Pharmacokinetics of two formulations of omeprazole administered through a gastrostomy tube in patients with severe neurodevelopmental problems

Authors


Professor Koen Boussery, Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Harelbekestraat 72, B-9000 Gent, Belgium. Tel.: +32 9 264 8110, Fax: +32 9 264 8197, E-mail: koen.boussery@ugent.be

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• In tube-fed patients with severe neurodevelopmental problems, omeprazole for the treatment of gastro-oesophageal reflux disease often needs to be administered through the feeding tube.

• In daily practice, various procedures are used to administer the commercially available, enteric-coated omeprazole formulations through a feeding tube.

• No bioavailability data are available to support a rational choice between the available administration procedures.

WHAT THIS STUDY ADDS

• This study demonstrates a substantial interindividual variability in omeprazole pharmacokinetics after administration through the gastrostomy tube in patients with severe neurodevelopmental problems.

• In most patients, plasma concentration–time profiles seem more favourable with a suspension formulation than with a MUPS® formulation.

• Consequently, there is no apparent advantage in choosing a MUPS® formulation over the more easily administered suspension formulation.

AIMS Omeprazole is often administered through a gastrostomy tube as either (i) a Multiple Unit Pellet System (MUPS®) tablet disintegrated in water (MUPS® formulation), or (ii) a suspension in 8.4% sodium bicarbonate (suspension formulation). This bioavailability study evaluates this practice in tube-fed patients with severe neurodevelopmental problems.

METHODS Nonblinded, two-phase cross-over trial.

RESULTS In seven of 10 patients, bioavailability was higher for the suspension formulation than for the MUPS® formulation. Median (90% confidence interval) area under the plasma concentration–time curve ratio (MUPS® over suspension) was 0.5 (0.06–2.37).

CONCLUSIONS In this population, omeprazole MUPS® formulation has no apparent advantage over the more easily administered suspension formulation.

Introduction

Gastro-oesophageal reflux disease is a frequently occurring condition among institutionalized patients with severe neurodevelopmental problems [1]. Based on a limited number of studies [2, 3], the proton pump inhibitor (PPI) omeprazole is regarded as the therapy of choice in this patient population. As PPIs are acid-labile molecules, oral omeprazole dosage forms are enteric coated to protect the omeprazole until delivery and absorption in the duodenum [4]. However, patients with severe neurodevelopmental problems often depend on a feeding tube for the administration of drugs because of oral motor dysfunction with uncoordinated and unsafe swallowing [1]. As enteric-coated formulations should not be crushed, they cannot be administered through a feeding tube. Various alternatives for delivering omeprazole and other PPIs as a liquid formulation have been proposed. In daily practice, tube-fed patients often receive omeprazole doses either as (i) an omeprazole Multiple Unit Pellet System (MUPS®) tablet disintegrated in water (‘MUPS® formulation’), or (ii) a suspension of omeprazole in 8.4% sodium bicarbonate (‘suspension formulation’). Both of these options are recommended by the British National Formulary for Children [5]. However, no bioavailability data for these formulations are available in tube-fed patients with severe neurodevelopmental problems. Therefore, this trial evaluated the omeprazole pharmacokinetics in tube-fed patients with severe neurodevelopmental problems after administration as a MUPS® formulation and as a suspension formulation.

Methods

Methods and patient characteristics are more elaborately described in Appendix 1. In summary, a two-phase cross-over study included 10 institutionalized patients who fulfilled the following criteria: (i) suffered from severe neurodevelopmental problems with swallowing disorders; (ii) had a gastrostomy feeding tube in place (size 15 French); and (iii) were treated with omeprazole (20 or 40 mg once daily) because of oesophagitis grade B–D for at least 2 weeks. Study phases were two subsequent 14 day periods in which the standard omeprazole dose (20 or 40 mg, depending on the previous treatment schedule of the individual patient) was administered through the gastrostomy tube either as a MUPS® formulation, or as a suspension formulation. On the last day of each 14 day period, a plasma concentration–time profile was recorded until 8 h postdose. Pharmacokinetic variables were determined by noncompartmental analysis and the log-linear trapezoidal method (‘WinNonlin Professional’ software; Pharsight Corporation, California, USA.). Shapiro–Wilk test, Student's paired t-test and Wilcoxon signed rank test (SPSS version 15.0; SPSS Inc., Chicago, IL, USA) were used when appropriate.

Results

Figure 1 represents the individual plasma concentration–time profiles for both formulations. The corresponding pharmacokinetic parameters are summarized in Table 1 (individual data are available in Appendix 2).

Figure 1.

Individual plasma concentration–time profiles for omeprazole, after administration as a disintegrated MUPS® formulation (squares) or as a suspension formulation (circles). Plasma levels were measured from predose up to 8 h postdose (except for patient 4, for whom the 8 h postdose sample is missing for the suspension formulation). Plasma levels below the lower limit of quantification (1.5 ng ml−1; indicated by the dashed line) are not shown.

Table 1.  Mean (±SD) area under the plasma concentration–time curve (AUCt), maximum measured plasma drug concentration (Cmax) and time to Cmax (tmax) for omeprazole after administration as a suspension formulation and as a disintegrated MUPS® formulation; and associated median (90% confidence interval) ratio (MUPS® formulation over suspension formulation)
  Suspension MUPS P value Ratio of MUPS/suspension
  • *

    Values normalized to omeprazole dose (mg (kg bodyweight)−1).

  • **

    AUCt for patient 4 was omitted in overall analysis because no AUC values up to 8 h postdose were available for this patient.

AUCt*1000 ± 1019608 ± 5720.2000.50 (0.13–2.60)
(µg.h.l−1)/(mg kg−1)(n= 9)**(n= 9)**  
C max * 2107 ± 3934747 ± 14810.0440.34 (0.06–2.37)
(µg l−1)/(mg kg−1)(n= 10)(n= 10)  
t max (h)0.57 ± 0.162.36 ± 1.740.005
 (n= 10)(n= 10)  

Discussion

When considering the individual concentration–time profiles and the corresponding pharmacokinetic parameters for omeprazole, two observations are striking: (i) the high variability between individuals; and (ii) the substantial differences between the two formulations within each individual. Considerable interindividual variability, particularly in area under the plasma concentration–time curve (AUC) data, has been described before for both intravenous and oral administration of omeprazole in children [6, 7] and adults [8, 9]. This high variability can be largely attributed to genetic polymorphism of the cytochrome P450 (CYP) isoform CYP2C19 [4, 10]. Also, other aspects, such as age, concomitant medication and differences in weight-normalized dose, could add to the high interindividual variability.

Regardless of the interindividual variability, the main focus of this study was the intra-individual comparison of two omeprazole formulations for delivery through the gastrostomy tube. In our study population, the mean maximum measured plasma drug concentration (Cmax) was significantly higher for the omeprazole suspension formulation, and mean time to Cmax was significantly lower. Also, the mean AUC was shown to be substantially higher after administration as a suspension formulation, but this difference was not statistically significant. These are rather unexpected observations, because in healthy adults the omeprazole suspension was shown to have a low relative bioavailability (58.4% in comparison with a standard omeprazole capsule containing enteric-coated granules) [11], whereas an intact omeprazole MUPS® tablet was shown to be bio-equivalent with a standard omeprazole capsule containing enteric-coated granules [12]. One could therefore have expected a better bioavailability for the MUPS® formulation than for the suspension formulation. Yet, in this study, the suspension formulation seemed to have a higher bioavailability than the MUPS® formulation in seven of 10 patients. Although the therapeutic target AUC for omeprazole is not known, the efficacy of omeprazole correlates with AUC in both adults [13–15] and children [16, 17]. The suspension formulation therefore seems the better option for the administration of omeprazole through the gastrostomy tube in patients with severe neurodevelopmental problems. Nevertheless, in three of 10 patients the MUPS® formulation had a better bioavailability than the suspension formulation. It is noteworthy that in all three of them, AUC and Cmax values were in the lower range for both formulations.

Patients with severe neurodevelopmental problems frequently have an associated dysmotility in the foregut (i.e. the part of the gastrointestinal tract between the mouth and the second part of the duodenum), causing several gastrointestinal problems, such as a delayed gastric emptying [1]. One could therefore speculate that a similar phenomenon to the one described by Tuleu et al. [18] may occur in these patients, and that a longer residence time of the pellets from the disintegrated MUPS® tablet in the acid environment of the stomach may result in an increased permeability of the enteric coating around the pellet and a degradation of the omeprazole inside the pellet. The fine dispersion of omeprazole in the suspension formulation, on the other hand, may facilitate its gastric emptying through the pylorus and lead to a more favourable pharmacokinetic profile in most patients. Why this benefit for the suspension formulation was not seen in three of the 10 patients remains unclear, but one could speculate on the influence of interindividual variability in the delay of gastric emptying.

In conclusion, the present study demonstrates a substantial interindividual variability in omeprazole pharmacokinetics after administration through the gastrostomy tube in patients with severe neurodevelopmental problems. In most patients, plasma concentration–time profiles seem more favourable with the suspension formulation than with the MUPS® formulation. Consequently, there is no apparent advantage with regard to the bioavailability of omeprazole in choosing a MUPS® formulation over the more easily administered suspension formulation.

Competing Interests

There are no competing interests to declare.

Acknowledgments

The authors wish to thank the participating patients and their parents, and Dr A. Poffyn and the nursing staff of the institute ‘MPI Heilig Hart’ for their co-operative support.

Appendices

Appendix 1: Methods – elaborate description

This nonblinded, single-centre study was performed between April 2007 and November 2007 in a medium-sized institution for children and adults with a moderate to severe intellectual disability. The study protocol was approved by the ethics committee of Ghent University Hospital (Belgium), and was registered in the clinicaltrials.gov database (identifier: NCT00426595). Study procedures were performed according to the principles of the Declaration of Helsinki, and to the current opinions on ethical challenges in the involvement of persons with mental retardation in clinical trials [1]. All subjects were enrolled via informed parental consent.

Patients

Institutionalized patients weighing over 15 kg were eligible for inclusion in the study if they: (i) suffered from severe neurodevelopmental problems with swallowing disorders; (ii) had a gastrostomy feeding tube in place (size 15 French); and (iii) were treated with omeprazole (20 or 40 mg once daily) because of oesophagitis grade B–D for at least 2 weeks. Patients were excluded if they had an infection or moderate to severe hepatic impairment (defined as alanine aminotransferase and/or aspartate aminotransferase levels >3 times the upper limit of the reference interval). Individuals were also excluded if treated with anticoagulants or immunosuppressive drugs, or when treatment with a known inhibitor or inducer of omeprazole metabolism was initiated recently (i.e. since ≤14 days). The parents of all 18 eligible patients were invited for an information session on the study by one of the investigators (M.V.W.). The parents of 11 patients attended, of whom 10 gave informed consent. It was stressed that nonparticipation would in no way influence further care of their children.

Demographic characteristics, dosing and concomitant medication for each patient are presented in the table below. All enrolled subjects were Caucasian, presented with normal indices for liver and kidney function (serum levels for aminotransferases, albumin and creatinine), and completed both 14 day treatment periods.

Patient Sex Age (years) Weight (kg) Height (cm) Dose (mg) Concomitant medication
 1F21.526.813920Primidone
Cisapride
Macrogol
Fluticasonpropionaat + salmeterol (inhaled)
Sorbitol 70%
 2F15.730.3 N.D. 20Baclofen
Diazepam
Alizapride
Iron
Sorbitol 70%
 3M11.821.014040Calcium citrate
Topiramate
Valproic acid
Carbocistein
Ethosuximide
 4F24.846.515220Calcium carbonate
Lynestrenol
Macrogol
 5M9.815.210820Phenobarbital
 6F7.815.011420Tetrazepam
Carbamazepin
Macrogol
Paraffin
 7F13.223.513540Lamotrigin
Alizapride
Carbamazepin
Macrogol
Cisapride
 8M14.439.915220Clonazepam
Vigabatrin
Topiramate
Oxcarbazepine
Fluticasonpropionaat + salmeterol (inhaled)
 9F17.829.4 N.D. 20Lorazepam
Spironolactone
Macrogol
Ipratropiumbromide (inhaled)
Salbutamol (inhaled)
Valproic acid
Carbamazepin
10F26.732.014140Valproic acid
Clobazam

Study design

Using a computer-generated randomization list, subjects were assigned to one of two sequence groups in a two-phase cross-over study design. The phases were two subsequent 14 day periods in which the standard omeprazole dose (20 or 40 mg, depending on the previous treatment schedule of the individual patient) was administered through the gastrostomy tube either as a MUPS® formulation, or as a suspension formulation. On the last day of each 14 day period, venous blood samples were obtained using an indwelling venous catheter, immediately prior to the next omeprazole administration (i.e. time = 0) and at 0.5, 1.0, 1.5, 2.0, 2.5, 3, 4, 6 and 8 h postdose. All procedures took place in the institution, in an effort not to disturb the daily routine of the patients. Local anaesthetic cream was applied before placing the catheter.

Preparation and dosing

Enteral feeding was stopped from at least 6 h before until at least half an hour after each omeprazole administration, and the gastrostomy tube was flushed with 10 ml water before each administration. The omeprazole suspension in 8.4% sodium bicarbonate (4 mg ml−1) was prepared in bulk at the start of each 14 day period by the pharmacy department of Ghent University Hospital. The appropriate number of 40 mg omeprazole capsules (Omeprazole Mylan®; Mylan Pharmaceuticals, Hoeilaart, Belgium) were opened, the contents suspended in an appropriate amount of 8.4% sodium bicarbonate solution and the enteric-coated omeprazole beads allowed to disintegrate with gentle agitation, all according to a standardized protocol. During the 14 day period, the omeprazole suspension was stored in amber bottles at 4°C, and 5 or 10 ml of this suspension was administered daily (after thoroughly shaking the bottle) through the gastrostomy tube. Subsequently, the gastrostomy tube was flushed again with 10 ml water. Omeprazole MUPS® tablets were disintegrated daily at the bedside as follows: an omeprazole MUPS® tablet (20 or 40 mg; Losec®; Astra-Zeneca, Brussels, Belgium) was halved and the two halves were placed into the barrel of a centric 10 ml syringe. Ten millilitres of water at room temperature was drawn into the syringe, the syringe was gently shaken until full disintegration of the tablet (approximately 30 s to 1 min), and contents of the syringe were immediately emptied into the gastrostomy tube. The syringe was rinsed with 10 ml water and the flush contents were also emptied into the gastrostomy tube. A small preliminary in vitro study (results not shown) showed by visual inspection that this procedure results in a complete passage of the disintegrated tablet through a 15 French size gastrostomy tube.

During the whole study protocol, all other drugs that needed to be administered through the gastrostomy tube were administered at least 2 h before or 1 h after administration of omeprazole. During each 14 day period, daily omeprazole doses were administered by nurses who were trained in correct administration of the two formulations before the start of the study. On the day of the blood sampling, the omeprazole dose was administered by one of the authors (M.V.W. or S.V.D.V.), in the presence of at least one other co-author (J.D.S. or J.V.B.).

Specimen handling and analytical technique

Venous blood samples (3 ml each) were drawn in a sodium heparin tube. Within 15 min of venipuncture, samples were spun at 1360 g for 5 min (room temperature). Plasma was immediately removed from each tube and transferred to a polystyrene tube. Samples were then stored in a freezer (−20°C) for the remainder of the day. At the end of each sampling day, samples were transferred from the institution to the Laboratory of Medical Biochemistry and Clinical Analysis on ice and stored at −80°C until analysis.

Omeprazole plasma levels were determined by a validated analytical method, as described elsewhere [2].

Data analysis

The following pharmacokinetic variables were determined by noncompartmental analysis, using ‘WinNonlin Professional’ software (version 5.2.1; Pharsight Corporation, California, USA): area under the plasma concentration–time curve from time zero to the time of the last postdose quantifiable plasma concentration (AUCt), maximum measured plasma drug concentration (Cmax) and time to Cmax (tmax). The AUCt was determined using the log-linear trapezoidal method. As omeprazole dosing was not uniform across the study group, dose-normalized values of AUCt and Cmax were calculated by dividing the pharmacokinetic parameter by the omeprazole dose in micrograms per kilogram bodyweight.

Statistical comparison of the estimated pharmacokinetic values was performed using SPSS version 15.0 software (SPSS Inc., Chicage, IL, USA). Statistical comparisons for AUCt and Cmax values were performed with logarithmically transformed data. The Shapiro–Wilk test was used to check Gaussian distribution, and Student's paired t-test was used to compare normally distributed data. For the comparison of tmax values, a nonparametric analysis (Wilcoxon signed rank test) was applied. The significance level was based at 0.05, and all data are represented as means ± SD.

Appendix 2: Individual pharmacokinetic parameters for omeprazole after administration as a suspension formulation and as a disintegrated MUPS® formulation

  SUSPENSION MUPS
patient dose (mg) AUCt (µg.h.L−1)* Cmax (µg/L) tmax (h) AUCt (µg.h.L−1)* Cmax (µg/L) tmax (h) tlag (h)
  • *

    AUCt is calculated from time 0 to 8 hours postdose for all patients, except for patient 4.

  • **

    AUCt calculated from time 0 to 6 hours postdose because of a missing value at 8 hours postdose for the suspension formulation.

 12060.966.30.55158.3157.11.08 
 220117.3131.90.50529.3533.21.17 
 3401185.31559.60.5068.918.14.121.08
 42018727.5**5618.80.525946.0**2109.81.00 
 5201138.61150.20.53168.370.46.003.00
 620375.0570.40.5549.164.81.58 
 7401681.0772.31.03830.8354.44.051.53
 8201030.2938.60.50633.0276.11.53 
 920485.6377.80.50608.6238.72.05 
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