PHARMACOKINETICS OF
INTRAVENOUS OMEPRAZOLE IN NEONATES AND INFANTS
Andersson T1, Göthberg G2,
Friberg L2, Gatzinsky V2, Lundborg P3,
Rosen E3
1 Clinical Pharmacology,
AstraZeneca LP, Wayne, PA, USA
2 Östra Hospital,
Göteborg, Sweden
3 Clinical Research &
Development, AstraZeneca, Mölndal, Sweden
Objective: To determine the
pharmacokinetics (PK) of an intravenous dose at steady state of omeprazole
in young children requiring acid suppression.
Methods: 8 patients, aged 8 days
to 17 months, received omeprazole 0.4-1.2 mg/kg bid. Plasma concentrations
of parent compound and metabolites were determined over 6 hours post-dose.
Results: In the very young
children, <10 days (n=3), the t½ and clearance of
omeprazole, 1.6-2.1 hrs and 0.12-0.20 L/h/kg, respectively, is
substantially longer and lower, respectively, than the corresponding values
in the children aged 4.5-17 months (n=5) and in adults reported previously.
These t½ and clearance values expressed per body weight are
closer to those previously reported in poor metabolizers (PM) with regard
to CYP2C19. There is also a 5 months child that shows a very low metabolism
rate of omeprazole. This child is most probably inhibited by concomitant
fluconazole, but may also be a PM. A high ratio between the area under the
plasma concentration vs time curve (AUC) of omeprazole and the AUC of the
hydroxy-metabolite (OH) in 2 of the 3 very young children together with a
long t½ of the sulphone metabolite (S), 11-25 hrs, demonstrate a
low CYP2C19 activity. The S t½ in the 4.5-17 months old, 2.1-3.5
hrs, equals that in normal adults reported previously.
The t½ of OH is a reflection
of CYP3A4 activity, since CYP3A4 is responsible for the elimination of OH.
The long OH t½ of 3-10 hrs in the very young children, suggests
also a low CYP3A4 activity. In the rest of the children, the OH t½
was 0.75-1.2 hrs, equals that in normal adults reported previously.
Conclusion: Very young children, <10
days, metabolize omeprazole and form the two major metabolites, the
hydroxy- and the sulphone-metabolites, but at a lower rate than children
4.5-17 months, suggesting that CYPs 2C19 and 3A4 are not fully mature at
this young age. In children aged 4.5-17 months, the metabolism rate seems
to be within the range reported in adults.