Pharmacokinetics of ranitidine in preterm and term neonates with gastroesophageal reflux
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 neonates requiring therapeutic management in intensive care units. However, studies on PK of this drug in a risk group like newborns are very scarce. This is the basis justifying this study.
Fontana et al. [20], on studying PK values of ranitidine in term neonates reported t½el values of 3.45?±?0.31 h; Vd, of 1.52?±?0.91 L/kg; and Cl of 5.02?±?0.46 mL/kg/h. Wiest et al. [21], on their part reported t½el values of 2.09 h; Vd, of 1.61 L/kg; and Cl of 13.9 mL/kg/h in neonates from 2 to 21 months of age. A comparison of Vd values in both studies with 1.6 L/kg reported in adults by Schaiquevich et al., [22], reveals that plasma protein binding and tissue distributions of this drug are similar in different age groups.
The value of t½el in the study of Fontana et al. [20], was more prolonged than that reported by Wiest et al. [21] (3.45 vs 2.09 h). Consequently, Cl was less (5.02 vs 13.9 mL/kg/h). In a study carried out by Mallet et al. [4], t½el value of 2.8 h was obtained in neonates of 6 weeks to 6 months old while in other studies made in older neonates by Zhang et al., [23] and in adult by Schaiquevich et al., [22], t½el values of 1.8 and 1.9 h respectively were 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 neonates where t½el values were found to increase in the first three weeks of neonatal life [24].
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 ranitidine pharmacokinetics and other drugs that are usually combined with it for the treatment of this pathology is important, 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, antacids and other drugs. In the present study, total clearance of ranitidine was well correlated with glomerular filtration velocity. An administration of ranitidine (3 mg/kg/24 h) 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, and that the treatment response must be monitored with repeated measurement of gastric pH and the doses adjusted in conformity with the response obtained.
This study would permit the determination and identification of ranitidine concentrations in newborn patients. Kuusela, [25] studied critically ill pre-term and full-term newborns to determine the optimum ranitidine doses through gastric pH monitoring. The same was investigated by Fontana et al. [12]. 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 in order to maintain their intraluminal gastric pH over 4.
The prevailing adjusted doses on prescription of this drug for newborn patients have the disadvantage of either sub-therapeutic concentration levels or concentration levels with high risk of overdosing [26]. Therefore, the identification of these concentrations is of paramount importance if we want to get the maximum therapeutic benefit. The results of the present study suggest a modification in the treatment regimens in Neonatology service of General Hospital of Durango, Mexico, as was recommended in previous studies [27, 28].