kepada soal-selidik

tersebut, 34 hospital (28.1%) memberikan perkhidmatan itu dengan makmal TDM

mereka sendiri, 44 hospital (36.4%) menggunakan makmal hospital lain dan 43

hospital (35.5%) tidak memberikan perkhidmatan tersebut. Bahagian kedua kajian ini

dijalankan untuk menilai kos menyediakan perkhidmatan TDM di kalangan pesakit

yang dimasukkan ke hospital. Penilaian ini dijalankan di dua buah hospital

menggunakan kaedah pengumpulan data secara retrospektif. Data dari pesakit

dewasa yang dimasukkan ke hospital yang didiagnos bronkopneumonia dan dirawat

dengan gentamisin di antara tahun-tahun 2001 hingga 2005 dikaji. Data yang diambil

dari Hospital Universiti Sains Malaysia (HUSM) digunakan untuk menentukan kos

yang dikaitkan dengan pemberian perkhidmatan TDM tersebut. Data yang dikumpul

xx
dari Hospital Kulim digunakan untuk membandingkan kos dan hasilan antara

kumpulan pesakit yang menerima perkhidmatan TDM (Kumpulan TDM) dan

kumpulan yang tidak menerima perkhidmatan tersebut (Kumpulan Tiada TDM).

Semua kos kemasukan hospital dikira dalam nilai Ringgit Malaysia (RM),

termasuklah perkhidmatan TDM, penyiasatan makmal dan klinikal, dos gentamisin,

kakitangan wad, dan tempoh tinggal di hospital. Ukuran hasilan termasuk tempoh

demam, tempoh tinggal di hospital semasa terapi gentamisin dan kejadian

nefrotoksisiti. Data dari HUSM menunjukkan kos perkhidmatan TDM

menyumbangkan lebih kurang 23% kepada jumlah kos kemasukan hospital. Di

antara kos perkhidmatan TDM, kos alatan makmal adalah yang tertinggi (42%)

diikuti dengan kos reagen dan alatan pakai habis (39.7%), pasukan TDM (9.6%) dan

ruang makmal (8.6%). Data dari Hospital Kulim menunjukkan kos yang dikaitkan

dengan tempoh tinggal di hospital dan jumlah kos kemasukan hospital adalah lebih

tinggi dan signifikan dalam Kumpulan TDM berbanding dengan Kumpulan Tiada

TDM. Walau bagaimanapun, tidak terdapat perbezaan yang signifikan dalam lain-

lain parameter hasilan di antara dua kumpulan tersebut. Sebagai kesimpulannya,

kajian ini menunjukkan bahawa perkhidmatan TDM disediakan oleh kebanyakan

hospital di negara ini. Data dari HUSM menunjukkan perkhidmatan ini dalam

pesakit bronkopneumonia tidak mempengaruhi keseluruhan kos hospital. Data dari

Hospital Kulim pula menunjukkan perkhidmatan ini meningkatkan jumlah kos

kemasukan ke hospital dengan signifikan dan tidak memberikan impak yang

signifikan ke atas hasilan klinikal pesakit.

xxi
 THERAPEUTIC DRUG MONITORING SERVICE IN MALAYSIA:

CURRENT PRACTICE AND COST EVALUATION

ABSTRACT

Therapeutic drug monitoring (TDM) has been recognized as a useful clinical tool in

drug therapy. Although it was started in the 1980s in this country, very few studies

had been performed to evaluate the service. Therefore, this study aims to evaluate the

practice of the TDM service in Malaysian hospitals and to determine the cost and

impact on clinical outcomes of providing this service in hospitalized patients. The

study consists of two related parts. The first part determined the current TDM

practice among government hospitals in Malaysia using a survey questionnaire.

Questionnaires were mailed to 128 hospitals in Malaysia. Data were collected for

general characteristics of the hospitals, administrative, clinical, and laboratory

activities related to TDM service. Out of 121 hospitals which responded to the

survey, 34 hospitals (28.1%) provided the service using their own TDM laboratories,

44 hospitals (36.4%) provided the service using other hospitals’ laboratories and 43

hospitals (35.5%) did not provide the service at all. The second part of this study was

conducted to evaluate the cost and clinical outcomes of providing the TDM service

in hospitalized patients. This evaluation was carried out in two hospitals using

retrospective data collections. Data from all hospitalized adult patients diagnosed

with bronchopneumonia and treated with gentamicin between the years 2001 to 2005

were included. Data collected from Hospital Universiti Sains Malaysia (HUSM)

were used to determine the cost of providing the TDM service. Data collected from

Hospital Kulim was used to compare the cost and outcome between the group which

xxii
was provided with the TDM service (TDM group) with the group which was not

provided with the service (Non-TDM group). All hospitalization costs were

calculated in Ringgit Malaysia (RM), which included TDM service, laboratory and

clinical investigations, gentamicin doses, ward staff, and hospital stay. Outcome

measures included duration of fever, length of hospital stay during gentamicin

therapy and nephrotoxicity incidence. Data from HUSM show that the cost of TDM

service contributed about 23% toward the total hospitalization costs. Among TDM

service costs, the cost of laboratory equipments was the highest (42%) followed by

reagents and consumables (39.7%), TDM team (9.6%), and laboratory space (8.6%).

Data from Hospital Kulim show that the costs of hospital stay and total

hospitalization were significantly higher in the TDM group compared to the Non-

TDM group. However, there was no significant difference in outcome parameters

between the two groups. In conclusion, this study has shown that TDM service is

offered by the majority of hospitals in the country. Data from HUSM show that

providing TDM service to bronchopneumonia patients did not significantly affect the

overall hospital cost. Data from Hospital Kulim show that TDM service significantly

increased the total cost of hospitalization and had no significant impact on patients’

outcome.

xxiii
 CHAPTER ONE

GENERAL INTRODUCTION

1
1.0 GENERAL INTRODUCTION

Therapeutic drug monitoring is used in pharmaceutical services to enhance patient

care. It was first introduced to the clinical practice in the early 1970s. Since the

initiation of this service, different studies evaluating TDM laboratory activities,

studying the impact of the service on patient outcome, surrogate endpoints, and

pharmacoeconomic evaluations have been done worldwide.

TDM service in Malaysia started in 1984 (Hassan, 1990). After more than 20 years

of experience, 73 hospitals are providing the service (Ministry of Health, 2005).

Although it started long time ago in Malaysia, very few studies have been performed

regarding the service. This study has been performed with two main objectives. First

was to identify the current practice of the service in government hospitals in

Malaysia. The second objective was to evaluate the cost and benefits of providing the

service. The study was divided into two parts to achieve each objective separately.

The first part of the study focused on the general provision of the service;

availability, laboratory procedures, and staff activities. It was performed using a

survey methodology. The second part evaluated the impact of this service in one of

the most monitored drugs in Malaysian hospitals on cost and clinical outcome. This

second part was carried out in two different hospitals; one university and one public

hospital. Preliminary findings suggested that patients on gentamicin were always

provided with TDM service in the university hospital. The cost of providing TDM

service was compared to other hospital costs in hospitalized patients with

bronchopneumonia. In the public hospital, not all patients on gentamicin were

provided with TDM service. In this setting, the benefits (in terms of cost and clinical

2
outcome) of providing TDM service to hospitalized patients with bronchopneumonia

were calculated.

3
 CHAPTER TWO

CURRENT PRACTICE OF THERAPEUTIC DRUG MONITORING

SERVICE IN GOVERNMENT HOSPITALS IN MALAYSIA

4
2.1 INTRODUCTION

2.1.1 Therapeutic Drug Monitoring (TDM) service

2.1.1(a) Principles of TDM

Drug concentration in plasma was first analyzed in the late 1950s and early 1960s.

The measurement was initially carried out for the purpose of research rather than for

routine clinical service (Pippenger, 1979). Not until when the pharmacological

activity of a drug was shown to be related to its concentration, did the concentration

measurement were routinely done (Spector, 1988).

Therapeutic drug monitoring (TDM) is based on the assumption that, if there is a

relationship between the concentration of a drug in a biological fluid and its effect,

then the measurement of the biological fluid drug concentrations may be useful for

patient care (Watson, 1997; Potter, 2000; Gross, 2001; Gram, 2001). It is defined as a

measurement made in the laboratory, which is applied to a small group of drugs in

which there is a direct relationship between serum drug concentration and

pharmacological response (Watson, 1997; Schumacher and Barr, 1998).

The range of drug concentrations most commonly associated with optimal effect and

an acceptable incidence of toxicity is called the therapeutic range. Pharmacokinetics

is a mathematical relationship between a drug dosage regimen and the resulting drug

concentrations. Clinical pharmacokinetic is the application of these mathematical

principles in conjunction with other measures of clinical observation (Mackichan and

Comstock, 1986; Nation and Rayner, 2004a). In practice, therapeutic drug

monitoring makes use of the measurement of drug concentration and clinical

pharmacokinetics to manage patient drug therapy.

5
2.1.1(b) Clinical applications of TDM

There are many applications of TDM in clinical setting. TDM is used to evaluate the

degree of therapeutic response, provide useful information regarding the

appropriateness of drug therapy, evaluate for patient compliance with drug regimen,

detect suspected adverse effects, and to confirm drug toxicity (Shirrell, 1999; Gross,

2001; Pippenger, 2006). It is also useful in confirming drug interactions, diagnosis of

overdosed patients, and mainly dosage adjustment (Spector et al., 1988).

Very old and very young patients and patients with abnormal organ functions, such

as renal or hepatic impairments exhibit variation in drug pharmacokinetics. Because

of these wide variabilities, TDM is a useful tool in dosage individualization in these

patients (Walson, 1998).

In general, patients that may need to be monitored by TDM service include patients

with the following characteristics and conditions; renal impairment, hepatic

impairment, history of hematological abnormalities, marked cardiac dysfunction,

severe airway disease, diabetes mellitus, obstetric problem, on dialysis, elderly

patients, children and neonates, obese and malnourished, and burn patients. Those

patients who receive drugs that have narrow therapeutic index, high incidence of

adverse effects, high incidence of drug interactions, drugs that may induce reactions

or hypersensitivity, or newly marketed drugs can also be included (Malaysian

Ministry of Health, 2001).

6
2.1.1(c) TDM process

The TDM team includes clinical pharmacologists, clinical pharmacists and analytical

scientists as well as other personnel who participate in patient care such as doctors

and nurses (Gross, 2001; Shenfield, 2001). Doctors usually request TDM tests for

specific patients according to some specific indications. The nurse is responsible for

collecting the blood samples for analysis. Performing the TDM tests is mainly a

responsibility of the analytical scientist or technician who is well trained and

qualified for this process. After performing the tests and obtaining the results, the

clinical pharmacologist or pharmacist interprets these results and converts them into

useful information and recommendations to the requested doctor (Koren et al., 1985;

Gross, 2001).

Figure 2.1.1 shows a TDM process adapted from Barr and Schumacher (1995). The

TDM process consists of four main components that begins and ends with patient

care; pre-analytical, analytical, post-analytical, and the regulatory environment.

Regulatory environment is the condition and atmosphere that surrounds the

analytical procedure. The pre-analytical component consists of 4 steps; the first step

starts with the clinical question that arises when the clinician comes across the

patient. In the next step, the clinician chooses the test(s) that might answer this

question. The clinician orders the test in the third step. At the end of this component,

the sample is taken and sent to the clinical laboratory for analysis.

7
 Regulatory Environment

Analytical

1. Sample 2. Analysis 3. Result

prepared performed verified

4. Specimen 1. Result
collected reported P
P o
r s
e t
a 3. Test 2. Clinical
a
n ordered answer n
a a
l l
y y
t t
i 2. Test 3. Action
selected i
c taken
c
a a
l l

1. Clinical 4. Effect on
question patient care

Patient
Care

Figure 2.1.1 TDM process (adapted from Barr and Schumacher, 1995)

The second component, which is the analytical component, consists of three steps.

The first step is the sample preparation, which consists of transporting the sample to

the analysis site and separation of serum or plasma from cellular blood to prepare it

for analysis. The second step is performing the analysis using an appropriate assay

technique. The third step in this component is to verify the drug analysis result.

8
The third component has four steps. The first step is reporting the result by either

hard or soft copy or both. In the second step, this result is expected to give an answer

for the previous clinical question raised in the first component. In the last two steps

of this component, the clinician can take action accordingly to meet the patient care

needs.

2.1.1(d) Sample matrices

Usually drugs are monitored in venous blood, serum or plasma. Whole blood may be

used for some drugs like cyclosporine, tacrolimus, sirolimus, and everolimus which

distribute between erythrocytes and plasma (Gross, 2001; Dasgupta, 2008). Saliva

can be used instead of blood in case of infants and children (Zalzstein et al., 2003).

In addition, saliva can be used in the elderly and pregnant women and sometimes in

adult patients when venipuncture is difficult. It can be easily collected and preferred

by the medical staff as it minimizes their contact to blood samples (Barr and

Schumacher, 1995). Drugs that can be monitored using saliva are phenytoin,

carbamazepine, theophylline, digoxin, and lithium. In addition, drugs of abuse such

as morphine and cocaine can also be monitored by saliva (Pichini, 1996).

Using urine as a biological matrix for drug monitoring has many advantages. Urine

samples can be easily collected and are well accepted by patients. Moreover, urine is

preferred because its window for identifying drug use is broader compared to blood.

The use of urine in TDM service is applicable to anticonvulsant and psychoactive

drugs (Elmquist, 1991; Wu, 1998).

9
There are some other biological matrices that can be used but to a lesser extent such

as tears, which can easily be collected. It seems to be more homogenous and more

constant in their composition than saliva. Due to its pH, only unionized and acidic

drugs with high pKa values distribute in tears in a predictable manner, which limits

its use to small variety of drugs like valproic acid (Pichini, 1996; Nakajima et al.,

2000).

Hair as a biological matrix can keep drugs and metabolites indefinitely, in contrast to

serum or urine in which drug concentrations decrease rapidly with time. Therefore,

hair can be used for forensic purposes as well as in drugs of abuse. Hair testing has

some drawbacks due to the difficulty in producing reference material for laboratory

practices and to the differences in hair characteristics from one patient to another.

Similar to hair, nails are used in drug abuse and forensic examination. Moreover,

they can be used in antifungal drugs monitoring. Recently, sweat is being used for

determination of drugs of abuse although sampling procedure and method of analysis

are very complicated (Pichini, 1996; Palmeri et al., 2000; Pragst and Balikova,

2006). Moreover, sweat is another biological matrix that can be used in forensic

examination for detection of drugs of abuse. It can be used in nonvolatile drugs like

heroin. The sampling procedure is an easy process, which applied by using sweat

patches. It is a noninvasive procedure, requires minimal handling by the operator and

is acceptable by patients (Fucci and Giovanni, 2007).

Many studies that are conducted for bile measurement were carried out for patients

who have previously undergone biliary tract surgery. Penicillins, cephalosporins,

aminoglycosides, and cardiac glycosides are some drugs that have been determined

10
using bile analysis. Feces are limited to studies in new drug development and may

provide information on excretion of drugs and metabolites through its route of

excretion (Pichini, 1996).

Fetus blood and amniotic fluid can be used for detecting of drugs that can affect the

fetus such as some antibiotics, anticonvulsants and tranquillizers. Additionally, the

importance of drug investigation in breast milk is to determine the amount of drug

that can be ingested by the breastfeeding infant. Phenobarbital, theophylline, and

some psychoactive drugs as well as drugs of abuse might be detected in breast milk

(Pichini, 1996; Loebstein and Koren, 2002; Moretti et al., 2003).

Drug measurement in cerebrospinal fluid (CSF) is necessary to establish if the

concentration of a drug in the central nervous system (CNS) is desirable for the drug

effect or not. Collection of CSF is not an easy technique since it is done by lumbar

puncture. Examples of drugs that are monitored by CSF measurement are antibiotics

that are used in CNS infections, anticonvulsants, psychoactive drugs, and protease

inhibitors (Pichini, 1996; Aarnoutse et al., 2001).

Monitoring of drugs in bronchial secretions and peritoneal fluid are rarely used. They

are used for patients with serious diseases and require invasive techniques for sample

collection. Using interstitial fluid as a biological matrix in neonates may provide

information regarding the toxic agents that may be absorbed through the skin. It can

be used for analgesics and theophylline that may be applied transdermally. Drug

concentration monitoring in cervical mucus is mainly carried out for

pharmacotoxicological purposes. For example, it is used to detect the presence of

11
nicotine and its metabolite in the cervix due to its risk of cervical neoplasia.

Examining the seminal fluid is used to determine the presence and concentrations of

some drugs that may affect the physiology or activity of semen in man as well as the

pharmacological and adverse drug reaction in women exposed to drugs excreted in

semen. Drugs like antimicrobials, sulfasalazine, salicylate, propranolol, and protease

inhibitors are monitored in the seminal fluid (Pichini, 1996; Aarnoutse et al., 2001).

2.1.1(e) Analytical techniques used in TDM

In the late 1950s and early 1960s, Ultraviolet Spectrophotometry was the first

method applied for the analysis of drug concentration in the plasma but it has some

disadvantages. It required large volume samples as well as extraction techniques

were time consuming and complex. It is considered as the most used technique for

the determination of methotrexate (Pippenger, 1979; Rubino, 2001).

In the middle of 1960s, Gas-Liquid Chromatography (GLC) was introduced as a

method of separating classes of drugs rapidly and quantitatively at the same time but

its main disadvantage was the complexity of its instrumentation. In 1970s, GLC was

performed routinely in clinical chemistry laboratories and it is used to measure the

concentrations of some antidepressant drugs (Pippenger, 1979; Lacassie et al., 2000).

Radioimmunoassay (RIA) technique was the first immunoassay technique that is

used in drug monitoring. It has an advantage that it can measure drug concentration

in microvolumes. It has some disadvantages of complexity of its instrumentation as

well as time consuming procedure, disposal of radioactive waste, and short shelf-life

12
of its reagents. It can be used to detect digoxin (Pippenger, 1979; Barr and

Schumacher, 1995).

An automated, homogeneous Enzyme Immunoassay Techniques (EMIT) was

available in 1970s which enables TDM service to be available to all laboratories.

However, it is limited to those drugs for which antibodies are available. It uses a

simple technology and has rapid turnaround time with a high accuracy rate. Enzyme-

Linked Immunosorbent Assay technique (ELISA) has almost the same technique as

other enzyme immunoassays. Separation steps are required for completing the

analytical procedure and that is why ELISA is called a heterogeneous method.

Besides, it is limited to those drugs that antibodies are available (Pippenger, 1979;

Sym et al., 2001).

High Pressure Liquid Chromatography (HPLC) solves a lot of problems regarding

the assay of multiple drugs and their metabolites within the same class. It can be

applied for many drugs but it has the disadvantages associated with the high

turnaround time and that highly skilled personnel are needed to perform the

procedures (Pippenger, 1979; Barr and Schumacher, 1995; Jebabli et al., 2007).

However, it is used to some extent in teaching hospitals and for research purposes

(Gogtay et al., 1999). In the late 1990s, Turbulent Flow Chromatography (TFC) a

new chromatographic technique was introduced. It is a fully automated and simple

technique. It requires short time for sample preparation and analysis. Mainly it is

used for monitoring antidepressant drugs and their metabolites (Sauvage et al.,

2006).

13
Fluorescence Polarization Immunoassay (FPIA) is now the most widely used

technique worldwide. It is easy to perform, does not need highly skilled personnel

and has shorter turnaround time. Like other immunoassay techniques, measuring

serum drug concentration is based on an antigen-antibody reaction. FPIA technique

has some drawbacks such as in some drugs like cyclosporine, where metabolites

interfere with the reagents’ antibodies; and the high cost of its reagents used in the

drug analysis (Lee et al., 1991; Morris, 1994; Barr and Schumacher, 1995; Sym et

al., 2001). Other techniques that are rarely used in TDM service include Flame

emission/absorption methods. These method are used to measure the concentration of

drugs like lithium (Thomson et al., 1998).

2.1.1(f) Drugs monitored and sampling time

Drugs monitored by TDM service share some characteristics either they have

relatively narrow therapeutic range (TR), or a conventional dose response

relationship is deficient (Cuddy, 2000). Others have pharmacological action that is

difficult to be measured clinically (McInnes, 1989). Wolf (1996) has proposed the

criteria for drugs that should be monitored by TDM service. They include drugs with

dangerous toxicity, have narrow therapeutic range, are used in long term therapy, are

used in life threatening disease, have interindividual pharmacokinetic variability,

drugs with nonlinear pharmacokinetics, drugs with wide distribution in the body, and

the availability of reliable analytical techniques to measure the drug’s concentration.

Ideally, the drug should be monitored only when it reaches steady state. However,

plasma concentration can be measured before steady state in some cases, but still

sampling time should be taken into consideration. Sampling time varies with

different drugs. To optimize the drug concentration values, blood samples should be

14
taken at specific times with respect to the last dose taken. Usually drugs are

measured just before the last dose (trough level). Aminoglycosides and vancomycin

are measured at the trough level and the peak (after giving the last dose) level

(Aronson and Hardman, 1993b).

Aminoglycosides like gentamicin (TR peak = 4-8 µg/ml, TR trough = 1-2 µg/ml),

amikacin (TR peak = 15-25 µg/ml, TR trough < 5 µg/ml), and tobramycin (TR peak

= 4-8 µg/ml, TR trough =1-2 µg/ml), have the same characteristics and they all have

a narrow therapeutic index. Moreover, their mechanism of action depends directly on

the peak drug concentration in the serum, while the ototoxicity and nephrotoxicity

are related mainly to the total amount of drug given. TDM may be useful in keeping

the aminoglycosides within the therapeutic range while avoiding toxicity (Triggs and

Charles, 1999; Dasgupta, 2008). If the drug is given by IV infusion, the sample

should be taken after 15 minutes at the end of the infusion for post-therapy

measurement. In case of pre-therapy measurement the sample should be taken just

before the next dose. In patients with normal renal function, gentamicin

concentration measurement should be carried out within the first 24 hours of

treatment to optimize drug therapy (Aronson and Reynolds, 1993a).

Vancomycin (TR peak = 30-40 µg/ml, TR trough = 5-15) has almost the same side

effects as aminoglycosides. But it has a different mechanism of action with a so

called time-dependent killing, which works better when its trough concentration in

the site of infection is higher than the minimum inhibitory concentration (MIC) of

the infected organism. Its concentration-independent mechanism has raised

considerable arguments regarding the benefits of measuring the vancomycin

15
concentration. However, not all patients with vancomycin require concentration

monitoring. The peak level of vancomycin should be taken within half to one hour

after completing the one hour infusion to allow the completion of the distribution

phase (Begg et al., 1999; Bauer, 2001; Dasgupta, 2008).

Anticonvulsants like phenytoin (TR= 10-20 µg/ml), phenobarbital (TR= 15-40

µg/ml), valproic acid (TR= 50-100 µg/ml), ethosuximide (TR= 40-75 µg/ml), and

carbamazepine (TR= 4-12 µg/ml), are generally monitored in plasma or serum

because the concentrations are identical in these two biological matrices (Eadie,

2001; Dasgupta, 2008). Phenytoin lacks a predictable dose-response relationship, and

serum drug concentration measurement has proved to be a better indicator of clinical

response (Cuddy, 2000). The concentration of phenytoin should be measured after a

few days of starting the treatment but practically, the concentration is measured after

three to four weeks of continuous dosing (Aronson et al., 1993a). Other drugs also

should be monitored when they reach steady states. For example, phenobarbital is

monitored after 3-4 weeks, carbamazepine after 2-3 weeks and valproic acid on the

second day. However, patients should be monitored in case of worsening of epilepsy

or when they have signs of drug toxicity (Bauer, 2001).

Theophylline (TR= 10-20 µg/ml) shares the same criteria of lacking a predictable

dose response relationship. Theophylline concentrations may provide diagnostic and

predictive information about therapy in overdose cases (Cuddy, 2000; Dawson and

Whyte, 2001; Dasgupta, 2008). In case of IV infusion, the sample should be taken

after 4-6 hours of infusion; the infusion should be stopped for 15 minutes before

taking the sample (Aronson et al., 1993b).

16
Monitoring of digoxin (TR= 0.8-2.0 ng/ml) can be useful in controlling the

therapeutic or toxic effect. Steady state of digoxin can be reached, in case of normal

renal function, after eight days of treatment. Digoxin sampling may be carried out at

least six hours after the last dose or just before the next dose (Cuddy, 2000; Aronson

and Hardman, 1993a; Dasgupta, 2008).

The narrow therapeutic ratio along with the variation in the pharmacokinetics of

immunosuppressant drugs such as cyclosporine (TR= 100-400 ng/ml), tacrolimus

(TR= 5-15 ng/ml), sirolimus (TR= 4-20 ng/ml), everolimus (TR= 5-15 ng/ml), and

mycophenolic acid (TR= 1-3.5 µg/ml) from one person to another highlighted the

importance of individualizing the drug therapy using TDM service. TDM service is

useful to avoid the rejection of the transplant organ in case of the subtherapeutic

levels and to prevent the toxic effects of the drug in case of drug overdose.

Cyclosporine sample should be taken before the next dose (Reynolds and Aronson,

1993; Dasgupta, 2008).

Lithium (TR= 0.8-1.2 µEq/l) has a narrow therapeutic ratio and its pharmacokinetics

vary from one patient to another. This makes it difficult to accurately predict the

dosage regimen of this drug. Lithium samples should be taken after 12 hours from

the last dose (Aronson and Reynolds, 1993b; Dasgupta, 2008).

Because of their potential toxicities, serum concentration of drugs like salicylates,

ethanol and paracetamol are monitored in some hospitals in all patients who are

presented with mental problem (Wu, 1998). Paracetamol should be monitored in all

patients who ingested large amount or unsafe dose of the drug. Due to high

17
variability in its pharmacokinetics and metabolic profile in children and neonates,

paracetamol should be monitored to avoid the subtherapeutic and toxic

concentrations. Paracetamol sample should be taken at least 4 hours after ingestion of

the drug (Dawson and Whyte, 2001; Oliveira et al., 2002).

Other drugs that are also monitored by TDM service include amiodarone (TR= 1-2.5

µg/ml), quinidine (TR= 2-5 µg/ml), procainamide (TR= 4-10 µg/ml), and lidocaine

(TR= 1.5-5 µg/ml), methotrexate (TR> 0.01 µicromol), caffeine (TR= 5-15 µg/ml),

disopyramide (TR= 1.5-5 µg/ml), and some antituberculin drugs (Gogtay et al.,

1999; Baylor, 2007; Dasgupta, 2008).

18
2.1.2 Literature review of TDM service

TDM service is a widely used clinical service all over the world. However, among

hospitals and institutions which provide this service there are variations in the

availability, number and source of samples, analytical and clinical activities,

participation in quality assurance programs, and educational programs offered.

2.1.2(a) TDM service in developed countries

In Australia TDM service was started in the late 1970s and the early 1980s

(Shenfield, 2001). Although TDM service started a long time ago, there are still

many hospitals that do not provide this service while others provide it partially with

the assistance of other institutions. However, until the late 1990s, about 75% of

hospitals in Australia provided TDM service. About 65% of these hospitals perform

drug assay measurements in their own laboratories (Morris, 1998). A survey

performed by Morris (1994) looking at cyclosporine-A (CsA) monitoring, reported

that 93% of TDM laboratories in Australia perform more than 500 CsA tests

annually; 10% of these tests were received from external sources rather than the unit

that offer the analysis. Most of these laboratories were not included in external

quality assurance programs. They use different types of reporting procedures

included phone calls, online computer system, and face-to-face communications

(Morris, 1994). The number of cyclosporine-A samples that monitored in these

laboratories increased up to 12770 samples in the year 2000, while the number of

laboratories that registered in the International Proficiency Testing Scheme increased

to 71% (Morris and Lam, 2002).

19
In Spain, TDM service was started in 1980. The majority of TDM units in the

country began their services in the biochemistry department. The biochemistry

department provides the results while the central pharmacology unit in the hospital

provides the recommendations to the doctors. Vall d’Hebron is a public institution

that covers four main hospitals and receives samples from other outpatient clinics

with an average of 8800 tests performed in 1990. The service is available for 12

hours daily, Mondays through Fridays except for emergency and some specific cases

that had to be performed during weekends. Drugs monitored by the TDM service are

anticonvulsants, aminoglycosides, vancomycin, theophylline, and cyclosporine (Pou

and Campos, 1992).

In the Netherlands, TDM service started in the early 1980s. It is performed mainly by

the hospital pharmacist and it is a part of the pharmacy department in hospitals.

Vinks et al. (1992) reported that in The Hague Hospitals Central Pharmacy

incorporated many different pharmaceutical services including TDM service. This

centre performs the TDM service for all participating local hospitals in the area for

an average of 12000 samples carried out each year. The service is available seven

days a week and operates 24 hours daily. The most common drugs monitored are

aminoglycosides and theophylline (Vinks et al., 1992).

Murphy et al. (1996) reported that the TDM service first started in USA in the 1970s.

TDM service was available during the daily working hours, Mondays to Fridays in

most hospitals. Twenty four hours-a-day services and on-call services were available

in a few hospitals only. Aminoglycosides, vancomycin, theophylline, and

cyclosporine, digoxin, antiepileptic drugs, lithium, methotrexate, caffeine,

20
ethosuximide, warfarin, and procainamide are the common drugs monitored by the

TDM service. TDM pharmacists participated in continuous educational programs to

increase their skills and competence (Murphy et al., 1996).

In the state of Georgia, TDM service was available in 23.3% of hospitals. TDM

laboratory was a part of the pharmacy department in 93% of the hospitals. Drugs

monitored were aminoglycosides, vancomycin, theophylline, cyclosporine, digoxin,

antiepileptic drugs, lithium, methotrexate, warfarin, and procainamide. An average of

1000 samples was performed annually in some hospitals (Murphy et al., 1991).

Howard et al. (1994) found that 70% of all veterans affairs medical centre in USA

provided TDM service. The majority (82%) of hospitals started providing the service

within the last nine years before this survey. However, more than half (68%) of

hospitals in veterans affairs started providing the service since 1990. In a recent

national survey, Pedersen et al. (2000) reported that 75% of hospitals in USA

provide TDM service for inpatients. The pharmacists in these hospitals routinely

provided recommendations for adjusting and calculating the dosage for those drugs

that are monitored in their hospitals.

In Japan, TDM service started in Kyushu University Hospital in 1981. The pharmacy

department provides the service within their own TDM laboratory which is located in

the hospital. An average of 4350 requests was performed annually in the unit. The

sources of these samples were mainly from inpatient and outpatient clinics.

Antiepileptics, aminoglycosides, theophylline, digitals, lithium, methotrexate, and

disopyramide were the most common drugs monitored by the unit (Ieiri et al., 1990).

21
In Canada, TDM service started in the Hospital of Sick Children in 1981. The TDM

laboratory was managed by a clinical pharmacist of the clinical pharmacology

division. The service was available seven days a week, 24 hours a day. Thirteen

different drugs (antibiotics, cardiovascular drugs, anticonvulsants, theophylline, and

methotrexate) were monitored daily in the hospital, with an average of 19200

samples performed yearly. It was found that the service had an impact of decreasing

the toxic level of drugs monitored (Koren, 1985).

A survey of 157 TDM laboratories, mainly from Europe, Asian and African

countries found that different reporting procedures were used in these laboratories.

They ranged from producing hard copy reports, phone calls, and fax, to using online

computer reporting. Some of these laboratories reported that insufficient information

in the TDM request form was the main problem faced by the TDM service (Thomson

et al., 1998).

2.1.2(b) TDM service in developing countries

In Iran, TDM service first started in 1984 at the Tehran University of Medical

Sciences Hospital. Drug samples were analyzed at their own TDM laboratory, which

was located in the hospital. Samples were received from their own hospital

departments as well as from other clinics and neighboring hospitals. Phenobarbital

and phenytoin were the first drugs monitored by the TDM unit. Many other drugs

were included later on to be monitored by the service (Bigdeli, 1992).

TDM service was started first in Turkey in the late 1980s by the Pharmacology

department in Istanbul Medical Faculty Hospital. Eighty-four percent of the samples

22
came from their hospital departments and 16% came from other hospitals. More than

5500 tests were monitored annually by the TDM unit. Drugs monitored were

antiepileptics, digoxin, theophylline, and salicylates (Yamantürk et al., 2000).

In South Africa, Cridland (1994) reported that TDM service was performed mainly

by the pharmacology and biochemistry departments of the Groote Schuur Hospital

(1470 beds). They performed about 20,300 samples annually. Seventy percent of

these samples came from the hospital departments while the rest came from other

medical institutions. Common drugs monitored by the hospital included theophylline,

digoxin, antiepileptics, and cyclosporine.

In developing countries like Saudi Arabia and Egypt, evaluation of TDM service has

been performed. Desoky et al. (2003) evaluated the impact of TDM service on the

distribution of the drug concentrations. They found no differences in the rates of

subtherapeutic, therapeutic or toxic drug levels for digoxin, carbamazepine,

phenytoin, and valproic acid between the two countries.

2.1.2(c) TDM service in Malaysia

Malaysia is located in South East Asia with an area of 329,750 square kilometer. It

has a population of 23,953,136 (Information Centre Malaysia, 2005). The first TDM

service in Malaysia was offered by the School of Pharmaceutical Sciences in the

Hospital Universiti Sains Malaysia (HUSM) in the year 1984 (Hassan, 1993).

Gentamicin was the first drug monitored by TDM service in HUSM (Ismail, 1990).

Commonly monitored drugs in HUSM were paracetamol, aspirin, theophylline,

23
aminoglycosides, vancomycin, antiepileptic drugs, digoxin, chloroquine, mefloquine,

and procainamide (Hassan, 1990).

In 1987, only four hospitals provided the TDM service. The number of hospitals that

provided the service increased to 9, 20, 61, and 73 in the years 1988, 1992, 2002, and

2005 respectively. Fourteen drugs are regularly monitored in government hospitals,

which include aminoglycosides, antiepileptics, digoxin, theophylline, cyclosporine,

methotrexate, tacroloimus, vancomycin, and lithium. The total number of cases

monitored increased from 25,756 in 1998 to 61,907 in 2005 (Ministry of Health,

1988, 1992, 2002a, 2005a).

24