Abstract
Purpose
Drug administration via feeding tubes is considered a process with many uncertainties. This review aimed to give a comprehensive overview of data available on feeding tube application and to carry out risk assessments for drug substances commonly administered to stroke patients.
Methods
Drugs frequently administered via feeding tubes were identified through a retrospective analysis of discharge letters from a stroke unit. Physicochemical, pharmacokinetic, and stability properties of these drugs and data on drug-enteral nutrition interactions were systematically searched for in the European Pharmacopoeia, Hagers Handbook of Pharmaceutical Practice, Birchers clinical-pharmacological data compilation, and the Martindale Complete Drug Reference, as well as from databases including DrugBank, DrugDex, PubChem, Google Scholar, and PubMed.
Results
Of the drugs most commonly administered via feeding tubes in the present stroke patient cohort, bisoprolol, candesartan, and ramipril could be considered the least critical due to their overall favourable properties. Acetylsalicylic acid, amlodipine, hydrochlorothiazide, omeprazole and esomeprazole, simvastatin, and torasemide pose risks based on pH or light-dependent instability or proposed food effects. The most critical drugs to be administered via feeding tubes are considered to be furosemide, levodopa, and levothyroxine as they show relevant instabilities under administration conditions and substantial food effects; the latter two even possess a narrow therapeutic index. However, little information is available on drug-tube and drug-formula interactions.
Conclusion
Feeding tube administration of medications turned out to be a highly complex process with several unmet risks. Therefore, investigations that systematically assess these risk factors using clinically relevant model systems are urgently needed.
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Introduction
Tube feeding is an inevitable requirement once patients are no longer able to take in sufficient amounts of nutrients. Very often, such patients can also no longer take solid dosage forms orally, so these are also administered via the feeding tube. In many cases, this type of administration is not authorised but, nevertheless, practiced due to a lack of alternatives. Several studies have been carried out and recommendations inferred on the administration of medicines via feeding tubes [1,2,3]. Liquid dosage forms should preferably be used [4]. If such formulations are not available for the drug in question, solid dosage forms should be manipulated in such a way that they can be administered via the tube. This is usually done by crushing and/or suspending. However, strict care must be taken to ensure that the integrity of the dosage form with regard to the intended in vivo release behaviour is not compromised by this manipulation or by administration via the gastric tube, as this would pose a risk to the patient. In the case of modified-release dosage forms, it is important to exclusively apply multiparticulate formulations (dosage forms that break down into smaller units with intact release behaviour when suspended), which must not be further fragmented under any circumstances. To ensure safe and effective administration of the medication, various guidelines emphasize the importance of flushing the tube before, between, and after drug administration [1, 2, 5]. Moreover, flushing the syringe after administration of the medication is also mentioned in several of the publications [2, 3, 5].
Hospitals and care facilities often have internal guidelines for drug administration through feeding tubes, which can differ greatly from each other and from the published recommendations [6]. The deviation from these recommendations might be due to a lack of knowledge of the guidelines and a lack of standardised handling procedures or practical reasons [7,8,9]. Recommendations in current guidelines, however, do not address the situation after the drug product has been administered from the syringe into the tube, and it is assumed that safe and effective drug therapy is achieved if proper administration (including preparation of the drug product and measuring of the dose) and flushing is considered. However, the whole drug administration process through feeding tubes is more complex. In everyday practice, different nutrient formulas, different feeding regimens (continuous, intermittent, bolus), and different types of feeding tubes (nasogastric or gastrostomy tubes) consisting of different materials (silicone, polyurethane, polyvinyl chloride) with different geometries (length, diameter, connector) are used and combined with different accessories (centric or eccentric syringes, low dose tip, extension systems). It should also be noted that the active ingredients administered via this route can differ significantly in their properties (solubility, pKa, logP, etc.) and that variations in the administration of these drugs via feeding tubes can have very different effects on the therapeutic success.
The aim of this work was, therefore, to reflect on the entire process from the selection of the drug to be administered to absorption and to consider what influences the drugs are exposed to at each individual step and what implications this may have for the efficacy and safety of the drug therapy. As many stroke patients require enteral feeding, at least temporarily, and medication is also administered via a feeding tube during this phase, stroke patients represent a very relevant patient group which is why they were selected for this study. Feeding tubes can be placed in the stomach or jejunum. In this study, we focused on gastric feeding tubes as these are preferred over jejunal feeding tubes. Thus, we could collect more data about drugs with evidence of frequent administration as solid dosage forms via feeding tube. Potential risks associated with feeding-tube administration were assessed based on the physicochemical properties of the drugs concerned, and a comprehensive literature search on known risks associated with the way these drugs are administered (e.g. via feeding-tube, with different foods) was conducted.
Material and methods
Establishment of a flowchart for establishing risk factors in the process of administering oral medicines via feeding tubes
Based on recommendations available in the literature for the administration of oral drugs via feeding tubes [1,2,3], a flowchart was created to systematically identify those factors that could compromise safe and effective drug therapy during the administration process. To take into account the complete “journey” of the drug until absorption, the flow chart was extended beyond the end of the administration recommendations (the drug is administered into the tube) until the drug in question reaches its site of absorption (typically the small intestine). In addition to identifying all possible critical points and discussing possible consequences for drug therapy, the flowchart should also be used to identify possible countermeasures that could ensure safe and effective therapy.
Retrospective data collection of tube-fed patients on a stroke unit
In order to be able to carry out a risk assessment, in November 2016, the IT department at Greifswald University Hospital provided discharge letters from patients on the stroke ward who had undergone a percutaneous endoscopic gastrostomy (PEG) during their stay. All shared data had already been anonymised at this point. From the discharge letters, the following data were extracted: age and sex, diagnoses, home and discharge medication (drug substance, dosage, dosing times) of the patient, and details of the feeding tube used. Discharge letters were excluded from the evaluation if no information on the PEG tube used was available, the feeding tube had been removed during the hospitalisation, the patient was not supplied with an enteral feeding tube, or when the patient had died in the hospital. The remaining discharge letters were included into the evaluation.
For patients whose discharged letters were included into the evaluation, the medication was examined more closely. Orally administered drugs at hospital admission and at discharge were identified. If no dosage form was specified in the discharge letter and both oral and parenteral routes of the drug in question were possible, it was assumed that it was administered orally for the worst-case scenario. However, if the information on the medication in the discharge letter was so imprecise that a clear identification of the drug was not possible, the corresponding drug was excluded from the evaluation.
Literature research on the drugs most frequently administered via feeding tubes in the stroke-unit patients
The retrospective data evaluation revealed which drugs were most frequently prescribed and thus also most frequently administered via a feeding tube to the patient population studied. A literature search for these drugs was conducted to collate the available information on the drug substances’ chemical, physicochemical, and pharmacokinetic properties, stability data, food effects, and interactions with enteral nutrition.
In the first step, data were collected from the European Pharmacopoeia, Hagers Handbook of Pharmaceutical Practice, Birchers clinical-pharmacological data compilation, and the Martindale Complete Drug Reference, as well as from databases including DrugBank, PubChem, and DrugDex. In the second step, a systematic search for publications was conducted in PubMed. For each drug substance, the following search terms were utilised: drug name (dn) AND interaction AND food, dn AND food-drug-interaction, dn AND pharmacokinetics, dn AND solubility, dn AND pharmacokinetic AND human AND oral, dn AND solubility AND human AND oral, dn AND pka AND solubility, dn AND pharmacokinetics AND pka, dn AND fasted AND fed, dn AND fasted AND food, dn AND feeding tubes, dn AND enteral feed. If the number of hits generated by a certain search term was too high, the corresponding search term was extended by human AND oral. All hits were individually checked for suitability. Additional publications were identified by checking the references of the assessed publications or by using the “similar articles” function in PubMed. The first and second steps were conducted from November 2016 until April 2017. In the third step, in 2022, in addition to the already established data set, information on stability was searched in PubMed and Google Scholar using the search terms: dn AND stability, dn AND stability AND aqueous, dn AND stability AND suspension, dn AND stability AND water, dn AND stability AND syringe, dn AND stability AND photolysis, dn AND stability AND oxidation, dn AND stability AND hydrolysis. Of all hits, only those were considered for further work that related to oral or injectable preparations of the active substances in question (no combination products) and were scientifically sound.
Results
Identification of factors influencing the success of drug therapy when administering oral medicines via feeding tubes with the aid of a flowchart of the administration process
Based on information from various literature sources, the administration process varies across institutions. When creating the flowchart depicting drug administration via feeding tubes from the perspectives of the drug substance and the product (Fig. 1), three main phases of the administration process were identified:
Flow chart of the medication administration process from the drug (products) point of view. OROS, osmotic-controlled release oral delivery system; MUPS, multi-unit pellet system; ZOK, zero-order kinetic; GI, gastrointestinal
The pre-tube phase involves selecting a suitable dosage form and ensuring the stability of the drug (product) in aqueous solutions or as a suspension in a syringe. Monolithic dosage forms must be crushable and/or suspendable for this purpose. A monolithic dosage form is a type of pharmaceutical formulation in which one or multiple active ingredient(s) are uniformly distributed throughout a single, solid matrix. Common examples of monolithic dosage forms include “traditional” tablets or capsules. Some dosage forms with modified release properties are not suitable for administration via a feeding tube, as this would impair their release characteristics, which in turn would be a risk factor for overdosage or loss of efficacy. Accordingly, if modified-release dosage forms are to be administered, it is important to ensure that these are forms in which the controlled release originates from multi-particulate systems, such as the multi-unit pellet system (MUPS). Monolithic dosage forms with this designation can be dispersed in water prior to administration without loss of integrity and while maintaining the release behaviour of the pellet system. Not only can the dissolution/release behaviour be affected, but the preparatory step of supersaturating the formulation of the drug in a syringe can cause stability problems, which can be caused, for example, by sensitivity to light or oxygen and can lead to a drug degradation resulting in a decrease in the drug content even before administration or, in the worst case, to the formation of toxic degradation products. Degradation is a time-dependent process, so immediate administration would be preferred. But in clinical practice, often the drug products are prepared in advance and not at the bedside. Depending on the stability of the suspended drug product, the extent of degradation by light or oxygen can differ. The administration of too low a dose of the drug can also be caused by the drug adsorbing to the syringe material or incomplete emptying of the syringe.
The pre-tube phase is followed by the in-tube phase. As soon as the drug is administered into the feeding tube, interactions with the enteral access devices and/or enteral nutrition residues can occur. These can include tube occlusion because of a too-small diameter or drug adsorption to the feeding tube material. The amount of drug adsorbed to the tube material is (at least temporarily) not available for intestinal absorption. However, since the tube is used again for its original purpose after administration, namely the administration of enteral nutrition, desorption of the drug by rinsing the tube with enteral nutrition formula is conceivable. Furthermore, the inner surface of the feeding tube can change due to food residues and biofilm formation and is therefore subject to constant changes, so that fluctuations in the adsorbed and desorbed quantity are conceivable. Depending on the extent of adsorption/desorption and the therapeutic index of the drug, the risk associated with its enteral administration is more or less pronounced.
The final phase of the administration process begins when the drug leaves the feeding tube. As with the oral administration of solid oral dosage forms, the drug must be dissolved at the site of absorption in order to be absorbed. Low solubility of the drug, changes in solubility due to feeding, and the interaction of drugs with food components can affect the extent and rate of drug absorption. Additional water supply, interruption of the food supply, and tube flushing can be measures to optimise drug efficacy. Patients fed by the enteral route often suffer from diarrhoea that leads to a reduced residence time of the drugs in the gastrointestinal tract. This is of disadvantage for drugs with low permeability and for drugs with small absorption sites. A decrease in absorption and, consequently, a loss of efficacy can be the consequences.
If all these theoretically possible complications could be avoided or minimised, this would provide suitable prerequisites for a safe and effective drug therapy via feeding tubes.
Drugs administered through feeding tubes in a stroke unit
A flow chart of the selection process for letters of discharge that were evaluated is shown in Fig. 2. From 170 patients originally selected by the IT department, letters of discharge of 151 patients were included in the evaluation of medication.
Flow chart showing the results of the inclusion/exclusion process for the selection of patients for data analysis
The most frequently used oral medications in the investigated patient cohort are listed in Table 1, sorted by the absolute number of patients who received these medications. These drugs are normally administered as immediate-release formulations through the feeding tube. Omeprazole and esomeprazole are only available with an enteric coating due to the acid-labile properties of the drug substances. The table also shows the usual dosage as well as the dosage range and dosing schedule in this population.
Literature review for the most commonly prescribed drugs in the investigated population
A literature review and risk assessment were conducted for the first 10 drug candidates in Table 1. Furthermore, levothyroxine sodium and levodopa were included in the risk assessment. Since interactions with food and stability problems after oral administration are widely known for these two drugs, they are also likely to occur with enteral administration.
The initial literature search (steps 1 and 2) in the European Pharmacopoeia, Hagers Handbook of Pharmaceutical Practice, Birchers clinical-pharmacological data compilation, Martindale Complete Drug Reference, PubChem, DrugBank, Drug Dex, and PubMed focused on physicochemical and pharmacokinetic properties, interactions with food/enteral nutrition and information about feeding tube administration. The second literature review (step 3) was conducted in PubMed and Google Scholar and focused on the stability of the selected drug substances in the context of administration via feeding tubes. Photolysis, hydrolysis, and oxidation sensitivity were additional interests.
The overall aim of the various steps of the literature search was to obtain an overview of the available information on important aspects of the administration of drugs of interest via feeding tubes. Information on stability aspects was particularly important for a risk assessment of the pre-tube phase. Data from previously published in vitro (determination of recovery) or in vivo studies (measurements of plasma levels or surrogate parameters) on the administration of drugs with the corresponding active substances via nasogastric feeding tubes or PEGs were important for estimating interactions with the tube material and drug loss within the tubes (phase in the tube). Information on interactions with oral or enteral nutrition was important to assess the effect of possible drug-enteral nutrition interactions on the amount of drug available for absorption.
The data acquired on the physicochemical and pharmacokinetic properties of the drugs are summarised in Table 2. The compilation of the relevant literature determined within the framework of the overall literature review can be found in Table 3. The particularities of the individual drugs that should be considered within the framework of a risk assessment as a result of relevant literature data are discussed in the following section.
Discussion
Risk assessment
The likelihood of safe and effective administration of drugs via feeding tubes and the risk that this route of drug administration will be the cause of absorption variability leading to ineffective systemic drug concentrations or unintended or toxic side effects depend on several drug-related factors. A higher risk of variability is typically associated with drugs with a narrow therapeutic index. With such drugs, even small variations in the amount of drug taken can have large effects. In addition to the variability caused by the administration process, the solubility of the drug in the gastrointestinal tract is another aspect to consider. Dissolution of the drug in the conditions of the upper gastrointestinal tract is a prerequisite for intestinal absorption of the drug. If the drug has poor or limited solubility under these conditions, the proportion of the dose absorbed may be significantly reduced [187]. Soluble maximum doses of the drug substance in 250 ml over the pH range of 1–6.8 at 37 °C [188] means high solubility in the BCS context. If a drug is categorised in different BCS classes, it is likely that is BCS class I or III and BCS class II or IV, respectively. This indicates varied assessment not of the solubility but of the permeability of the drug substance. Different methods are used to assess the permeability. The assessment should be based on pharmacokinetic data in humans; animal or cell culture data should only be additional [188].
In contrast, according to the European Pharmacopoeia, solubility is determined in water at 15–25 °C [14]. This is why slightly to very slightly soluble drugs like acetylsalicylic acid or hydrochlorothiazide can still be categorised into BCS classes with high solubility. The water solubility of the drugs in question can be used as a further indicator since these or the corresponding drugs are dispersed in water before administration. Good water solubility can prevent solid, unadministered drug residues in syringes and feeding tubes, thus reducing the risk of underdosing.
By categorising the drugs examined in this study according to their therapeutic index and their solubility under gastrointestinal conditions and taking the results of the literature search into account, it should be possible to assess whether their administration via feeding tubes poses a lower or higher risk of deviations in the amount of drug available for absorption and thus ultimately also for the intended efficacy.
Group 1: drugs with a wide therapeutic index and a high solubility according to the BCS (Class I/III)
Bisoprolol is very soluble in water [14], and stability and food interaction data can be interpreted as unproblematic for feeding tube administration. Nevertheless, the European Pharmacopoeia recommends protection from light and storage in an airtight container for the pure drug substance [14]. No studies were found for feeding tube administration.
According to the European Pharmacopoeia, ramipril is sparingly soluble in water, and the drug substance should be protected from light [14]. In general, stability and food interaction studies indicate an unproblematic feeding tube administration. Further attention should be paid to its degradation in alkaline solutions. The pH of the drug product suspension should be measured to ensure sufficient stability conditions. One practice-oriented study investigated the stability of suspended ramipril capsule content and could show sufficient stability. No studies were found for feeding tube administration.
Acetylsalicylic acid is slightly soluble in water [14]. The European Pharmacopoeia recommends storage in an airtight container [14] since acetylsalicylic acid is sensitive to hydrolysis even in moist air. However, literature data show sufficient stability of the drug substance in suspension in distilled water. One should be aware that tablet lubricants can accelerate the degradation of the drug substance. The adsorption of acetylsalicylic acid to different plastics is unproblematic, but further studies for administration through feeding tubes are missing. Food does not affect bioavailability.
Amlodipine is slightly soluble in water and the European Pharmacopoeia recommends storage protected from light and in an airtight container [14]. Stability data indicate possible problems (photostability, sensitivity to oxidation, and hydrolysis), but data are partly contradictory, or the relevance for feeding tube administration is difficult to assess due to different test conditions (e.g. exposure to sunlight or UV light). No practice-oriented studies and studies for feeding tube administration were found. Food does not affect bioavailability.
Hydrochlorothiazide is very slightly soluble in water [14]. The recommendation to protect hydrochlorothiazide from light was found in the literature [37]. However, study results indicate a sufficient photostability of hydrochlorothiazide for feeding tube administration. For oxidation and hydrolysis, partly contradictory results were found, but there is a tendency towards lower stability of hydrochlorothiazide in alkaline solutions. No practice-oriented studies and studies for feeding tube administration were found. Contradictory literature was found for drug-food interactions. These observations might relate to the pH-dependent stability of hydrochlorothiazide, a question which deserves further investigation.
Torasemide is practically insoluble in water and, according to the European Pharmacopoeia, should be protected from light [14]. Stability data are only generated in forced degradation studies so the relevance for feeding tube administration is not clear. One study investigated the stability of torasemide in 5% dextrose solution under normal fluorescent light and found it to be stable under these conditions. No practice-oriented studies and studies for feeding tube administration were found. Contradictory literature was found for drug-food interactions.
Group 2: drugs with a wide therapeutic index and a low solubility according to the BCS (Class II/IV)
Esomeprazole is slightly soluble as magnesium salt [14]. The European Pharmacopoeia recommends storage protected from light and in an airtight container [14]. The stability studies found show no problems in terms of sensitivity to light and oxidation. But, as it is widely known, proton pump inhibitors are acid-labile drug substances. Therefore, they have to be enteric-coated. Many practice-oriented stability studies show sufficient stability of feeding tube-suitable pellet/sachet formulations. Additionally, many studies about feeding tube administration were found in the literature, indicating good handling and recovery of the drug product and drug substance, respectively. One study even investigated the bioavailability of esomeprazole administered via a feeding tube compared to oral intake. No difference in bioavailability could be observed in this study. Data about drug-food interactions are contradictory, saying that there is no food effect or a decreased AUC (area under the curve), whereby the reduced AUC, maybe, does not have an impact on intragastric acidity.
Omeprazole is very slightly soluble and should be protected from light and stored in an airtight container in the refrigerator [14]. Stability data indicate that there could be a problem when omeprazole is exposed to light or oxidising agents. The drug substance is definitely instable under acidic conditions and, therefore, has to be enteric-coated. Many practice-oriented stability studies were conducted in different solutions (0.9% sodium chloride, 5% dextrose, 8.4% bicarbonate). They have in common that omeprazole degrades faster under light exposure and at room temperature. However, stability is still good enough for extemporaneously prepared suspension for feeding tube administration. Studies about feeding tube administration show good recovery of omeprazole. It is recommended to administer omeprazole 1 h before a meal [104], but data about drug-food interactions are contradictory.
According to the European Pharmacopoeia, simvastatin is practically insoluble in water and should be protected from light and stored under nitrogen or with antioxidants in an airtight container [14]. Stability studies showed no explicit results regarding stability. No practice-oriented studies and studies for feeding tube administration were found. Food does not affect bioavailability.
Candesartan cilexetil is practically insoluble in water [14]. It is quite stable against photodegradation and oxidation but shows pH-dependent hydrolysis. No practice-oriented studies and studies for feeding tube administration were found. Food does not affect bioavailability.
Furosemide is practically insoluble in water and should be protected from light [14]. Stability studies found in the literature also indicate a sensitivity to light. Furosemide seems to be instable in an acidic environment, whereby there are contradictory results. However, practice-oriented studies indicate sufficient stability for feeding tube administration. Studies about feeding tube administration could not be found. Food seems to have a negative effect on bioavailability.
Group 3: narrow therapeutic index drugs
According to the European Pharmacopoeia, levodopa is slightly soluble in water and should be protected from light [14]. However, the found literature indicates sufficient photostability. Oxidation was observed but only to a small extent. Levodopa was most stable under acid conditions. One practice-oriented study was conducted to assess the stability of levodopa in tap water. The study showed sufficient stability of levodopa in tap water. Studies about feeding tube administration could not be found. Food with high protein content can influence levodopa therapy.
Levothyroxine sodium is very slightly soluble and should be stored protected from light in an airtight container in the refrigerator [14]. The results of the literature search indicate a sensitivity to light which could be problematic. However, practice-oriented studies resulted in sufficient stability for feeding tube administration. On the one hand, the studies about feeding tube administration do not show a significant or clinically relevant loss of levothyroxine. On the other hand, an increase of the necessary levothyroxine dose to maintain a euthyreot metabolic state was observed when levothyroxine was administered via feeding tubes. Many interactions like complexation of multivalent cations and adsorption to soy bean are known for levothyroxine.
Conclusion
For some drug substances, much literature was found in the context of feeding tube administration. Omeprazole and esomeprazole have one of the most comprehensive literature on the selected drug substances. This includes many practice-oriented stability studies as well as feeding tube administration studies. This information is needed for a concluding risk assessment. This work shows that there is a lack of these studies for most of the investigated drug substances. In addition, the used drug product can have a great influence on stability and/or feeding tube administration which is why we cannot give any recommendations.
Current state and future needs
Typically, for each registered drug substance, there is already some data available on the stability of the pure substance from simple stability studies or forced degradation studies. These provide a first indication of the degradation pathways of the drug but allow only limited conclusions to be drawn about stability in the context of feeding tube administration. In addition to the stability data generated for new active substances/drugs as part of the marketing authorisation process, stability tests for injectable preparations in the appropriate syringes are available for some drugs. The results of such tests already provide a good indication of the stability of the drug when administered via a feeding tube, but the underlying test design differs in the time periods investigated and, in the case of finished drug products, often in the excipients contained in the finished drug product. On the other hand, as solid dosage forms consisting of drug substance and excipients are usually manipulated for administration via the feeding tube, the influence of all excipients contained in the finished drug product would have to be taken into account. Targeted in-use stability studies on the individual manipulated drug products for feeding tube administration would therefore be desirable.
The enteral feeding market offers a wide range of products that may differ in terms of the materials and geometries used. Results of studies with one type of tube and syringe may not be applicable to all other tubes and syringes. The Food and Drug Administration (FDA) Draft Guidance “Oral Drug Products Administered Via Enteral Feeding Tube: In Vitro Testing and Labelling Recommendations” [189] states that the different geometries of feeding tubes should be considered and tested accordingly. It also recommends that at least the smallest diameter for which a feeding tube application is to be approved should be tested. This is consistent with the observations of Shah et al., who investigated how many of the esomeprazole-containing pellets passed through the tube. In this study, more pellets were retained in the smaller tubes [102]. However, in a systematic study by Karkossa et al. in which different pellet formulations were administered in vitro through different feeding tubes using different syringes and extension systems, it was shown that the diameter of the feeding tube or pellet size does not allow a clear prediction of the quantitative performance of the administration [190]. In another in vitro study, Karkossa et al. determined the recovery of ibuprofen after the administration of various ibuprofen suspensions after the administration via different types of feeding tubes [191]. The results of these experiments also indicated that the diameter of the feeding tube is a poor indicator of whether a given dose of a drug product can be successfully administered. These and a number of other studies of a similar nature [94, 100, 102] clearly show, as already mentioned above, that the success of drug administration via a feeding tube is determined by a complex interplay of the properties of the administered drug and the administered drug product, the geometry and material of the syringe and feeding tube, the volume of the administered suspension/solution, the flushing volume, as well as all preparatory measures and many other details.
As became clear in the present study, in daily practice, many pharmaceutical forms available on the market are administered in manipulated form via enteral feeding tubes without knowing whether this allows safe administration of the intended drug dose. At this point, it is also important to remember that the primary purpose of a feeding tube is to ensure the patient’s nutrition. Accordingly, enteral formulas are fed to the patients concerned via the feeding tube for many hours every day. Although feeding should normally be stopped and the feeding tube rinsed with water prior to drug administration, food residues may accumulate on the inner surface of the tube, altering the tube surface and leading to interactions with the administered drug. The impact of such conditions on the administration process or on dose recovery should also be investigated in in vitro studies where possible. It should further be noted that the nature and extent of such interactions may depend on the type and composition of the enteral formula, as has been demonstrated with levothyroxine [152, 153, 192]. Given the complexity of the issue, it quickly becomes clear that an in vitro simulation of administration cannot fully reflect in vivo conditions. Especially when it comes to estimating the influence of food residues on the successful application of a drug dose, the simulation would have to be taken even further, because in vivo different bacteria also enter the feeding tube, which in turn form biofilms there due to the good nutrient supply. Formation of such biofilms can create a completely different surface structure (from abiotic to biotic) in the lumen of the tube [193]. It would be interesting to also map the impact of biofilms on the success of the administration process of the respective drug in in vitro experiments, but a realistic simulation would probably only be possible in ex vivo experiments with feeding tubes removed from patients after the end of enteral nutrition.
Finally, it is important to check whether the modified drug still exhibits the originally intended release behaviour in the gastrointestinal tract. This is particularly relevant for pellets with modified drug release and has already been investigated in studies with esomeprazole and omeprazole pellets [100, 163] but should also be of interest for other drugs.
Limitations
The first and second literature searches on physicochemical and pharmacokinetic properties were conducted from November 2016 to April 2017. Due to limited resources, the additional (third) literature search on stability and practice-oriented information was conducted in 2022. Since it is unlikely that physicochemical and pharmacokinetic properties change, we do not think a repetition of the first and second literature searches was necessary.
Conclusion
In this work, a flow chart of the administration process of oral drugs via enteral feeding tubes was created, which takes into account all essential steps from the selection of the drug product to the absorption of the administered drug in the gastrointestinal tract. This flow chart can be used to identify critical points in the administration process where drug loss can occur, thereby compromising a safe and effective drug therapy. The new flow chart was used for the first time in this study to carry out a risk assessment with regard to the administration of drugs via feeding tubes using the data available in the literature for the drugs that are proven to be most commonly administered in a specific stroke unit. It was found that the most commonly administered drug products comprise several drug substances that are considered highly problematic for this route of administration, as they have a narrow therapeutic index, are unstable in aqueous solutions or in the presence of light, or are subject to food effects. When the critical points identified in the flow chart and the drug properties determined in the literature are compared with the information available for the administration of the drugs in question via enteral feeding tubes, it is clear that there is a lack of reliable data that can demonstrate safe administration via this route. This highlights the need for systematic studies to assess the risk of this route of administration in terms of safe and effective drug therapy. The established flow chart can provide valuable guidance for the planning of such studies and thereby make a valuable contribution to de-risking the administration of drugs via feeding tubes.
Data availability
No datasets were generated or analysed during the current study.
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Sommerfeldt, J., Sartorius, H., von Sarnowski, B. et al. Drug administration via feeding tubes—a procedure that carries risks: systematic identification of critical factors based on commonly administered drugs in a cohort of stroke patients. Eur J Clin Pharmacol (2024). https://doi.org/10.1007/s00228-024-03723-4
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DOI: https://doi.org/10.1007/s00228-024-03723-4