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Effect of Gestational Age on Pharmacokinetics of Ranitidine in
Newborns
Running title: Pharmacokinetics of Ranitidine in Newborns
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Abstract
Objective. The aim of this study was to determine the effect of gestational age
on pharmacokinetics of ranitidine in newborns.
Methods. Thirty pre-terms babies and 20 full-terms were enrolled for the study.
All the children received 3mg/kg/day of ranitidine. After administration, blood
samples were taken at following times: 0, 0.5, 0.75, 1, 2, 4, and 8 h. Ranitidine
levels were determined using high pressure liquid chromatography (HPLC)
technique.
Results. Pharmacokinetics of ranitidine had a bi-exponential behavior with a
half-life elimination of (t1/2β) 2.79 h, area under curve (AUC) of 1688 ng/mL,
volume of distribution (Vd) of 1.44 L/kg, and clearance (Cl) of 5.9 L/kg/h. The
median plasmatic concentration in pre-terms was 1113 ng/mL while it was 280
ng/mL for full-terms. The percentage of children with concentrations equal to or
greater than 400 ng/mL was 68%, whereas those with 100 to 400 ng/mL was
22%, showing statistically significant differences (p<0.05).
Conclusions. Plasma levels of ranitidine depend on the gestational age of the
newborns. Based on respective characteristics, adequate dosage of ranitidine in
children should take into consideration their gestational age.
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Introduction
Ranitidine decreases gastric acid secretion and improves esophagitis. It is then
fundamental to have a good knowledge of its pharmacokinetic activities in order
to optimize treatment for every patient 1-4. In normal human fetus, several organ
systems mature between 34 and 37 weeks, and the fetus reaches adequate
maturity by the end of this period.
In a study by Garg et al 5 on pharmacokinetics of ranitidine, it was found that on
multiple dosing scheme, ranitidine parameters were similar to those obtained by
single dosing scheme. Its concentration adjusts in a bi-exponential manner after
intravenous administration. The half-life elimination is almost 2 h, and a little
more prolonged after oral administration 6. Hepatic metabolism is another
elimination route, suggesting that the drug has enterohepatic re-circulation for
bi-exponential rate7.
Due to the high risk of either overdosing or under-dosing in newborns, which
could lead to therapeutic failure, the study of pharmacokinetics and
pharmacodynamics of ranitidine in these patients is very important
1,8-9.
The
absence of specific ranitidine dosing scheme for newborns has lead physicians
to employ modified recommended doses from older and mature children for this
group of patients. The result of this is usually overdosing or sub-therapeutic
dosing scheme.
In a study carried out by Fontana et al.10 in 27 full-term newborns without liver
or kidney problems, using a dose of 2.4 mg/Kg of ranitidine, a half-life
elimination (t1/2el) of 207.1  19.1 min and a total distribution volume (Vd) of
1.52  0.91 L/kg with a total plasmatic clearance (CL) of 5.02  0.46 mL/kg/min
were observed. Assuming that these measurements do not change with
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different dosing schemes, they could be used to derive a treatment plan for
newborn infants.
Kuusela 11, studied critically ill pre-term and full-term newborns to determine the
optimum ranitidine doses through gastric pH monitoring. Their results showed
that critically ill newborns were able to secrete intraluminal gastric acid, and that
ranitidine concentrations correlated with gastric pH values ≥ 4. They concluded
that a significantly lower dose of ranitidine is needed in pre-term compared to
full-term newborns to maintain their intraluminal gastric pH over 4.
In view of the above findings, the aim of this study was to determine the effect of gestational
age on pharmacokinetics of ranitidine in newborns that would help in drawing up ranitidine
therapeutic scheme for this age group.
Methods
A prospective, clinical, and descriptive study of 50 newborns (30 males and 20
females) receiving ranitidine at Neonatal Intensive Care Unit (NICU) of General
Hospital of Durango, Mexico, was carried out with the objective of determining
the pharmacokinetic of the drug. The characteristics of the patients based on
gestational age were as follows: 6 pre-term babies (babies born before 37 weeks
of gestation) and small for their gestational age (SGA) (weight < 10th percentile);
20 pre-terms, appropriate for their gestational age (AGA) (weight between 10 and
90 percentile); 4 pre-terms, large for their gestational age (LGA) (weight > 90
percentile); 7 full-terms (babies born between 37 and 42 weeks), small for their
gestational age (SGA); and 13 full-terms, appropriate for their gestational age
(AGA) 12. All the patients required treatment with ranitidine by medical
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prescription. Determination of serum creatinine and its renal clearance was
carried out to avoid nephrotoxicity.
Once the values were confirmed to be normal, the patients were made to receive
a first dose of 3 mg/kg/day of ranitidine by intravenous route. A sample of 0.5 mL
of whole blood was extracted from each infant either at 0.5, 0.75, 1, 2, 4, or 8 hrs
following drug administration.
For ethical reasons, no more than one randomly selected blood sample was
taken from each patient in accordance with established sampling times
(randomly scheduled for each patient, with a total of 50 tests). The research
protocol was approved by the Research Ethics Committee of the General
Hospital of Durango, México, and an informed consent was obtained from the
parent or guardian of each patient. The study was carried out from July 2004 to
august 2005. Acceptance into the study did not involve greater risks than those
related to sampling. The volume was minimal and did not put at risk the balance
or imbalance of fluids. The sample size was calculated using the formula
reported by Castilla and Cravioto 13.
Pre-term and full-term neonates of 0 to 28 days old that required ranitidine
treatment with normal liver and kidney functions were included in the study. All
patients requiring treatment with ketoconazol or other anti-secretory agents
were excluded.
Analytical procedure
Plasma ranitidine concentrations were analyzed using High pressure liquid
chromatography (HPLC), Agilent 1100 chromatographic system. The method
was adapted from a previously published method by Castañeda et al
14.
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Quantification was carried out by using the ratio of area under the curve for
ranitidine and nizatidine as standard internal calibration curves, and linearity
was assessed in concentrations 0, 50, 100, 250, 500, 1000 and 1500 ng/mL for
solution and plasma. A correlation coefficient of r=0.999 was determined
between intra and interday.
Mean accuracy of known concentration ranged from 99.4 % to 103.5 %.
Recovery was assessed by determining three concentration levels in plasma
and solution (75, 600, and 1200 ng/mL). The minimal concentration that could
be accurately measured was 15 ng/mL. A coefficient of variation (CV) of less
than 7% was obtained. The percentage of recovery was 108 %, which is within
the range recommended by Official Mexican Standard
15.
The response of
plasma samples, to which ranitidine had been added at the afore-mentioned
concentrations was compared with the response of ranitidine solutions at the
same concentrations.
To 500 l of plasma, 50 l of Nizatidine (internal standard) and 50 l of NaOH
2.5 M were added. The mixture was lightly shaken in vortex, after which 3 mL of
dichloromethane was added and again shaken for 1 min in vortex, and
centrifuged for 5 min at 3000 rpm. Once centrifuged, the organic phase was
separated from the aqueous phase and air-evaporated at a temperature of
45°C. It was then reconstructed with 200 l of mobile phase, and 50 l of this
was injected to the system 14. A chromatographic symmetry C18 of 5 m and
UV detector with diode arrangement with flow velocity of 1 ml/min at a
wavelength of 313 nm was used. For mobile phase, a mixture of monobasic
potassium phosphate 0.05 M, pH 6.5 and acetonitril (88/12, v/v) was used, with
an injection volume of 100 l.
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The pharmacokinetic profile of ranitidine was estimated from a plasma
concentration obtained at different times randomly scheduled for each patient,
with a total of 50 tests. Non-linear regression was used to fit plasma ranitidine
concentrations to a two-compartment (bi-exponential) model 16. The WinNonlin
software (Version 2) 17, was used for all non-linear regression, and to generate
all pharmacokinetic parameters.
Statistical analysis
Parametric and nonparametric statistics depending on data distribution and its
variability were used. For hypothesis testing, Student t test and Mann-Whitney
test 13 were used.
Results
Fifty newborns, admitted in Neonatology Unit of Hospital General de Durango,
Mexico, that required therapeutic management with ranitidine were studied. All
newborns presented risk factors susceptible to digestive tract bleeding.
The average value and standard deviation of the gestational age were 34.2 ±
4.16 months for female newborns and 35.8 ± 2.7 months for males without
statistical difference p = 0.103. However, even when the birth weights were
different in the male and female newborns with average value of 2330.7 ± 677 g
for girls and 2,680.5 ± 661 for boys, there was no statistically significant
difference p = 0.715. All patients did not show any clinical signs or laboratory
evidence of renal and/or liver dysfunctions.
The median, minimum, and maximum blood concentration values of ranitidine in
the newborns according to time and their corresponding number of samples are
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shown in table 1. Plasma concentration data were fit to a two compartment (biexponential) model, after applications of residual methods. Calculated
pharmacokinetic parameters are reported in table 2.
In table 3, the median, minimum, and maximum values of plasma concentration
of ranitidine of the newborns based on gestational age are shown. Although, the
number of cases are different considering the gestational age, the highest
number of subjects corresponded to AGA pre-term newborns (20 cases), and
the lowest to LGA pre-terms (4 cases). These two groups presented the most
elevated concentration values of ranitidine at zero hour with median value of
1484 ng/mL and 1337ng/mL respectively.
In the case of intravenous unique dose, the plasma concentration of ranitidine
was ≥ 400 ng/mL in 34 (68%) of the newborns. Concentrations within the
normal therapeutic range (100-400ng/ml) were seen in 11(22%) of the children
while 5 (10%) had a concentration below sub-therapeutic range (< 100 ng/mL).
The analysis showed statistically significant differences with X2 = 28.12 and p ≤
0.01. There is cyclic variation in the plasma concentration of ranitidine which
decreases as the gestational age increase. This explains the variability in
ranitidine plasma concentration in early gestational age.
Within the first 90 min, the pH value of all the patients was ≤ 4. There was an
increase of > 5, with the intragastric pH being > 4 in a minimum of 15 h. t½el
was 6.61±2.75 h, and 41.5 ± 22.2 % of the dose was eliminated in urine in 24 h.
Total clearance of ranitidine was well correlated with glomerular filtration
velocity. A continuous infusion of ranitidine (2 mg/kg/24h) for 72 h was reduced
for 24 h, suggesting that in full-term newborns with stable hepatic and liver
functions, the administration of ranitidine needs not be more frequent than 12 h,
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and that the treatment response must be monitored with repeated measurement
of gastric pH and the doses adjusted in conformity with the response obtained.
Discussion
Ranitidine is a drug used in the treatment of digestive tract bleeding, primarily in
the upper segment, due to mucus alteration during neonatal stage. In addition, it
is highly used in the prevention of gastric bleeding in children requiring
therapeutic management in intensive care unities. However, studies on PK of
this drug in a risk group like newborns is very scarce. This is the basis for the
justification of this study.
Fontana et al 10, on studying PK values of ranitidine in this group of children
reported t½el values of 207.1±19.1 min; Vd, of 1.52±0.91 L/kg; and Cl of 5.02
±0.46mL/kg/min. Wiest et al 18, on their part reported t½el values of 125.4 min;
Vd, of 1.61 L/kg; and Cl of 13.9 mL/kg/min in children older than 2 to 21 months.
A comparison of Vd values in both studies with 1.6 L/kg reported in adults by
McNeil et al 19, reveals that plasma protein binding and tissue distributions of
the drug are similar in different age groups.
The values of t½el in the study of Fontana et al 10, was more prolonged than that
reported by Wiest et al 18, (207.1 min vs 125.4 min). Consequently, Cl was less
(5.02 vs 13.9 mL/kg/min). In a study carried out by Mallet et al 4, a t½el value of
168 min was obtained in children of 6 weeks to 6 months old while in other
studies made in older children by Blumer et al 20 and in adult by McNeil 19, t½el
values of 108 min and 114 min respectively was reported. These evidentially
depict that the most prolonged t½el value reported in newborns precisely reflects
the lowest glomerular filtration velocity different from what is observed in older
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children where t½el values were found to increase in the first three weeks of
neonatal life 21.
The use of ranitidine with other drugs in a disease such as gastro-esophageal
reflux is common. Gastro-esophageal reflux is a common sickness of upper
gastrointestinal motility that widely differs in severity and prognoses. The
knowledge of pharmacokinetic of ranitidine and other drugs combined with it for
the treatment of this pathology is important. To the best of our knowledge, this
would help to optimize the therapeutic benefits. Patients with gastro-esophageal
reflux are usually elderly people and the pharmacokinetic variability in this group
of population is evident. Moreover, the gastro-esophageal reflux, the basal
pathology, is usually accompanied by symptoms and other pathologies that
require medical management with other compounds. The ideal therapy for
esophageal reflux should have a linear pharmacokinetic and a relatively longer
plasma half life (t½el), a duration that would permit its administration once a day,
as well as a stable effect independent of its interactions with food, anti-acids
and other drugs.
The social benefit of this study is that it would permit the determination and
identification of ranitidine concentrations in newborn patients. The prevailing
adjusted doses in prescription of this drug for newborn patients have the
disadvantage of either sub-therapeutic concentration levels or concentration
levels with high risk of overdosing. Therefore, the identification of these
concentrations is of paramount importance so as to get the maximum
therapeutic benefit. The results of this study suggest a modification in the
treatment regimens in Neonatology service of General Hospital of Durango,
Mexico, as has been recommended in previous studies
22.
However, there are
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important limitations in the results presented. We recommend further studies to
investigate the possible relationship between after-birth age and
pharmacokinetics of the children as their internal organs get mature in spite of
their gestational background. At the same time, the results could contribute to a
rational management of ranitidine by national and international medical
community.
Conclusions
Plasma levels of ranitidine depend on the gestational age of the newborns.
Based on respective characteristics, adequate dosage of ranitidine in children
should take into consideration their gestational age.
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Acknowledgement
We thank Dr Cyril Ndidi Nwoye, a native English speaker and a renowned,
professional translator, for working in the translation and correction of the
manuscript.
Conflict of interest
We declare that there is no conflict of interest.
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1990;19:11-31
3. Abad-Santos F, Carcas AJ, Guerra P, et al. Evaluation of sex differences in
the pharmacokinetics of ranitidine in humans. J Clin Pharmacol 1996;36:748751
4. Mallet E, Mouterde O, Dubois F, et al. Use of ranitidine in young infants with
gastro-oesophageal reflux. Eur J Clin Pharmacol 1989;36:641-642
5. Garg DC, Eshelman FN, and Weidler DJ. Pharmacokinetics of ranitidine
following oral administration with ascending doses and with multiple-fixed
doses. J Clin Pharmacol 1985;25:437-443
6. Lebert PA, MacLeod SM, Mahon WA, et al. Ranitidine kinetics and dynamics.
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9. Miller R. Pharmacokinetics and bioavailability of ranitidine in humans. J
Pharm Sci 1984;73:1376-1379
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Ranitidine pharmacokinetics in newborn infants. Arch Dis Child 1993;68:602603
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11. Kuusela AL. Long-term gastric pH monitoring for determining optimal dose
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Neonatal 1998;78:151-153
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criterion (AIC) in the evaluation of linear pharmacokinetic equations. J
Pharmacokinet Pharmacodyn. 1978;6:165-175
17. WinNonlin (v.2.1). Pharsight, Palo Alto, Ca. USA
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critically ill infants. Dev Pharmacol Ther 1989;12:7-12
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Abbreviations:
PK, Pharmacokinetics
GA, Gestational age
SGA, Small for gestational age
AGA, Appropriate for gestational age
LGA, Large for gestational age
h, hour
HPLC, High Pressure Liquid Chromatography
t½el, Half-life elimination
t½β, bi-exponential half-life elimination
AUC, Area under curve
Vd, Volume of distribution
Cl, Clearance
NICU, Neonatal Intensive Care Unit
CV, Coefficient of variation
Mil/min, milliliter per minute
v/v, Volume/volume
l, microliter
m, micrometer
UV, Ultraviolet
NaOH, Sodium hydroxide
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Table 1. Plasma concentrations of ranitidine in newborns at different time.
_______________________________________________________________
No. of
Time
Concentrations of ranitidine in ng/mL
samples
(h)
(Median, minimum and maximum values)
_______________________________________________________________
0.5
13
3475 (741 - 7817)
0.75
9
1500 (1015 - 3918)
1
9
675 (209 - 866)
2
9
335 (107 - 932)
4
5
154 (111 - 684)
8
5
90 (46 - 85)
_______________________________________________________________
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Table 2. Pharmacokinetic parameters after data adjustment for a model of two
compartments.
_____________________________________________________________
AUC (Area under curve)
1688.9 ng/mL/h
t½ of K10
1.69 h
t½ α (Half life absorption)
0.3899 h
t½ β (Half life elimination)
2.79 h
K10 ( Velocity constant)
0.9105 h-1
K12 (Velocity of transference)
0.5395 h -1
K21 (Velocity of transference)
1.76 h -1
Vd (distribution Volume)
1.44 L/Kg
Cl (Clearance)
5.9 mL/Kg/h
_______________________________________________________________
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Table 3. Median, minimum and maximum values of plasma concentrations of
ranitidine (ng/ml) in newborns of both sexes, based on gestational age.
_______________________________________________________________
Diagnoses*
No. of
Cases
Values
Median
minimum
maximum
_______________________________________________________________
SGA Pre-term
6
518
197.66
937.6
AGA Pre-term
20
1484
61.20
7817.6
LGA Pre-term
4
1337
684.18
3687.9
SGA term
7
217
55.39
3080.7
AGA term
13
343
45.94
1075.7
* Classification according to Jurado García 15