International Journal of Clinical Medicine, 2013, 4, 331-342
http://dx.doi.org/10.4236/ijcm.2013.48059 Published Online August 2013 (http://www.scirp.org/journal/ijcm)
331
Therapeutic Drug Monitoring of Chelating Agent
Deferoxamine for β-Thalassemia Major Patients
Rawa Ratha1, Tagreed Altaei2*
1Department of Clinical Pharmacy, College of Pharmacy, Sulaimany University, Sulaimany, Iraq; 2Department of Pharmacology and
Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq.
Received May 24th, 2013; revised June 25th, 2013; accepted July 9th, 2013
Copyright © 2013 Rawa Ratha, Tagreed Altaei. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Purpose: Therapeutic drug monitoring is used to prevent or decrease the risk associated with the toxic effects of medi-
cation. This study aims to evaluate the potential advantages of Therapeutic Drug Monitoring (TDM) of subcutaneous
Deferoxamine injection and prevention of clinical problems in β-thalassaemia major patients. Patients & Methods:
Fifty-four thalassemia patients were allocated into two groups; missing, and not missing deferoxamine dose. TDM of
Deferoxamine injection and its clinical outcomes were critically studied under the following subheadings: assessment of
the adequacy of Deferoxamine usage, serum peak and trough concentrations of Deferoxamine and ferroxamine with
needed pharmacokinetics, cardiac parameters and biomarkers, biochemical and hematological indices, adverse effects/
toxicity, urinary assessment of Fe, Zn, selenium, and copper levels, compliance to treatment, dose adjustment in corre-
lation to therapeutic index and life style. Results: Demographic data showed no significant difference. Peak plasma
concentrations were 144.83 ± 69 and 43.54 ± 39.16 µg/L, while trough concentrations were 33 ± 26.32 and 31.13 ±
21.58 µg/L of Deferoxamine and ferroxamine, respectively. The elimination rate constant was 0.0237 ± 0.00029 min−1,
half-life was 34 min, and distribution volume was 0.93 ± 0.078. Although cardiac parameters showed no significant
differences, there were significant differences in CK-MB, and hsCRP levels; troponin I value could not be detected.
Biochemical and hematological studies showed significant differences in Ferritin B, urea, SGPT, SGOT, alkaline phos-
phatase, serum albumin and serum calcium. Assessment of adverse effects/toxicity showed significant differences. The
correlation of serum ferritin to therapeutic index, and the life style including Vitamin C and/or E administration were
assessed for the compliance to treatment. Conclusion: Therapeutic monitoring of chelation therapy by Deferoxamine in
β-thalassemia patients is necessary to ensure effective treatment, compliance, and to avoid adverse side effects and tox-
icity.
Keywords: Therapeutic Drug Monitoring; Deferoxamine; β-Thalassemia Major
1. Introduction
Therapeutic drug monitoring involves not only measur-
ing drug concentrations, but also the clinical interpreta-
tion of the result. This requires knowledge of the phar-
macokinetics, sampling time, drug history and the pa-
tient’s clinical condition [1].
Homozygotes for beta-thalassemia may develop either
thalassemia major or thalassemia intermedia. Thalasse-
mia major patients come to medical attention within the
first 2 years and require regular blood transfusion to sur-
vive. Differentiation of thalassemia major from thalas-
semia intermedia at presentation is a difficult and critical
issue that should be strongly pursued [2].
Iron overload occurs when the intake of iron is in-
creased over a prolonged period of time and is commonly
seen in patients with beta-thalassaemia major, who re-
ceive frequent blood transfusions. The iron excess is ini-
tially stored in thereticuloendothelial system (which has a
capacity of about 10 - 15 g), and then in all parenchymas
[3], resulting in life-threatening complications, namely
cardiopathy, liver and endocrine dysfunction and reduced
patient’s survival. The damage is characterized by exces-
sive iron deposition. Without adequate iron chelation
therapy, almost all patients with beta-thalassemia will
accumulate potentially fatal iron levels [4].
Particular attention has been directed to the early di-
*Corresponding author.

Therapeutic Drug Monitoring of Chelating Agent Deferoxamine for β-Thalassemia Major Patients
332
agnosis and treatment of cardiac disease because of its
critical role in determining the prognosis of individuals
with β-thalassemia. Assessment of myocardial siderosis
and monitoring of cardiac function combined with inten-
sification of iron chelation can result in excellent long-
term prognoses [5-7].
The most common secondary complications are those
related to transfusional iron overload, which can be pre-
vented by adequate iron chelation. After 10 to 12 trans-
fusions, chelation therapy is initiated with Deferoxamine
(DFO), which is derived from ferrioxamine B, a sidera-
mine isolated in 1960 from Streptomyces pilosus. It has a
high binding affinity for trivalent iron, which can be ex-
ploited to clinically remove excess iron from blood and
tissue [8]. It is administered five to seven days a week from
12-hour continuous subcutaneous infusion via a portable
pump. Recommended dosage depends on the individual’s
age and the serum ferritin concentration. The dose may
be reduced if serum ferritin concentration is low. Defer-
oxamine therapy prevents the secondary effects of iron
overload, resulting in a consistent decrease in morbidity
and mortality [9]. The advantages of DFO are its high
affinity for ferric iron, high efficiency in attaining nega-
tive iron balance and absence of iron redistribution. Its
disadvantages are that it is not orally bio-available, fast
rate of metabolism necessitating prolonged parenteral in-
fusions, poor compliance, chelates zinc (sometimes caus-
ing clinical zinc deficiency) and high cost. Ascorbate re-
pletion (daily dose not to exceed 100 - 150 mg) increases
the amount of iron removed after DFO administration
[10].
The primary signs of chelator toxicity are hearing loss,
temporary loss of sight, cataracts, renal dysfunction,
growth failure, and symptoms related to iron deficiency,
(which may occur when total body iron is low but high
doses of Deferoxamine are still being administered [11],
and rarely, renal impairment and interstitial pneumonitis.
DFO administration also increases susceptibility to Yer-
sinia infections. The major drawback of DFO chelation
therapy is low compliance resulting from complications
of administration [12]. In addition to that, many trace
metals are decreased, including selenium, zinc, and cop-
per etc. [13].
Iron chelation is essential for patients with transfusion-
dependent anemia, who inevitably develop iron overload
and the risk of life-threatening end organ damage. The
heart, along with liver and endocrine glands, is one of the
main organs where iron deposition causes severe com-
plications [10].
In clinical practice, the effectiveness of DFO chelation
therapy is monitored by routine determination of serum
ferritin concentration. However, serum ferritin concen-
tration is not always reliable for evaluating iron burden
because it is being influenced by other factors, the most
important being the extent of liver damage [12]. Lack of
response of an individual may result from inadequate
dosing, high transfusion requirement, poor treatment ad-
herence, or unfavorable clinical pharmacology of the che-
lation regime [14].
The indications for therapeutic drug monitoring have
widened to include efficacy, compliance, toxicity avoid-
ance, and therapy cessation monitoring [15]. A straight-
forward relationship between administered dose, serum
concentration, clinical outcome, or adverse effects is of-
ten lacking. Nowadays, the focus lies in therapeutic drug
monitoring and individualized therapy to find adequate
treatment, to explain treatment failure or non-response,
and to check patient compliance. However, extensive re-
search in this field is still mandatory [11].
This study aimed to evaluate the potential advantages
of TDM of chelating agent; subcutaneous Deferoxamine
injection as part of medical treatments and prevention of
clinical problems in β-thalassaemia major patients. The
TDM assessment will be performed by determining the
following: adequacy of Deferoxamine dose response, car-
diac variables and biomarkers, biochemical and haema-
tological tests, adverse effects/toxicity (systemic and to-
pical) with urinary elements excretion, and patients’ com-
pliance to Deferoxamine treatment.
2. Patients & Methods
This study was a prospective, single-center investigation
carried out in Sulaimani Thalassemia Center/Kurdistan
Iraq, for the standard maintenance chelation monother-
apy of subcutaneous Deferoxamine (20 - 50 mg/Kg/day),
over 8 - 12 h administer at home. The study included 54
patients with β-thalassemia major, allocated to two groups;
missing Deferoxamine dose versus non-missing dose, be-
tween March 2012 and February 2013. Inclusion criteria:
Major β-Thalassemia patients that are regularly blood
transfused and used subcutaneous Desferroxamin injec-
tion as an iron chelator. And those patients willing to par-
ticipate in this study aging between 5 - 43 years old in
both genders. While, exclusion criteria were: Patients who
are shifting between Desferroxamin injection and De-
ferasirox tablet, pregnancy or expected pregnancy within
six months, lactation, presence of active infection, his-
tory of tuberculosis, HIV, hepatitis B or C, severe pan-
creatitis (necrotizing pancreatitis or pancreatitis leading
to multi organ failure), malignancy, ongoing treatment
with other chelating agents, bone marrow suppression,
and any inflammatory or infectious disease that induced
high false serum ferritin levels. The Scientific and Re-
view Board at the College of Pharmacy/Hawler Medi-
cal University approved the study protocol, and all par-
ents or patients provided written informed consent, in ac-
cordance with the Declaration of Helsinki.

Therapeutic Drug Monitoring of Chelating Agent Deferoxamine for β-Thalassemia Major Patients
333
The TDM assessment was performed as discussed un-
der the following subheadings.
2.1. Adequacy of Deferoxamine Dose Response
Performed by Short Hospital Admissions
The drug was infused via a thin needle inserted subcuta-
neously and connected by an infusion line to a portable
battery electrical device. Five ml of distilled water was
added to a bottle containing 500 mg of Deferoxamine
powder and shook well to make (10%) 5 ml clear solu-
tion. The infusion continued for 8 - 10 h and was given 5
- 7 times per week at a mean daily dose of 20 - 50 mg/kg
body weights. The dose of Deferoxamine was adjusted
according to body iron (serum ferritin level) and age.
Dose adjustment was made with reference to the serum
ferritin level using the therapeutic index (Porter JB. 1989);
the aim was to keep the index 0.025 constant at all time.
Obtaining prospective pharmacokinetic (PK) data; peak
and trough concentrations of deferoxamine and ferrox-
amine using HPLC (Shimadzu, Koyota, Japan) analysis
method, with needed pharmacokinetics; rate of elimina-
tion (Ke), half-life (t1/2), and volume of distribution (Vd),
in addition to the data concerning administrating both
groups of patients, that is missing drug dose versus non-
missing dose was the main objective of this research.
2.2. Cardiac Variables and Biomarkers
Cardiac variables determine are heart rate, systolic and
diastolic B.P, ejection fraction, and mild dilated right
ventricular) while biomarkers include Troponin I (VI-
DAS® TROPONIN l ULTRA “TNIU”), Ck-MB (VI-
DAS® CK-MB), and high sensitive CRP (i-CHROMA™
hs CRP)].
2.3. Biochemical and Hematological Tests
This was performed by measuring serum ferritin, serum-
creatinine, blood urea, SGPT, SGOT, alkaline phosphate,
total serum bilirubin, serum albumin, serum calcium,
WBC, and platelets using SIEMENS ADVIA centaur®,
FLEXOR equipment (which istype EL 200 automatic
close system).
2.4. Adverse Effects/Toxicity
This was evaluated by closely monitoring patient for any
systemic and topical adverse effects or toxicity from
treatment, and by 24-h urine sample collection for meas-
uring the urinary Fe, Zn, selenium, and copper elements
excretion levels; using inductive coupled plasma-Optical
emission spectrometer (ICP-OES) by Perkin Elmer (mo-
del Optima 2100 DV).
2.5. Patients’ Compliance to Deferoxamine
Treatment
In addition to the above tested parameters evaluated, re-
lationship of dose treatment to serum ferritin and thera-
peutic index were also evaluated. Lifestyle, including ad-
ministration of tea, and Vitamin C and/or E was as well
determined.
3. Statistics
Data were analyzed using the statistical package for so-
cial sciences (SPSS version 17). Student t-test of two in-
dependent samples was used to compare between means,
while Chi-square test of association was used to compare
between proportions, p ≤ 0.05 was considered as statisti-
cally significant.
4. Results
4.1. Demography
Fifty-four patients were included in this study, of which
19 males (63.3%) and 11 females (36.7%); 8 males
(33.3%) and 16 females (66.7) were in G1 (missing DFO
dose) and G2 (not missing DFO dose) respectively. Ages
of patients in G1 and G2 were (14.7 ± 7.414) and (18.5 ±
10) respectively (Table 1).
Table 1. Demography of fifty-four thalassemia patients used for this analysis.
Variables G1 (No. = 30) G2 (No. = 24) p value
Age (year) 14.7 ± 7.414 18.5 + 10 0.115
Male No. (%) 19 (63.3%) 8 (33.3%)
Gender
Female No. (%) 11 (36.7 %) 16 (66.7%)
0.028*
Weight (Kg) 34.916 ± 14.614 37.808 ± 13.152 0.46
BMI 17.333 ± 2.996 18.234 ± 2.736 0.265
Height (cm) 138.633 ± 19.813 141.347 ± 16.848 0.6
Body temperature 35.772 ± 1.096 35.725 ± 1.048 0.87
Splenoctomy No. (%) 12 (41.4) 10 (41.7) 0.983
Each value represents the mean ± standard deviation or number and percentage, *p ˂ 0.05.

Therapeutic Drug Monitoring of Chelating Agent Deferoxamine for β-Thalassemia Major Patients
334
4.2. TDM of DFO Chelation Therapy
4.2.1. Adequacy of DFO Dose
Variables measured under this section are; age of thalas-
semia diagnosis (year), duration of DFO administration
(year), number of DFO vials administered by subcutane-
ous route per day and off days/week (Results are pre-
sented in Table 2) Patients who had one off day of the
treatment/week were 16 (53.3%) and 13 (54.2%); fol-
lowed by two off days/week, 9 (30%) and 8 (33.3%) and
no off day of treatment, 3 (10%) and 3 (12.5%) for G1
and G2 respectively, while no DFO administration was 2
(6.7%) for G1 and 0 (0%) for G2, all with no statistical
significant difference between them.
The pharmacokinetic parameters of DFO and FO,
which include peak concentration mg/L, trough concen-
trations mg/L, rate of elimination, half life, and volume
of distribution are as shown in Table 3.
4.2.2. Cardiac Variables and Biomarkers
There were no significant difference in the measured car-
diac parameters between the two groups, except in CK-
MB and high sensitive C-reactive protein which had val-
ues 3.58 ± 4.04 and 1.56 ± 1.2 µg/L for G1 and 3.93 ±
3.7 and 1.91 ± 1.9 mg/L for G2 respectively (Table 4).
Table 2. Data concerning the drug dosage.
Variables G1 (No. = 30) G2 (No. = 24) p value
Age of diagnosis (year) 1.42 ± 1.66 2.03 ± 3.13 0.422
Duration of DFO used (year) 6.65 ± 4.21 6.76 ± 4.53 0.92
No. of DFO vials administered by S.C/day 2.25 ± 1.09 2.77 ± 1.05 0.086
No off days 3 (10%) 3 (12.5%)
One off day 16 (53.3%) 13 (54.2%)
Two off days 9 (30%) 8 (33.3%)
Off days/week
No DFO administration 2 (6.7%) 0(0%)
0.78
Each value represents the mean ± standard deviation or number and percentage.
Table 3. DFO pharmacokinetic parameters.
Variables DFO FO
Peak conc. (mg/L) 36.88 ± 6.8 15.83 ± 5.37
Trough conc. (mg/L) 86.8 × 10−7 ± 7.23 × 10−7 83.95 × 10−7 ± 9.43 × 10−7
Ke (min−1) 0.0237 ± 0.00029 0.022 ± 0.0006
t½ (min) 29.2 ± 0.36 31.45 ± 0.864
Vd (L/Kg) 0.93 ± 0.078 2.32 ± 0.61
Each value represents the mean ± standard deviation.
Table 4. Cardiac variables and biomarkers.
Variables G1 (No. = 30) G2 (No. = 24) p value
Heart rate (beat/min) 90.433 ± 13.142 90.043 ± 12.178 0.912
Systolic B.P (mmHg) 98.846 ± 9.623 103.409 ± 12.089 0.152
Diastolic B.P (mmHg) 57.692 ± 8.629 61.818 ± 8.387 0.1
Ejection fraction (%) 65.3 ± 5.175 65 ± 6.518 0.74
Mild dilated right ventricular 3 (15%) 0 (0%) 0.535
Troponin (µg/L) 0.0013 ± 0.007 0.0142 ± 0.069 0.376
CK-MB (µg/L) 3.58 ± 4.04 1.56 ± 1.2 0.026*
High sensitive CRP (mg/L) 3.93 ± 3.7 1.91 ± 1.9 0.027*
Each value represents the mean ± standard deviation or number and percentage. *p ˂ 0.05.

Therapeutic Drug Monitoring of Chelating Agent Deferoxamine for β-Thalassemia Major Patients
335
4.2.3. Biochemical and Hematological Assessment
The highest significant differences were seen in serum
ferritin with value (6937.96 ± 2748.2) µg/L, and 3890.25
± 2770.98) µg/L for G1 and G2 groups respectively.
Blood urea (mg/dl) in patients ≤ 12 years old was 26.39 ±
5.69 and 20.74 ± 4.31, while for patients ˃12 years old it
was (29.76 ± 7.21) and (23.16 ± 6.4), SGPT was (68.93 ±
31.61), and (46.35 ± 23.9) units/L, SGOT was (64.39 ±
30.7) and (47.78 ± 19.26) units/L, alkaline phosphatase
(units/L) in patients ≤ 12 year olds was (526.84 ± 230.02)
and (300.41 ± 148.17) while in patients ˃12 years old it
was (365.05 ± 141.36) and (235.14 ± 97.85) in G1 and
G2 respectively. Serum albumin also showed highest sig-
nificant difference of 4.29 ± 0.3 and 4.7 ± 0.4) similar to
serum calcium which gave 8.22 ± 0.9) mg/dl and 9.28 ±
0.88) mg/dl for G1 and G2 respectively, as showed in
Table 5.
4.2.4. Monitoring of Adverse and Toxic Effect of DFO
in Enrolled Major β-Thalassemia Patients
1) Urinary elements excretion
There were significant differences in urinary elements
excreted. The value of Fe was (814.74 ± 654.49) and
(3166.07 ± 2761.44) with (p = 0.018); Zn (384.66 ±
195.79) and (585.58 ± 361.84) with (p = 0.038) and Cu
(62.63 ± 19.52) and (90.92 ± 57.34) with (p = 0.044),
measured in µg/day in G1 and G2 respectively (Figures
1-4). Moreover the color of urine was reddish brown.
Each value represents the mean ± standard deviation.
2) DFO adverse effects
Figure 5 showed that highest incidence of DFO ad-
verse effects were arthralgia-myalgia, bone pain, growth
retard, headache, dizziness, stomach pain, visual distur-
bance and hearing problem. There was significant dif-
ferent showed in diarrhea and fever between the two
Table 5. Biochemical and hematological assessment.
Variables G1 (No. = 30) G2 (No. = 24) p value
Serum ferritin (ng/ml or µg/L) 6937.96 ± 2748.2 3890.25 ± 2770.98 0.001*
≤12 year 0.36 ± 0.095 0.35 ± 0.107 0.79
Serum creatinine
(mg/dl) ˃12 year 0.48 ± 0.154 0.48 ± 0.144 0.939
≤12 year 26.39 ± 5.69 20.74 ± 4.31 0.023*
Blood urea (mg/dl)
˃12 year 29.76 ± 7.21 23.16 ± 6.4 0.03*
SGPT (units/L) 68.93 ± 31.61 46.35 ± 23.9 0.014*
SGOT (units/L) 64.39 ± 30.7 47.78 ± 19.26 0.045*
≤12 year 526.84 ± 230.02 300.41 ± 148.17 0.043*
Alkaline phosphate
(units/L) ˃12 year 365.05 ± 141.36 235.14 ± 97.85 0.026*
Total serum bilirubin (mg/dl) 1.82 ± 1.14 2.11 ± 1.32 0.407
WBC (WBC/cmm) 12.45 ± 8.3 10.13 ± 8.28 0.344
≤12 year 244459.72 ± 110964.93 315214.28 ± 113739.78 0.201
Platelet in cells/µL
˃12 year 432030.3 ± 218042.79 456916.66 ± 274220.79 0.808
Serum albumin (g/dl) 4.29 ± 0.3 4.7 ± 0.4 0.001*
Serum calcium (mg/dl) 8.22 ± 0.9 9.28 ± 0.88 0.003*
Each value represents the mean ± standard deviation. *p ˂ 0.05.
0
5000
[Fe] in urin
G 1 (No.=30)G 2 (No.=24)
Figure 1. Urinary excretion of iron, *p ˂ 0.05.
0
1000
[Zn] in urine
G 1 (No.=30)G 2 (No.=24)
Figure 2. Urinary excretion of zinc, *p ˂ 0.05.

Therapeutic Drug Monitoring of Chelating Agent Deferoxamine for β-Thalassemia Major Patients
336
0
100
[Cu] in urine
G 1 (No.=30)G 2 (No.=24)
Figure 3 .Urinary excretion of copper, *p ˂ 0.05.
0
200
400
[Se] in urine
G 1 (No.=30)G 2 (No.=24)
Figure 4. Urinary excretion of selenium, *p ˂ 0.05.
Figure 5. The percentage of DFO adverse effects, *p ˂ 0.05.
groups.
3) Distribution of the site of subcutaneous DFO injec-
tion and related adverse effects
Figure 6 showed the percentage distribution of the dif-
ference site of DFO subcutaneous injection. Patients that
were administered via abdomen were 6 (21.4%) and 6
(25%); patients that used upper arm were 15 (53.6%) and
16 (66.7%) and patients that used both sites were 7 (25%)
and 2 (8.3%) in G1 (missing DFO dose) and G2 (not
missing DFO dose) respectively. There were no statisti-
cal significant differences between these two groups.
Adverse effects of S.C injection were swelling seen in
26 (92.9%) and 23 (95.8%) patients followed by infiltra-
tion in 26 (92.9%) and 20 (83.3%) patients; pain in 23
(82.1%) and 18 (75%) patients; pruritus in 24 (85.7%)
and 19 (79.2%) patients and erythema in 20 (71.4%)
and19 (79.2%) patients in both G1 and G2 respectively
Figure 6. The distribution of the site of S.C DFO injection.
(Figure 7).
There was no statistical correlation between site of S.C
DFO injection (abdomen, upper arm and both sites) and
the injection site adverse effects (erythema, pruritus, pain,

Therapeutic Drug Monitoring of Chelating Agent Deferoxamine for β-Thalassemia Major Patients
337
swelling and infiltration) in both groups as showed in
Figure 8.
4) Compliance to treatment
Figure 7. The percentage of S.C. injection adverse effects in
both groups.
Relations of DFO dose to serum ferritin and DFO ther-
apeutic index, explain the compliance to treatment, which
presented in Table 6.
Figure 8. The site of S.C DFO injection (abdomen, upper
arm and both sites) and side effects (erythema,pruritus,
pain, swelling and infiltration) for enrolled patients.
Table 6. Relations of DFO dose to serum ferritin and DFO therapeutic index.
G1 (missing DFO Dose) G2 (not missing DFO Dose)
Dose of DFO
mg/kg/day
Serum ferritin
µg/L Therapeutic index Dose study
Dose of DFO
mg/kg/day
Serum ferritin
µg/L Therapeutic index Dose study
33.33 5257.8 0.0063 (1) 23.51 2991.77 0.0078 (1)
38.79 7328 0.0052 (1) 25.92 3970 0.0065 (1)
34 6748 0.005 (1) 30.3 4000.5 0.0075 (1)
35.21 1481 0.023 (2) 32.89 4115 0.0079 (1)
31.25 8965.25 0.0034 (1) 31.77 2857 0.011 (1)
35.71 6490 0.0055 (1) 66.66 2500 0.026 (2)
27.77 8518.75 0.0032 (1) 26.51 3817 0.0069 (1)
35.21 7578.25 0.0046 (1) 26.73 3189.25 0.0083 (1)
34.48 1954.75 0.017 (3) 34.6 1307.5 0.026 (2)
36.49 6315.4 0.0057 (1) 32.25 569.33 0.056 (2)
37.73 1244.25 0.03 (2) 28.84 3161 0.009 (1)
31.25 1488 0.021 (2) 29.41 3202.33 0.009 (1)
37.03 9265.25 0.0039 (1) 28.26 2667 0.01 (1)
20.92 3827.375 0.0054 (1) 43.19 1062.5 0.04 (2)
32.05 2545 0.012 (3) 48.78 1214.2 0.04 (2)
34.88 5818.33 0.0059 (1) 23.47 3599 0.0065 (1)
G1 (missing DFO Dose) G2 (not missing DFO Dose)
Dose of DFO
mg/kg/day
Serum
ferritin µg/L
Therapeutic
index
Dose
study
Dose of DFO
mg/kg/day
Serum
ferritin µg/L
Therapeutic
index Dose study
28.84 914 0.031 (2) 29.85 4010.9 0.0074 (1)

Therapeutic Drug Monitoring of Chelating Agent Deferoxamine for β-Thalassemia Major Patients
338
Continued
43.47 1170 0.037 (2) 33.89 1292.42 0.026 (2)
26.63 6093.33 0.0043 (1) 35.97 860.33 0.041 (2)
37.8 8011.83 0.0047 (1) 34.42 1409.2 0.024 (2)
33.33 6227 0.0053 (1) 43.47 4398.5 0.0098 (1)
23.98 1200 0.019 (3) 27.25 3572 0.0076 (1)
36.36 5000 0.0072 (1) 19.76 752.83 0.026 (2)
34.48 10102.83 0.0034 (1) 21.66 3484.5 0.0062 (1)
43.47 6145.6 0.007 (1)
34.72 5804.2 0.0059 (1)
40 14721.2 0.0027 (1)
(1)Means low dose, calculated as (19) 70% and (15) 62.5% for patients in G1 and G2 respectively taking a lower dose than the standard recommended average
daily dose. (2)Means high dose calculated as (5) 18.5% and (9) 37.5% for patients in G1 and G2 respectively taking a higher dose than the standard recom-
mended average daily dose. (3)Means corrected dose calculated as (3) 11.5% for patients only in G1 taking a correct dose as the standard.
Life style of enrolled major β-Thalassemia patient
Table 7 illustrated these life style variables; exercise,
eating prohibited food, drinking tea, missing Vitamin C
or E in both G1 (missing DFO dose) and G2 (not miss-
ing DFO dose).
There was a highly significant difference between G1
and G2 in the percentage of patients that miss both Vita-
min C and E (80 and 12.5%) and those that did not miss
any (6.7 and 62.5%).
5. Discussion
Therapeutic drug monitoring (TDM) is the measurement
of drugs and their active metabolites in patients receiving
medications for the purpose of optimizing their therapeu-
tic effect while minimizing adverse effects [16]. Patient
demographic characteristics are critically important so
that the contributions of age, disease state, ethnicity, and
other variables to inter-individual variation in pharma-
cokinetics and pharmacodynamics can be considered.
An important part of therapeutic drug monitoring is
the timing of the blood collection. When the drug is ad-
ministered, the blood concentration increases until it
reaches a peak and then the concentration begins to fall.
The lowest concentration (trough) is usually just before
the next dose. In this study the measured trough concen-
tration of Deferoxamine and ferroxamine were 33 and
52.96 µg/L, respectively.
Deferoxamine plasma half-life was 20 - 30 min [4]
while maximum peak plasma concentration was achieved
after 4 half life (80 min). Deferoxamine and ferroxamine
steady state concentrations were 144 and 42.44 µg/L,
respectively, and the calculated rate of elimination (Ke)
was (0.0237 ± 0.00029 min−1), so the DFO T1/2 was 34
min in enrolled patients at Sulaimani thalassemia center.
The difference with other studies may be due to the
Table 7. Life style variables (exercise, eating prohibited
food, drinking tea, missing Vitamin C or E) in both groups
of patients.
Variables G1
(No. = 30)%
G2
(No. = 24)%p value
Exercise 15 (50) 9 (37.5) 0.358
Eating prohibited food 18 (60) 9 (37.5) 0.1
Not drinking 2 (6.7) 1 (4.2)
1 - 2 times 10 (33.3) 6 (25)
2 - 3 times 5 (16.7) 3 (12.5)
3 - 4 times 10 (33.3) 8 (33.3)
4 - 5 times 2 (6.7) 4 (16.7)
Drinking
tea
5 - 6 times 1 (3.3) 2 (8.3)
0.816
Missing Vit.C 3 (10) 5 (20.8)
Missing Vit.E 1 (3.3) 1 (4.2)
Missing both 24 (80) 3 (12.5)
Missing
Vitamin
C or E
Not missing any2 (6.7) 15 (62.5)
0.0*
Each value represents the number and percentage. *p ˂ 0.05.
blood sampling time for peak concentration, or may be
the pharmacokinetics factors, such as protein binding.
One of the most important complications of regular
blood transfusion is iron overload that eventually in-
volves many organs like heart and cause myocardial in-
jury [17]. Serum ferritin is a marker used to determine
the development of cardiac complications [18] and the
management of cardiac complications, which involves
optimal transfusion therapy and strict compliance with
chelation therapy [19]. CK-MB and troponin I are con-
sidered as one of these specific cardiac enzymes that are

Therapeutic Drug Monitoring of Chelating Agent Deferoxamine for β-Thalassemia Major Patients
339
used for evaluation of heart involvement [20,21]. The
present study showed a highly statistically significant dif-
ference in serum ferritin level in the two groups studied
(non compliant, and compliant), (p ˂ 0.01).
According to Sakha et al. (2008) [17], studying LVEF
for major thalassemia patients treated with Deferoxamine
injection showed that some patients had normal left ven-
tricular ejection fraction (LVEF = 50% - 70%), while
others had reduced LVEF (20% - 45%). Cardiac markers
(Troponin and CK-MB) are not helpful for the recogni-
tion of cardiac involvement in major thalassemia, and also
do not predict cardiac damage of thalassemia patients,
but may be helpful in serial measurement.
Echocardiography was performed in this study for en-
rolled patients in both groups, all had a normal left ven-
tricular ejection fraction (LVEF = 50% - 70%), and there
was no statistical difference between the two groups (p =
0.74). Those, who are adequately transfused but who are
poorly chelated, may present with dominant right-sided
heart involvement [22]. This study confirms that, only 3
patients (15%) from non-compliant group had mild di-
lated right ventricular, while there was no complain from
the G2 (non missing dose) group.
The statistical analysis between the two studied groups
showed no significant difference in troponin I level,
which was within normal range; this result agrees with
the results of Sakha et al. (2008) [17], but disagrees in re-
gards to CK-MB. This study showed a statistical signifi-
cant difference in CK-MB level, higher than normal level
in non-compliant (missing dose) more than compliant
group, which indicate myocardial injury.
Numerous prospective studies in healthy volunteers
have confirmed that high-sensitivity CRP (hsCRP) pre-
dicts cardiovascular events (CVEs), while hsCRP is a
strong independent predictor of risk of future MI, stroke,
peripheral arterial disease, and vascular death [23].
High-sensitivity C-reactive protein may be clinically
useful in identifying individuals who are at higher risk
for CAD. A high sensitivity C-reactive protein level of
less than 1.0 mg/L indicates low risk for cardiovascular
disease, between 1.0 to 3.0 mg/L indicates moderate risk
and more than 3.0 mg/L indicates high risk [24]. In this
study high sensitive CRP showed a statistical significant
difference between the two groups (p = 0.027), the re-
sults revealed that non-compliant patients (missing dose)
are in high risk of developing atherosclerotic cardiovas-
cular disease but compliant patients are in average risk,
which is due to their levels of serum ferritin.
Iron overload is one of the major causes of morbidity
in all patients with severe forms of thalassemia. Excess
iron in vital organs, even in mild cases of iron overload,
increases the risk of for example liver disease (cirrhosis,
cancer). Various studies have found that Deferoxamine
arrests progressive liver fibrosis even when taken in in-
adequate doses, as judged by reduction in liver iron con-
centration and improvement in liver function test [25].
There were significant increases in SGPT and SGOT
levels in a group of patients that indicate liver damage
because of iron overload in their body [26].
The level of liver enzymes was raised in non-compli-
ant group than normal range; the raised mean level of all
the studied liver enzymes (SGOT, SGPT, serum alkaline
phosphatase) showed a statistically significant difference
(p > 0.05), in non-compliant group compared to the com-
pliant one.
There was a significant difference in blood urea be-
tween the studied groups, higher than normal range [27].
The results of this study agree with it, since there was a
significant increase in serum urea in transfusion depend-
ent β-thalassemia patients using Deferoxamine. Compli-
cations from continuous therapy may arise due to iron
overload and toxicity of iron chelating therapy, which
may affect many organs in the body including the renal
system. Renal damage can be attributed to chronic ane-
mia, iron over load and deferroxamine therapy [28]. The-
refore monitoring of renal functions is recommended.
Total serum bilirubin was measured in both groups and
there was no statistical difference between them, but the
value was higher than normal range, which may be ex-
plained by the study of Kassab-Chekira et al. (2003) [29],
who mentioned that bilirubin increase observed in beta-
thalassemia may be related to hemolysis process.
There was a significant decrease in serum creatinine in
transfusion dependent β-thalassemia patients using De-
feroxamine. This result agrees with the findings of You-
nus et al. (2012) [27] that determine low-level serum cre-
atinine in groups of patients above 12 years old. This sig-
nificant decrease in the mean serum creatinine level may
be related to the lower body mass index due to growth
retardation and lower muscle mass, usually encountered
in β-thalassemia patients [30].
Growth retardation occurs in both groups at a rate of
46.7 and 45.8% respectively, but no statistical significant
difference was shown between the two groups of patients.
This means that growth retardation in these patients is
multi factorial, that is, it may have occur due to iron over-
load, Deferoxamine use and/or serum zinc level which
has adversely affected their growth velocity [31].
According to the study of Aziz et al. 2009 [32], albu-
min decreased significantly in patients with iron overload;
this was similar to the results obtained by Livreaet al.
(1996) [33] which shows that serum albumin was in the
normal range in all thalassemia patients. This study agrees
with the above-mentioned studies, in which measured
serum albumin for all enrolled patients, were signifi-
cantly lower in non-adherent patients more than those ad-
herents to treatment, but both were within normal range.
Comparing the two studied groups, there was no sta-

Therapeutic Drug Monitoring of Chelating Agent Deferoxamine for β-Thalassemia Major Patients
340
tistical significant difference in WBCs and platelet count,
but the WBCs in both groups were slightly higher. High
platelet in both groups of patients may be due to the
number of patients having splenoctomy. This result
agrees with the study of Wirawan et al. (2004) [34],
which observed that leukocytosis and thrombocytosis in
post splenoctomy groups is due to no more pooling and
phagocytosis of WBCs and platelets after splenoctomy
[35].
Calcium level will be low in iron overload β-thalas-
semia patients due to hypoparathyroidism [36], because
iron precipitation in tissues of parathyroid gland causes
insufficient production of parathyroid and calcitonin hor-
mones that regulate normal level of calcium in the blood
[37]. This study showed that calcium level was signifi-
cantly different in both groups.
According to the data published by Novartis pharma-
ceutical manufacturing factory in 2011 [38], Deferoxami-
nemesylate adequate average daily doses are 20- to 60-
mg/kg-body weight. Patients with a serum ferritin level
of less than 2000 μg/L require about 25 mg/kg/day; pa-
tients with a serum ferritin level between 2000 and 3000
μg/L require about 35 mg/kg/day and patients with higher
serum ferritin levels may require up to 55 mg/kg/day. It
is inadvisable to regularly exceed an average daily dose
of 50 mg/kg/day except when very intensive chelation is
needed in patients who are no longer growing. If ferritin
values fall below 1000 μg/L, the risk of Desferal toxicity
increases. Therefore, it is important to monitor these pa-
tients carefully and to consider lowering the total weekly
dose.
Alternatively, the mean daily dose may be adjusted ac-
cording to the ferritin value to keep the therapeutic index
less than 0.025 (that is, mean daily dose of Desferal in
mg/kg divided by the serum ferritin level in μg/L is be-
low 0.025). The therapeutic index is a valuable tool in
protecting the patient from excess chelation, but it is not
a substitute for careful clinical monitoring.
According to the above dosage information, dose of
Deferoxamine in these patients were studied and it showed
that 66.66% of patients taking a lower dose than the
standard recommended average daily dose required (un-
related to their serum ferritin levels) showed a high level
of serum ferritin that eventually resulted in iron over load
complications. Also, 27.45% of the patients who were
administered a higher dose than the standard recom-
mended average daily dose required, unrelated to their
serum ferritin levels, showed Deferoxamine toxicity,
while 5.88% of these patients were administered the ex-
act right recommended dose of Deferoxamine
The study of urinary iron excretion was recommended
for subcutaneous DFO infusion, the results from this
study showed that the urinary iron excretion in both
groups of patients was low compared to the study of
Dubey et al. (1992) [39] (p ≤ 0.05), because after infu-
sion of Deferoxamine there was a significant increase of
mean urinary and faecal iron excretion (p < 0001). On
average, 45% of iron was eliminated through urine while
55% was through stool [40]. The data suggests that the
amount of iron chelated in vivo is related to an increase
in the size of an intermediate chelatable pool rather than
the total amount of the iron load. The well-recognized
delay in urinary iron excretion appears to be related to
active tuular reabsorption of ferrioxamine [41].
Desferal has affinity for Cu2± and Zn2±, and has some
neurotoxic effects, which may be due to its ability to
chelate copper or zinc. After the infusion of DFO, faecal
and urinary zinc and copper excretion were significantly
increased; the depletion of these elements may be re-
sponsible for the neurotoxic effect of the drug [40]. This
study confirms that, there was a statistical significant dif-
ference between the two groups of patients; (p ≤ 0.05) as
regards urinary Zn and Cu excretion. Also the depletion
of iron, zinc, and copper may be related to the retinal
abnormalities [42,43]. More severe retinal or optic nerve
toxicity, or both, that consisted of night blindness, field
defects, visual loss, loss of color vision, and delayed vis-
ual evoked potential has been detected after intravenous
or subcutaneous infusion of similar large doses of De-
feroxamine for a prolonged period [40,44].
The most frequent adverse effects of DFO are local
reactions at the site of infusion, such as pain, swelling,
induration, erythema, burning, pruritus, wheals and rash,
occasionally accompanied by fever, chills and malaise.
Other complications mainly associated with high doses
of DFO in young patients are low ferritin values [45].
This monitoring study found that there was no statistical
significant difference between the two studied groups as
regards the site of DFO S.C. injection; abdomen, upper
arm or both abdomen and upper arm. Follow up of the
enrolled patients, revealed the common side effects of
DFO injection site to include pain, swelling, infiltration,
erythema, and pruritus. There was no statistical correla-
tion between sites used for injection and the side effects
at the site of the injection; this indicates that Deferoxam-
ine dose injection was not the cause of the side effects
experience by patients.
It was also discovered from this study that the adverse
effects of Deferoxamine include headache, dizziness, vis-
ual disturbance, hearing problem, nausea, vomiting, sto-
mach pain, urticarial, arthralgia-myalgia, and bone pain
(˃10%), with no statistical significant difference between
the studied groups. Hypotension was common (˃1%), in
both groups with no statistical significant difference be-
tween the two groups.
Diarrhea (G1, 25% and G2, 4.2%), and Pyrexia (G1,
63.3%; G2, 37.5%), which was very common in both
groups of patients showed significant differences.

Therapeutic Drug Monitoring of Chelating Agent Deferoxamine for β-Thalassemia Major Patients
341
The patients with diarrhea and fever required appro-
priate stool samples, blood culture and serological testing
for Yersinia infection [46], because of the increased risk
of Yersinia infection in iron overload, which could in-
crease further with DFO treatment [47]. Adverse effects
like drowsiness, impotence, or nausea reduce adherence,
which patients may not admit to [48].
6. Conclusions
This study, showed the importance of Therapeutic drug
monitoring of DFO in β-thalassemia major patients. The
adequacy of dose was not related to the poor drug re-
sponse in the enrolled patients. CK-MB and high sensi-
tive C-reactive protein was significantly higher, which
indicated a high risk of developing a myocardial injury
and atherosclerosis among non-compliant patients. Also
there were significant increases in; serum ferritin level,
Liver enzymes (SGOT, SGPT and Alkaline phosphatase),
and bloodurea, while there was a significant decrease in
serum calcium and albumin. In addition to that urinary
Fe, Zn and Cu excretion was significantly higher, also
diarrhea and fever was significantly higher in non-com-
pliant patients.
The highest percentage of non-compliant patients, due
to the drug’s complicated and painful route of administra-
tion, so the role of clinical pharmacist is very important
to be applied to these patients in any thalassemia center.
7. Acknowledgements
We are grateful to all enrolled patients & their parents
who consented to participate in this study and all Doctors
and laboratory staff that assisted in the conduct of the
study.
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