- Email: [email protected]
Pharmacokinetics of orally administered omeprazole in children
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2000 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 95, No. 11, 2000 ISSN 0002-9270/00/$20.00 PII S0002-9270(00)02049-9
Pharmacokinetics of Orally Administered Omeprazole in Children Tommy Andersson, Ph.D., Eric Hassall, M.B.Ch.B., F.R.C.P.C., Per Lundborg, M.D., Ph.D., Ross Shepherd, M.D., F.R.A.C.P., Michael Radke, M.D., Margaret Marcon, M.D., F.R.C.P.C., Agneta Dalva¨g, M.Sc., Steve Martin, M.D., F.R.C.P.C., Rolf Behrens, M.D., Sibylle Koletzko, M.D., Michael Becker, M.D., Eric Drouin, M.D., F.R.C.P.C., and Gunnar Go¨thberg, M.D., The International Pediatric Omeprazole Pharmacokinetic Group
OBJECTIVES: The aim of this study was to examine the pharmacokinetics of orally administered omeprazole in children. METHODS: Plasma concentrations of omeprazole were measured at steady state over a 6-h period after administration of the drug. Patients were a subset of those in a multicenter study to determine the dose, safety, efficacy, and tolerability of omeprazole in the treatment of erosive reflux esophagitis in children. Children were 1–16 yr of age, with erosive esophagitis and pathological acid reflux on 24 h-intraesophageal pH study. The “healing dose” of omeprazole was that at which subsequent intraesophageal pH study normalized. Children remained on this dose for 3 months, and during this period the pharmacokinetics were measured. RESULTS: A total of 57 children were enrolled in the overall healing phase of the study. Pharmacokinetic study was optional for subjects and was performed in 25 of the 57 enrolled. The doses of omeprazole required were substantially higher doses per kilogram of body weight than in adults. Values of the pharmacokinetic parameters of omeprazole were generally within the ranges previously reported in adults. However, the plasma levels, area under the plasma concentration versus time curve (AUC), plasma halflife (t ⁄ ), and maximal plasma concentration (Cmax), were lower in the younger age group, when the AUC and Cmax were normalized to a dose of 1 mg/kg. Furthermore, within the group as a whole, these values showed a gradation from lowest in the children 1– 6 yr of age to higher in the older age groups. 12
CONCLUSIONS: The pharmacokinetics of omeprazole in children showed a trend toward higher metabolic capacity with decreasing age, being highest at 1– 6 yr of age. This may explain the need for higher doses of omeprazole on a per kilogram basis, not only in children overall compared with adults but, in many cases, particularly in younger children. (Am J Gastroenterol 2000;95:3101–3106. © 2000 by Am. Coll. of Gastroenterology)
INTRODUCTION When gastroesophageal reflux (GER) results in complications, it is referred to as gastroesophageal reflux disease
(GERD). The complications of GER, such as esophagitis, stricture, Barrett’s esophagus, pulmonary disease, failure to thrive, and Sandifer’s syndrome, are well recognized to occur in children (1, 2). Although treatment of mild GER with histamine H2-receptor antagonists (H2RA) and/or prokinetics often is effective, proton pump inhibitors (PPIs) have been shown to be clearly superior to H2RA for treatment of severe GERD, maintenance of remission, and prevention of complications in adults (3– 6). In children, omeprazole has been shown to be safe and effective for treatment of erosive esophagitis and GERD symptoms that are refractory to other measures (7–10). Proton pump inhibitors block the final common pathway of acid secretion at the luminal surface of the parietal cell by binding to H⫹K⫹-ATPase, the so-called “acid pump” or “proton pump,” thereby providing potent suppression of gastric acid. Despite the relatively short half-life in plasma of omeprazole (⬍1 h in most cases), clinically adequate suppression of acid secretion lasts 12–15 h with a single morning dose, because of the covalent binding of omeprazole with proton pumps exposed at the parietal cell lumen. This explains why the degree and duration of acid suppression in a given individual is not directly related to the plasma concentration of the drug at any given time; however, it does correlate with the area under the plasma concentration versus time curve (AUC) (11). With the increasing use of orally administered PPIs in children, an understanding of age-related pharmacokinetics becomes important. The aim of this study was to determine the pharmacokinetics of orally administered omeprazole in children.
MATERIALS AND METHODS Patients The pharmacokinetic study was performed in a subset of children enrolled in a study of the efficacy, safety, and tolerability of omeprazole for healing of erosive esophagitis. Informed consent was obtained for the study, which was approved by the ethics review board at each participating institution. Although the methods of the pharmacokinetic
3102
Andersson et al.
study are presented here in detail, those for the overall study are described in detail elsewhere (8) and presented in brief as follows. Study Design Children ages 1–16 yr with both endoscopically diagnosed erosive esophagitis and pathological acid reflux on 24 hintraesophageal pH study were recruited for a multicenter international study. The “healing dose” of omeprazole in each child was that which controlled pathological acid reflux, i.e., the dose at which intraesophageal pH was ⬍4 for ⱕ6% of a 24-h study. Omeprazole was given by mouth as intact capsules to children able to swallow, and as granules in those unable to swallow, by mouth in fruit juice or yoghurt, or by gastrostomy tube when necessary. The drug was given as a single daily dose with the first meal of the day in most patients, and as a twice-daily dose in a few patients with persistent nocturnal symptoms. Pharmacokinetic studies were performed using the healing dose of omeprazole determined for each child and were an optional part of the overall clinical study. Follow-up endoscopy was performed after 3 months on the healing dose. Blood Sampling for Pharmacokinetic Studies Pharmacokinetics were assessed in steady state conditions, i.e., when the patient had been receiving the healing dose of omeprazole for ⱖ7 days. When possible, blood samples were obtained for determination of omeprazole plasma levels over a 6-h period after drug intake. An indwelling cannula for blood sampling was inserted in a forearm vein and secured. A reference blood sample (0.5 ml) was collected, after which omeprazole was administered 15 min before breakfast. Tube-fed children received their usual feeds. Further blood samples (0.5 ml) for determination of omeprazole were collected in heparinized tubes at 0.5, 1, 1.5, 2, 3, 4, and 6 h after drug intake. The samples were kept at room temperature for ⱖ5 min and then centrifuged for 10 min. The plasma was then transferred to plastic tubes and stored frozen (⫺20°C) until analysis. The total amount of blood drawn from each patient for the pharmacokinetic study was ⱕ4 ml. The plasma was analyzed for omeprazole at Bioanalytical Chemistry, Astra Ha¨ssle AB, Mo¨lndal, Sweden, using liquid chromatography (12). Pharmacokinetic Calculations The area under the plasma concentration versus time curve (AUC) was calculated according to the trapezoidal method up to the last data point. The AUC values were then normalized to a 1.0 mg/kg dose of omeprazole, i.e., AUC/dose, and plotted against age. The plasma elimination half-life of omeprazole was calculated, when possible, by linear regression of the terminal phase of the plasma concentration versus time curve. The maximum plasma concentration, Cmax, and the time to reach Cmax (tmax) were recorded.
AJG – Vol. 95, No. 11, 2000
RESULTS Of 57 patients enrolled in the healing phase of the study, 25 patients from nine centers participated in the pharmacokinetic part of the study. Of the 25 children, eight were 1– 6 yr, 11 were 7–12 yr, and six were 13–16 yr of age. Their ages and weights, as well as underlying disease and any concomitant medications, are given in Table 1, as are the healing doses of omeprazole given at the time of pharmacokinetic study. The total daily dose varied between 7.5 mg and 80 mg (0.7–3.5 mg/kg). The plasma concentration versus time profile of omeprazole during steady state in one child (patient 47-1), representing the typical plasma profile obtained in this study, is presented in Figure 1. The AUC, t1/2, Cmax, and tmax of omeprazole from the 25 children investigated are given in Table 2. The potential influence of age on the pharmacokinetics of omeprazole was also visualized by plotting the dose-normalized AUC values against age (Fig. 2). The AUC of omeprazole varied between 0.3 mol/L 䡠 h and 22 mol/ L 䡠 h. The AUC as corrected for dose varied between 0.1 mol/L 䡠 h and 27 mol/L 䡠 h. The median AUC, both dose-normalized and absolute, was lowest in the youngest age group, with normalized AUCs ⬍50% of those observed in the two older age groups; in addition, the oldest age group had a higher median dose-normalized AUC value than the middle age group. One child (patient 45-2) concomitantly took phenobarbital, a known inducer of drug metabolism, and this patient had the lowest dose-normalized AUC value for omeprazole (0.1 mol/L 䡠 h). Maximal plasma concentrations were generally achieved within 2 h of administration of drug, seemingly independent of age. Although the dose-normalized Cmax values varied widely between subjects, overall (i.e., based on their median values) they seemed to be age-related, with lower normalized Cmax values occurring in younger children, as for the AUC. The plasma elimination half-life of omeprazole could be estimated in 12 of the 25 patients (four from each age group), and varied between 0.55 h and 2.6 h. In general, there seemed to be an age dependence for plasma elimination half-life, just as there seemed to be for the variables AUC and Cmax; that is, there were shorter half-lives in the younger children. One child (patient 24-1) was apparently an exception to this; although only 6.6 yr old, he had the longest plasma elimination half-life (2.6 h) reported in this study.
DISCUSSION To date, despite the increasing use of proton pump inhibitors in children (7–10), no systematic study of the pharmacokinetics of these drugs after oral administration has been performed. In a previous study, the pharmacokinetics of intravenous omeprazole were studied in a small number of children (13). However, the subjects in that study were
AJG – November, 2000
Pharmacokinetics of Omeprazole in Children
3103
Table 1. Demographic Data and Dose of Omeprazole in the 25 Children With Erosive Reflux Esophagitis Included in the Pharmacokinetic Study of Omeprazole Patient No.
Age (yr)
Weight (kg)
11-5 11-6 26–2 24-2 41-4 47-2 11-7
1.6 1.9 2.8 4.2 5.0 5.1 6.1
11.6 10.7 14.5 15.7 13.8 16.2 24.5
Median
4.2
14.5
42-1
6.7
24.5
24-1 11-4 45-2
7.0 8.4 9.3
18.2 27.0 21.0
11-8 25-2 11-1 52-1 41-3
9.6 10.7 11.2 11.8 12.5
43.4 39.0 68.0 39.0 61.4
9.6
39.0
47-1
12.6
25.0
None
11-3 26-3
12.7 12.8
49.0 26.4
41-2
14.6
27.6
41-1
15.0
52.5
45-1 24-4 41-5 26-1
15.3 15.3 16.1 16.2
57.6 72.2 63.2 66.5
None Neurological impairment Neurological impairment Esophageal atresia None None None None
Median
15.0
52.5
Median
Underlying Disease None None None None None None None
Neurological impairment None None Neurological impairment None None None None None
Concomitant Medication Cisapride Amoxicillin
Cisapride
Phenobarbital, baclofen, phytomenadione, valproate
Vigabatrine
Allopurinol, methylprednisolone, sulphasalazine Valproate
Norfenefrine
Dose (mg/kg)
Dose (mg)
Grade of Esophagits
1.7 0.7 3.6 1.3 2.2 1.2 0.6
20.0 7.5 52.5 20.0 30.0 20.0 15.0
3 3 4 3 2 4 2
1.3
20.0
3
1.6
40.0
3
2.7 0.6 3.3
50.0 17.5 70.0
2 2 3
0.7 0.6 0.7 1.4 0.7
30.0 25.0 45.0 55.0 42.5
2 3 2 2 2
0.7
42.5
2
0.7
17.5
4
0.7 0.8
32.5 20.0
2 2
1.4
37.5
3
1.5
80.0
3
1.3 1.1 1.3 0.8
75.0 80.0 80.0 50.0
3 4 2 4
1.1
50.0
3
Results are divided according to age group (1– 6 yr, 7–12 yr, and 13–16 yr).
Figure 1. Plasma concentrations of omeprazole in one child (patient 47-1) with representative plasma profiles.
severely ill, with several underlying conditions that made the administration of omeprazole by the oral route impossible, the dose being calculated on the basis of body surface area. It is very seldom that omeprazole is given by the intravenous route in children, and most studies in children have calculated dosage based on body weight in kilograms. For these reasons, it is difficult to extrapolate results from that study to the much more common circumstance of giving omeprazole by the oral route, about which, to our knowledge, there are no studies of pharmacokinetics in children. The results from the clinical part of our study (8) showed that omeprazole is a highly effective and safe treatment for
3104
Andersson et al.
AJG – Vol. 95, No. 11, 2000
Table 2. Individual Pharmacokinetic Variables (AUC, t1/2, Cmax, and tmax) on Omeprazole, Including Dose Normalized Values on AUC and Cmax at Steady State Dosing in 25 children With Erosive Reflux Esophagitis Patient No. 11-5 11-6 26-2 24-2 41-4 47-2 11-7 Median 42-1 24-1 11-4 45-2 11-8 25-2 11-1 52-1 41-3 Median 47.1 11-3 26-3 41-2 41-1 45-1 24-4 41-5 26-1 Median
AUC (mol/L 䡠 h)
AUC-normal (mol/L 䡠 h)
5.8 0.3 12 1.1 11 7.3 1.6
t1/2 (h)
Cmax (mol/L)
Cmax-normal (mol/L)
tmax (h)
3.4 0.4 3.3 0.9 4.9 5.9 2.6
0.71
4.9 0.1 3.7 0.8 5.5 4.3 1.2
2.8 0.14 1.0 0.6 2.5 3.5 2.0
1.0 3.0 6.0 0.5 2.0 1.0 3.0
5.8
3.3
0.85
3.7
2.0
2.0
1.2 20 3.6 0.3 9.1 4.7 8.3 11 19
0.7 7.1 5.6 0.1 13 7.3 12 7.9 27
1.2 8.2 0.8 0.2 2.9 3.0 3.1 4.6 4.4
0.7 3.0 1.2 0.06 4.2 4.7 4.7 3.3 6.4
0.5 1.0 1.5 6.0 1.5 0.5 4.0 4.0 2.0
8.3
7.3
1.74
3.0
3.3
1.5
2.6 7.5 1.3 3.2 22 22 16 21 9.9
3.7 11 1.7 2.4 15 17 15 17 13
1.05
1.5 2.3 0.9 1.3 8.0 7.1 5.2 5.5 2.7
2.1 3.5 1.2 1.0 5.3 5.5 4.7 4.3 3.6
1.0 2.0 4.2 4.0 2.0 1.0 3.0 2.0 4.0
13
1.58
2.7
3.6
2.0
9.9
0.65 0.99 1.24
2.57 1.74 0.58
1.58 0.55 2.00 2.18
AUC ⫽ area under the plasma concentration vs time curve.
children with erosive esophagitis and symptoms of GERD. About half of the patients were healed on a daily dose of 0.7 mg/kg body weight, and another 20% were healed on 1.4 mg/kg/day. Thus, almost 75% of patients were healed on doses up to 1.4 mg/kg/day. With regard to the pharmacokinetic evaluation of drugs in children, of relevance is the ontogenic development of var-
Figure 2. Area under the plasma concentration versus time curve (AUC) values normalized by dose (AUC/dose in mg/kg) and plotted against age.
ious processes involved in the disposition of drugs. Many factors that determine drug disposition differ not only between children and adults but also between children of different ages, where the greatest differences may be found (14, 15). Therefore, it is important in this context to separate children with respect to age. The metabolism of drugs, including that by the cytochrome P450 system (CYP), seems to be subject to continuous changes up to puberty, and also to vary between individual isoenzymes (14, 15). In adults, omeprazole is completely metabolized, largely by the enzyme CYP2C19, with CYP3A playing a minor role (16 –18). Although the development of different CYP isoforms does not follow a uniform pattern, most CYP isoforms start to develop at birth reaching almost adult levels before 1 yr of age (19, 20). After the first year or so of life, children exhibit apparent metabolic rates that are severalfold higher than those observed in adults (21). Thereafter, a gradual decline is observed and metabolic rates similar to those in adults are reached around puberty. The isoform CYP2C19, which is almost wholly responsible for omeprazole metabolism, starts to develop at birth (20, 22). As both omeprazole and diazepam are metabolized by this enzyme
AJG – November, 2000
(16, 23), studies of the ontogeny of 2C19 using diazepam as substrate may serve as a guide to omeprazole metabolism. With diazepam, low activity of 2C19 was observed at birth, but at least half the activity of adult livers was observed in the livers of children at the age of 9 months (24). Another study reported a 3-fold longer elimination half-life of diazepam in neonates and infants ⬍6 months of age than in children ⬃5 yr of age (25), which could indicate a similar elimination pattern for omeprazole in the neonatal and infant stages, i.e., up to 1 yr. In the present study, however, the youngest child investigated was 1.6 yr; thus, the pharmacokinetics in children ⬍1 yr could not be evaluated. The data from this study are similar to those in adults in that, between individuals, there is wide variation in parameters measured and calculated. Although the pediatric AUC values were within the upper range of what has previously been reported with therapeutic doses in adults, the actual values for pharmacokinetic variables were within the ranges previously reported for adults (26). However, the children achieved these values generally with considerably greater doses on a per kilogram basis than in adults. The lowest two doses required for healing in children (0.7 and 1.4 mg/kg/ day) translate to dose requirements of 50 –110 mg for adults 70 – 80 kg in body weight; and the highest (3.5 mg/kg/day), to up to 260 mg/day. This, in and of itself, suggests that children overall have a higher metabolic capacity than do adults. Within the group of children, the values for AUC, AUC normalized, half-life, Cmax, and Cmax normalized all show a gradation from lowest in the children aged 1– 6 yr, to higher in those aged 7–12 yr, to highest in those 13–16 yr (for median values, see Table 2). This suggests an increasing metabolic rate with decreasing age in childhood. Somewhat puzzling is the fact that younger children experience healing of their esophagitis and obtained relief of GERD symptoms despite lower absolute median AUCs than did the older children. Although it is possible that the youngest children were more sensitive to therapy or had less chronic or “established” esophagitis, the wide range of absolute AUC values does not allow us to draw this conclusion; studies in larger numbers of young children would be required to verify this. One child, aged 9 yr, had the lowest AUC of all studied, some 25 times lower than the median for his age group. This can be explained by his concomitant phenobarbital therapy for seizures; this drug is well recognized to induce CYP2C isoforms (20, 25). The property of induction by phenobarbital has been shown for diazepam and is apparently present soon after birth (20). In contrast, patient no. 24-1, with the longest omeprazole half-life in the study, was receiving no other medication, and could therefore be a slow metabolizer of omeprazole, a circumstance present in about 3% of Caucasians (16). In conclusion, for omeprazole, these results suggest an increasing metabolic rate with decreasing age down to the second year of life in childhood. It is likely that this increased metabolic capacity is the major factor that accounts
Pharmacokinetics of Omeprazole in Children
3105
for higher dose requirements of omeprazole in young children compared with older children and adults. Pharmacokinetics for omeprazole have not been established for children below age 1 yr. Reprint requests and correspondence: Tommy Andersson, Ph.D., AstraZeneca LP, 725 Chesterbrook Blvd., Wayne, PA 19087-5677. Received Oct. 27, 1999; accepted Jan. 6, 2000.
REFERENCES 1. Orenstein SR. Gastroesophageal reflux disease. Semin Gastrointest Dis 1994;5:2–14. 2. Hassall E. Barrett’s esophagus: New definitions and approaches in children. J Pediatr Gastroenterol Nutr 1993;16: 345– 64. 3. Sontag SJ, Hirschowitz BI, Holt S, et al. Two doses of omeprazole versus placebo in symptomatic erosive esophagitis: The U.S. multicenter study. Gastroenterology 1992;102:109 – 18. 4. Klinkenberg-Knol EC, Jansen JMBJ, Festen HPM, et al. Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux esophagitis. Lancet 1987;1:349 –51. 5. Dent J, Yeomans ND, Mackinnon M, et al. Omeprazole v. ranitidine for prevention of relapse in reflux oesophagitis. A controlled double blind trial of their efficacy and safety. Gut 1994;35:590 – 8. 6. Marks RD, Richter JE, Rizzo J, et al. Omeprazole versus H2-receptor antagonists in treating patients with peptic stricture, and esophagitis. Gastroenterology 1994;106:97–115. 7. Gunasekaran TS, Hassall E. Safety and efficacy of omeprazole for severe gastroesophageal reflux in children. J Pediatr 1993; 123:148 –54. 8. Hassall E, Israel D, Shepherd R, et al. Omeprazole for treatment of chronic erosive esophagitis in children: A multicenter study of safety, tolerability and dose requirements. J Pediatr 2000 (in press). 9. De Giacomo C, Bawa P, Franceschi M, et al. Omeprazole for severe reflux esophagitis in children. J Pediatr Gastroenterol Nutr 1997;24:528 –32. 10. Kato S, Ebina K, Fojii K, et al. Effect of omeprazole in the treatment of refractory acid related disease in childhood: Endoscopic healing and twenty-four-hour intragastric acidity. J Pediatr 1996;128:415–21. 11. Lind T, Cederberg C, Ekenved G, et al. Effect of omeprazole—A gastric proton pump inhibitor—On pentagastrin stimulated acid secretion in man. Gut 1983;24:270 – 6. 12. Lagerstro¨m P-O, Persson B-A. Determination of omeprazole and metabolites in plasma and urine by liquid chromatography. J Chromatogr 1984;309:347–56. 13. Jacqz-Aigrain E, Bellaich M, Faure C, et al. Pharmacokinetics of intravenous omeprazole in children. Eur J Clin Pharmacol 1994;47:181–5. 14. Rane A. Drug disposition and action in infants and children. In: Yaffe SJ, Aranda JV, eds. Pediatric pharmacology. Therapeutic principles in practice, 2nd ed. Philadelphia: Saunders, 1992:10 –21. 15. Leeder JS, Kearns GL. Pharmacogenetics in pediatrics: Implications for practice. Pediatr Clin North Am 1997;44:55–77. 16. Andersson T, Regårdh CG, Dahl-Puustinen ML, et al. Slow omeprazole metabolizers are also poor S-mephenytoin hydroxylators. Ther Drug Monit 1990;12:415– 6. 17. Andersson T, Miners JO, Veronese ME, et al. Identification of
3106
18.
19. 20.
21. 22.
Andersson et al.
human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol 1993;36:521–30. Chiba K, Kobayashi K, Manabe K, et al. Oxidative metabolism of omeprazole in human liver microsomes: Cosegregation with S-mephenytoin 4⬘-hydroxylation. J Pharmacol Exp Ther 1993;266:52–9. Carrier O, Pons G, Rey E, et al. Maturation of caffeine metabolic pathways in infancy. Clin Pharmacol Ther 1988;44:145–51. Treluyer JM, Gueret G, Cheron G, et al. Developmental expression of CYP2C and CYP2C-dependent activities in the human liver: In-vivo/in-vitro correlation and inducibility. Pharmacogenetics 1997;7:441–52. Lambert GH, Schoeller DA, Kotake AN, et al. The effect of age, gender, and sexual maturation on the caffeine breath test. Dev Pharmacol Ther 1986;9:375– 88. Kearns GL. Pharmacogenetics and development: Are infants
AJG – Vol. 95, No. 11, 2000
23.
24. 25. 26.
and children at increased risk for adverse outcomes? Curr Opin Pediatr 1995;7:220 –33. Andersson T, Miners JO, Veronese ME, et al. Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br J Clin Pharmacol 1994;38:131–7. Treluyer JM, Cheron G, Sonnier M, et al. Cytochrome P-450 expression in sudden infant death syndrome. Biochem Pharmacol 1996;52:497–504. Morselli PL, Principi N, Tognoni G, et al. Diazepam elimination in premature and full term infants, and children. J Perinat Med 1972;1:133– 41. Andersson T, Cederberg C, Heggelund A, et al. The pharmacokinetics of single and repeated once-daily doses of 10, 20 and 40 mg omeprazole as enteric-coated granules. Drug Invest 1991;3:45–52.
Vol. 95, No. 11, 2000 ISSN 0002-9270/00/$20.00 PII S0002-9270(00)02049-9
Pharmacokinetics of Orally Administered Omeprazole in Children Tommy Andersson, Ph.D., Eric Hassall, M.B.Ch.B., F.R.C.P.C., Per Lundborg, M.D., Ph.D., Ross Shepherd, M.D., F.R.A.C.P., Michael Radke, M.D., Margaret Marcon, M.D., F.R.C.P.C., Agneta Dalva¨g, M.Sc., Steve Martin, M.D., F.R.C.P.C., Rolf Behrens, M.D., Sibylle Koletzko, M.D., Michael Becker, M.D., Eric Drouin, M.D., F.R.C.P.C., and Gunnar Go¨thberg, M.D., The International Pediatric Omeprazole Pharmacokinetic Group
OBJECTIVES: The aim of this study was to examine the pharmacokinetics of orally administered omeprazole in children. METHODS: Plasma concentrations of omeprazole were measured at steady state over a 6-h period after administration of the drug. Patients were a subset of those in a multicenter study to determine the dose, safety, efficacy, and tolerability of omeprazole in the treatment of erosive reflux esophagitis in children. Children were 1–16 yr of age, with erosive esophagitis and pathological acid reflux on 24 h-intraesophageal pH study. The “healing dose” of omeprazole was that at which subsequent intraesophageal pH study normalized. Children remained on this dose for 3 months, and during this period the pharmacokinetics were measured. RESULTS: A total of 57 children were enrolled in the overall healing phase of the study. Pharmacokinetic study was optional for subjects and was performed in 25 of the 57 enrolled. The doses of omeprazole required were substantially higher doses per kilogram of body weight than in adults. Values of the pharmacokinetic parameters of omeprazole were generally within the ranges previously reported in adults. However, the plasma levels, area under the plasma concentration versus time curve (AUC), plasma halflife (t ⁄ ), and maximal plasma concentration (Cmax), were lower in the younger age group, when the AUC and Cmax were normalized to a dose of 1 mg/kg. Furthermore, within the group as a whole, these values showed a gradation from lowest in the children 1– 6 yr of age to higher in the older age groups. 12
CONCLUSIONS: The pharmacokinetics of omeprazole in children showed a trend toward higher metabolic capacity with decreasing age, being highest at 1– 6 yr of age. This may explain the need for higher doses of omeprazole on a per kilogram basis, not only in children overall compared with adults but, in many cases, particularly in younger children. (Am J Gastroenterol 2000;95:3101–3106. © 2000 by Am. Coll. of Gastroenterology)
INTRODUCTION When gastroesophageal reflux (GER) results in complications, it is referred to as gastroesophageal reflux disease
(GERD). The complications of GER, such as esophagitis, stricture, Barrett’s esophagus, pulmonary disease, failure to thrive, and Sandifer’s syndrome, are well recognized to occur in children (1, 2). Although treatment of mild GER with histamine H2-receptor antagonists (H2RA) and/or prokinetics often is effective, proton pump inhibitors (PPIs) have been shown to be clearly superior to H2RA for treatment of severe GERD, maintenance of remission, and prevention of complications in adults (3– 6). In children, omeprazole has been shown to be safe and effective for treatment of erosive esophagitis and GERD symptoms that are refractory to other measures (7–10). Proton pump inhibitors block the final common pathway of acid secretion at the luminal surface of the parietal cell by binding to H⫹K⫹-ATPase, the so-called “acid pump” or “proton pump,” thereby providing potent suppression of gastric acid. Despite the relatively short half-life in plasma of omeprazole (⬍1 h in most cases), clinically adequate suppression of acid secretion lasts 12–15 h with a single morning dose, because of the covalent binding of omeprazole with proton pumps exposed at the parietal cell lumen. This explains why the degree and duration of acid suppression in a given individual is not directly related to the plasma concentration of the drug at any given time; however, it does correlate with the area under the plasma concentration versus time curve (AUC) (11). With the increasing use of orally administered PPIs in children, an understanding of age-related pharmacokinetics becomes important. The aim of this study was to determine the pharmacokinetics of orally administered omeprazole in children.
MATERIALS AND METHODS Patients The pharmacokinetic study was performed in a subset of children enrolled in a study of the efficacy, safety, and tolerability of omeprazole for healing of erosive esophagitis. Informed consent was obtained for the study, which was approved by the ethics review board at each participating institution. Although the methods of the pharmacokinetic
3102
Andersson et al.
study are presented here in detail, those for the overall study are described in detail elsewhere (8) and presented in brief as follows. Study Design Children ages 1–16 yr with both endoscopically diagnosed erosive esophagitis and pathological acid reflux on 24 hintraesophageal pH study were recruited for a multicenter international study. The “healing dose” of omeprazole in each child was that which controlled pathological acid reflux, i.e., the dose at which intraesophageal pH was ⬍4 for ⱕ6% of a 24-h study. Omeprazole was given by mouth as intact capsules to children able to swallow, and as granules in those unable to swallow, by mouth in fruit juice or yoghurt, or by gastrostomy tube when necessary. The drug was given as a single daily dose with the first meal of the day in most patients, and as a twice-daily dose in a few patients with persistent nocturnal symptoms. Pharmacokinetic studies were performed using the healing dose of omeprazole determined for each child and were an optional part of the overall clinical study. Follow-up endoscopy was performed after 3 months on the healing dose. Blood Sampling for Pharmacokinetic Studies Pharmacokinetics were assessed in steady state conditions, i.e., when the patient had been receiving the healing dose of omeprazole for ⱖ7 days. When possible, blood samples were obtained for determination of omeprazole plasma levels over a 6-h period after drug intake. An indwelling cannula for blood sampling was inserted in a forearm vein and secured. A reference blood sample (0.5 ml) was collected, after which omeprazole was administered 15 min before breakfast. Tube-fed children received their usual feeds. Further blood samples (0.5 ml) for determination of omeprazole were collected in heparinized tubes at 0.5, 1, 1.5, 2, 3, 4, and 6 h after drug intake. The samples were kept at room temperature for ⱖ5 min and then centrifuged for 10 min. The plasma was then transferred to plastic tubes and stored frozen (⫺20°C) until analysis. The total amount of blood drawn from each patient for the pharmacokinetic study was ⱕ4 ml. The plasma was analyzed for omeprazole at Bioanalytical Chemistry, Astra Ha¨ssle AB, Mo¨lndal, Sweden, using liquid chromatography (12). Pharmacokinetic Calculations The area under the plasma concentration versus time curve (AUC) was calculated according to the trapezoidal method up to the last data point. The AUC values were then normalized to a 1.0 mg/kg dose of omeprazole, i.e., AUC/dose, and plotted against age. The plasma elimination half-life of omeprazole was calculated, when possible, by linear regression of the terminal phase of the plasma concentration versus time curve. The maximum plasma concentration, Cmax, and the time to reach Cmax (tmax) were recorded.
AJG – Vol. 95, No. 11, 2000
RESULTS Of 57 patients enrolled in the healing phase of the study, 25 patients from nine centers participated in the pharmacokinetic part of the study. Of the 25 children, eight were 1– 6 yr, 11 were 7–12 yr, and six were 13–16 yr of age. Their ages and weights, as well as underlying disease and any concomitant medications, are given in Table 1, as are the healing doses of omeprazole given at the time of pharmacokinetic study. The total daily dose varied between 7.5 mg and 80 mg (0.7–3.5 mg/kg). The plasma concentration versus time profile of omeprazole during steady state in one child (patient 47-1), representing the typical plasma profile obtained in this study, is presented in Figure 1. The AUC, t1/2, Cmax, and tmax of omeprazole from the 25 children investigated are given in Table 2. The potential influence of age on the pharmacokinetics of omeprazole was also visualized by plotting the dose-normalized AUC values against age (Fig. 2). The AUC of omeprazole varied between 0.3 mol/L 䡠 h and 22 mol/ L 䡠 h. The AUC as corrected for dose varied between 0.1 mol/L 䡠 h and 27 mol/L 䡠 h. The median AUC, both dose-normalized and absolute, was lowest in the youngest age group, with normalized AUCs ⬍50% of those observed in the two older age groups; in addition, the oldest age group had a higher median dose-normalized AUC value than the middle age group. One child (patient 45-2) concomitantly took phenobarbital, a known inducer of drug metabolism, and this patient had the lowest dose-normalized AUC value for omeprazole (0.1 mol/L 䡠 h). Maximal plasma concentrations were generally achieved within 2 h of administration of drug, seemingly independent of age. Although the dose-normalized Cmax values varied widely between subjects, overall (i.e., based on their median values) they seemed to be age-related, with lower normalized Cmax values occurring in younger children, as for the AUC. The plasma elimination half-life of omeprazole could be estimated in 12 of the 25 patients (four from each age group), and varied between 0.55 h and 2.6 h. In general, there seemed to be an age dependence for plasma elimination half-life, just as there seemed to be for the variables AUC and Cmax; that is, there were shorter half-lives in the younger children. One child (patient 24-1) was apparently an exception to this; although only 6.6 yr old, he had the longest plasma elimination half-life (2.6 h) reported in this study.
DISCUSSION To date, despite the increasing use of proton pump inhibitors in children (7–10), no systematic study of the pharmacokinetics of these drugs after oral administration has been performed. In a previous study, the pharmacokinetics of intravenous omeprazole were studied in a small number of children (13). However, the subjects in that study were
AJG – November, 2000
Pharmacokinetics of Omeprazole in Children
3103
Table 1. Demographic Data and Dose of Omeprazole in the 25 Children With Erosive Reflux Esophagitis Included in the Pharmacokinetic Study of Omeprazole Patient No.
Age (yr)
Weight (kg)
11-5 11-6 26–2 24-2 41-4 47-2 11-7
1.6 1.9 2.8 4.2 5.0 5.1 6.1
11.6 10.7 14.5 15.7 13.8 16.2 24.5
Median
4.2
14.5
42-1
6.7
24.5
24-1 11-4 45-2
7.0 8.4 9.3
18.2 27.0 21.0
11-8 25-2 11-1 52-1 41-3
9.6 10.7 11.2 11.8 12.5
43.4 39.0 68.0 39.0 61.4
9.6
39.0
47-1
12.6
25.0
None
11-3 26-3
12.7 12.8
49.0 26.4
41-2
14.6
27.6
41-1
15.0
52.5
45-1 24-4 41-5 26-1
15.3 15.3 16.1 16.2
57.6 72.2 63.2 66.5
None Neurological impairment Neurological impairment Esophageal atresia None None None None
Median
15.0
52.5
Median
Underlying Disease None None None None None None None
Neurological impairment None None Neurological impairment None None None None None
Concomitant Medication Cisapride Amoxicillin
Cisapride
Phenobarbital, baclofen, phytomenadione, valproate
Vigabatrine
Allopurinol, methylprednisolone, sulphasalazine Valproate
Norfenefrine
Dose (mg/kg)
Dose (mg)
Grade of Esophagits
1.7 0.7 3.6 1.3 2.2 1.2 0.6
20.0 7.5 52.5 20.0 30.0 20.0 15.0
3 3 4 3 2 4 2
1.3
20.0
3
1.6
40.0
3
2.7 0.6 3.3
50.0 17.5 70.0
2 2 3
0.7 0.6 0.7 1.4 0.7
30.0 25.0 45.0 55.0 42.5
2 3 2 2 2
0.7
42.5
2
0.7
17.5
4
0.7 0.8
32.5 20.0
2 2
1.4
37.5
3
1.5
80.0
3
1.3 1.1 1.3 0.8
75.0 80.0 80.0 50.0
3 4 2 4
1.1
50.0
3
Results are divided according to age group (1– 6 yr, 7–12 yr, and 13–16 yr).
Figure 1. Plasma concentrations of omeprazole in one child (patient 47-1) with representative plasma profiles.
severely ill, with several underlying conditions that made the administration of omeprazole by the oral route impossible, the dose being calculated on the basis of body surface area. It is very seldom that omeprazole is given by the intravenous route in children, and most studies in children have calculated dosage based on body weight in kilograms. For these reasons, it is difficult to extrapolate results from that study to the much more common circumstance of giving omeprazole by the oral route, about which, to our knowledge, there are no studies of pharmacokinetics in children. The results from the clinical part of our study (8) showed that omeprazole is a highly effective and safe treatment for
3104
Andersson et al.
AJG – Vol. 95, No. 11, 2000
Table 2. Individual Pharmacokinetic Variables (AUC, t1/2, Cmax, and tmax) on Omeprazole, Including Dose Normalized Values on AUC and Cmax at Steady State Dosing in 25 children With Erosive Reflux Esophagitis Patient No. 11-5 11-6 26-2 24-2 41-4 47-2 11-7 Median 42-1 24-1 11-4 45-2 11-8 25-2 11-1 52-1 41-3 Median 47.1 11-3 26-3 41-2 41-1 45-1 24-4 41-5 26-1 Median
AUC (mol/L 䡠 h)
AUC-normal (mol/L 䡠 h)
5.8 0.3 12 1.1 11 7.3 1.6
t1/2 (h)
Cmax (mol/L)
Cmax-normal (mol/L)
tmax (h)
3.4 0.4 3.3 0.9 4.9 5.9 2.6
0.71
4.9 0.1 3.7 0.8 5.5 4.3 1.2
2.8 0.14 1.0 0.6 2.5 3.5 2.0
1.0 3.0 6.0 0.5 2.0 1.0 3.0
5.8
3.3
0.85
3.7
2.0
2.0
1.2 20 3.6 0.3 9.1 4.7 8.3 11 19
0.7 7.1 5.6 0.1 13 7.3 12 7.9 27
1.2 8.2 0.8 0.2 2.9 3.0 3.1 4.6 4.4
0.7 3.0 1.2 0.06 4.2 4.7 4.7 3.3 6.4
0.5 1.0 1.5 6.0 1.5 0.5 4.0 4.0 2.0
8.3
7.3
1.74
3.0
3.3
1.5
2.6 7.5 1.3 3.2 22 22 16 21 9.9
3.7 11 1.7 2.4 15 17 15 17 13
1.05
1.5 2.3 0.9 1.3 8.0 7.1 5.2 5.5 2.7
2.1 3.5 1.2 1.0 5.3 5.5 4.7 4.3 3.6
1.0 2.0 4.2 4.0 2.0 1.0 3.0 2.0 4.0
13
1.58
2.7
3.6
2.0
9.9
0.65 0.99 1.24
2.57 1.74 0.58
1.58 0.55 2.00 2.18
AUC ⫽ area under the plasma concentration vs time curve.
children with erosive esophagitis and symptoms of GERD. About half of the patients were healed on a daily dose of 0.7 mg/kg body weight, and another 20% were healed on 1.4 mg/kg/day. Thus, almost 75% of patients were healed on doses up to 1.4 mg/kg/day. With regard to the pharmacokinetic evaluation of drugs in children, of relevance is the ontogenic development of var-
Figure 2. Area under the plasma concentration versus time curve (AUC) values normalized by dose (AUC/dose in mg/kg) and plotted against age.
ious processes involved in the disposition of drugs. Many factors that determine drug disposition differ not only between children and adults but also between children of different ages, where the greatest differences may be found (14, 15). Therefore, it is important in this context to separate children with respect to age. The metabolism of drugs, including that by the cytochrome P450 system (CYP), seems to be subject to continuous changes up to puberty, and also to vary between individual isoenzymes (14, 15). In adults, omeprazole is completely metabolized, largely by the enzyme CYP2C19, with CYP3A playing a minor role (16 –18). Although the development of different CYP isoforms does not follow a uniform pattern, most CYP isoforms start to develop at birth reaching almost adult levels before 1 yr of age (19, 20). After the first year or so of life, children exhibit apparent metabolic rates that are severalfold higher than those observed in adults (21). Thereafter, a gradual decline is observed and metabolic rates similar to those in adults are reached around puberty. The isoform CYP2C19, which is almost wholly responsible for omeprazole metabolism, starts to develop at birth (20, 22). As both omeprazole and diazepam are metabolized by this enzyme
AJG – November, 2000
(16, 23), studies of the ontogeny of 2C19 using diazepam as substrate may serve as a guide to omeprazole metabolism. With diazepam, low activity of 2C19 was observed at birth, but at least half the activity of adult livers was observed in the livers of children at the age of 9 months (24). Another study reported a 3-fold longer elimination half-life of diazepam in neonates and infants ⬍6 months of age than in children ⬃5 yr of age (25), which could indicate a similar elimination pattern for omeprazole in the neonatal and infant stages, i.e., up to 1 yr. In the present study, however, the youngest child investigated was 1.6 yr; thus, the pharmacokinetics in children ⬍1 yr could not be evaluated. The data from this study are similar to those in adults in that, between individuals, there is wide variation in parameters measured and calculated. Although the pediatric AUC values were within the upper range of what has previously been reported with therapeutic doses in adults, the actual values for pharmacokinetic variables were within the ranges previously reported for adults (26). However, the children achieved these values generally with considerably greater doses on a per kilogram basis than in adults. The lowest two doses required for healing in children (0.7 and 1.4 mg/kg/ day) translate to dose requirements of 50 –110 mg for adults 70 – 80 kg in body weight; and the highest (3.5 mg/kg/day), to up to 260 mg/day. This, in and of itself, suggests that children overall have a higher metabolic capacity than do adults. Within the group of children, the values for AUC, AUC normalized, half-life, Cmax, and Cmax normalized all show a gradation from lowest in the children aged 1– 6 yr, to higher in those aged 7–12 yr, to highest in those 13–16 yr (for median values, see Table 2). This suggests an increasing metabolic rate with decreasing age in childhood. Somewhat puzzling is the fact that younger children experience healing of their esophagitis and obtained relief of GERD symptoms despite lower absolute median AUCs than did the older children. Although it is possible that the youngest children were more sensitive to therapy or had less chronic or “established” esophagitis, the wide range of absolute AUC values does not allow us to draw this conclusion; studies in larger numbers of young children would be required to verify this. One child, aged 9 yr, had the lowest AUC of all studied, some 25 times lower than the median for his age group. This can be explained by his concomitant phenobarbital therapy for seizures; this drug is well recognized to induce CYP2C isoforms (20, 25). The property of induction by phenobarbital has been shown for diazepam and is apparently present soon after birth (20). In contrast, patient no. 24-1, with the longest omeprazole half-life in the study, was receiving no other medication, and could therefore be a slow metabolizer of omeprazole, a circumstance present in about 3% of Caucasians (16). In conclusion, for omeprazole, these results suggest an increasing metabolic rate with decreasing age down to the second year of life in childhood. It is likely that this increased metabolic capacity is the major factor that accounts
Pharmacokinetics of Omeprazole in Children
3105
for higher dose requirements of omeprazole in young children compared with older children and adults. Pharmacokinetics for omeprazole have not been established for children below age 1 yr. Reprint requests and correspondence: Tommy Andersson, Ph.D., AstraZeneca LP, 725 Chesterbrook Blvd., Wayne, PA 19087-5677. Received Oct. 27, 1999; accepted Jan. 6, 2000.
REFERENCES 1. Orenstein SR. Gastroesophageal reflux disease. Semin Gastrointest Dis 1994;5:2–14. 2. Hassall E. Barrett’s esophagus: New definitions and approaches in children. J Pediatr Gastroenterol Nutr 1993;16: 345– 64. 3. Sontag SJ, Hirschowitz BI, Holt S, et al. Two doses of omeprazole versus placebo in symptomatic erosive esophagitis: The U.S. multicenter study. Gastroenterology 1992;102:109 – 18. 4. Klinkenberg-Knol EC, Jansen JMBJ, Festen HPM, et al. Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux esophagitis. Lancet 1987;1:349 –51. 5. Dent J, Yeomans ND, Mackinnon M, et al. Omeprazole v. ranitidine for prevention of relapse in reflux oesophagitis. A controlled double blind trial of their efficacy and safety. Gut 1994;35:590 – 8. 6. Marks RD, Richter JE, Rizzo J, et al. Omeprazole versus H2-receptor antagonists in treating patients with peptic stricture, and esophagitis. Gastroenterology 1994;106:97–115. 7. Gunasekaran TS, Hassall E. Safety and efficacy of omeprazole for severe gastroesophageal reflux in children. J Pediatr 1993; 123:148 –54. 8. Hassall E, Israel D, Shepherd R, et al. Omeprazole for treatment of chronic erosive esophagitis in children: A multicenter study of safety, tolerability and dose requirements. J Pediatr 2000 (in press). 9. De Giacomo C, Bawa P, Franceschi M, et al. Omeprazole for severe reflux esophagitis in children. J Pediatr Gastroenterol Nutr 1997;24:528 –32. 10. Kato S, Ebina K, Fojii K, et al. Effect of omeprazole in the treatment of refractory acid related disease in childhood: Endoscopic healing and twenty-four-hour intragastric acidity. J Pediatr 1996;128:415–21. 11. Lind T, Cederberg C, Ekenved G, et al. Effect of omeprazole—A gastric proton pump inhibitor—On pentagastrin stimulated acid secretion in man. Gut 1983;24:270 – 6. 12. Lagerstro¨m P-O, Persson B-A. Determination of omeprazole and metabolites in plasma and urine by liquid chromatography. J Chromatogr 1984;309:347–56. 13. Jacqz-Aigrain E, Bellaich M, Faure C, et al. Pharmacokinetics of intravenous omeprazole in children. Eur J Clin Pharmacol 1994;47:181–5. 14. Rane A. Drug disposition and action in infants and children. In: Yaffe SJ, Aranda JV, eds. Pediatric pharmacology. Therapeutic principles in practice, 2nd ed. Philadelphia: Saunders, 1992:10 –21. 15. Leeder JS, Kearns GL. Pharmacogenetics in pediatrics: Implications for practice. Pediatr Clin North Am 1997;44:55–77. 16. Andersson T, Regårdh CG, Dahl-Puustinen ML, et al. Slow omeprazole metabolizers are also poor S-mephenytoin hydroxylators. Ther Drug Monit 1990;12:415– 6. 17. Andersson T, Miners JO, Veronese ME, et al. Identification of
3106
18.
19. 20.
21. 22.
Andersson et al.
human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol 1993;36:521–30. Chiba K, Kobayashi K, Manabe K, et al. Oxidative metabolism of omeprazole in human liver microsomes: Cosegregation with S-mephenytoin 4⬘-hydroxylation. J Pharmacol Exp Ther 1993;266:52–9. Carrier O, Pons G, Rey E, et al. Maturation of caffeine metabolic pathways in infancy. Clin Pharmacol Ther 1988;44:145–51. Treluyer JM, Gueret G, Cheron G, et al. Developmental expression of CYP2C and CYP2C-dependent activities in the human liver: In-vivo/in-vitro correlation and inducibility. Pharmacogenetics 1997;7:441–52. Lambert GH, Schoeller DA, Kotake AN, et al. The effect of age, gender, and sexual maturation on the caffeine breath test. Dev Pharmacol Ther 1986;9:375– 88. Kearns GL. Pharmacogenetics and development: Are infants
AJG – Vol. 95, No. 11, 2000
23.
24. 25. 26.
and children at increased risk for adverse outcomes? Curr Opin Pediatr 1995;7:220 –33. Andersson T, Miners JO, Veronese ME, et al. Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br J Clin Pharmacol 1994;38:131–7. Treluyer JM, Cheron G, Sonnier M, et al. Cytochrome P-450 expression in sudden infant death syndrome. Biochem Pharmacol 1996;52:497–504. Morselli PL, Principi N, Tognoni G, et al. Diazepam elimination in premature and full term infants, and children. J Perinat Med 1972;1:133– 41. Andersson T, Cederberg C, Heggelund A, et al. The pharmacokinetics of single and repeated once-daily doses of 10, 20 and 40 mg omeprazole as enteric-coated granules. Drug Invest 1991;3:45–52.