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1 Effect of Gestational Age on Pharmacokinetics of Ranitidine in Newborns Running title: Pharmacokinetics of Ranitidine in Newborns 2 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. 3 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 4 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 5 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. 6 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. 7 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 8 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, 9 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 10 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 11 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. 12 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. 13 References 1. Benitz WE, Tatro DS: The Pediatric Drug Handbook, 2nd ed. Year Book Medical Publishers, Chicago, IL, 1988 2. Lauritsen K, Laursen LS, Rask-Madsen J. Clinical Pharmacokinetics of drugs used in the treatment of gastrointestinal diseases (part 1). Clin Pharmacokinet 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. I. Oral dose studies. Clin Pharmacol Ther 1981;30:539-544 7. Roberts CJ. Clinical pharmacokinetics of ranitidine. Clin Pharmacokinet 1984;9:211-221 8. Hatlebakk JG, Berstad A. Pharmacokinetic optimization in the treatment of gastro-oesophageal reflux disease. Clin Pharmacokinet 1996;31:386-406 9. Miller R. Pharmacokinetics and bioavailability of ranitidine in humans. J Pharm Sci 1984;73:1376-1379 10. Fontana M, Massironi E, Rossi A, Vaglia P, Gancia GP, Tagliabue P, et al. Ranitidine pharmacokinetics in newborn infants. Arch Dis Child 1993;68:602603 14 11. Kuusela AL. Long-term gastric pH monitoring for determining optimal dose of ranitidine for critically ill preterm and term neonates. Arch Dis Child Fetal Neonatal 1998;78:151-153 12. Jurado–García E, Abarca–Arroyo A, Osorio–Roldán C, Campos–Ordaz R, Saavedra–Mújica A, Álvarez–de los Cobos J, et al. Intrauterine gorwth. I: Evaluation of fetal body stature and weight in Mexico City. Statistical analysis of 16,807 consecutive single product living newborns. Bol Med Hosp Infant Mex. 1970;27:163–169 13. Luis Castilla S. Joaquín Cravioto M. Simplified Statistics for Investigation in Health Science. 2nd ed. Editorial Trillas 1999 México 14. Castañeda G, Flores Murrieta F, Granados-Soto Y, et al. Pharmacokinetics of oral Ranitidine in Mexicans. Arch Med Res 1996;27:349-352 15. Norma Oficial Mexicana de Emergencia NOM-EM-003-SSA-25/03/1998 16. Yamaoka K, Nakagawa T, Uno T. Application of Akaike`s information 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 18. Wiest DB, O´Neal W, Reigart JR, et al. Pharmacokinetics of ranitidine in critically ill infants. Dev Pharmacol Ther 1989;12:7-12 19. McNeil JJ, Mihaly GW, Anderson A, et al. Pharmacokinetics of the H2receptor antagonist ranitidine in man. Br J Clin Pharmacol 1981;12:411-415 20. Blumer JL, Rothstein FC, Kaplan BS, et al. Pharmacokinetic determination of ranitidine pharmacodynamics in pediatric ulcer disease. J Pediatr 1985;107:301-306 15 21. Guignard JP, Torrado A, DaCunha, Gautier E. Glomerular filtration rate in the first three weeks of life. J Pediatr 1975;87:268-272 22. Saltigeral P, Muelas M, Lares Asseff I. Pharmacokinetics of ceftriaxone in new born children. Rev Enf Inf Ped, 1977:11;21-25 16 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 17 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) _______________________________________________________________ 18 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 _______________________________________________________________ 19 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