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IN-DEPTH REVIEW |
Baxter R&D Europe,1 Nivelles, Belgium, and Medical Affairs,2 Baxter Healthcare SA, Zurich, Switzerland
Correspondence to: D. Faict, Baxter R&D Europe, Rue du Progrès 7, 1400 Nivelles, Belgium. dirk_faict{at}baxter.com
ABSTRACT
Peritoneal dialysis (PD) is an effective home-based therapy for
end-stage renal failure. Intraperitoneal administration of drugs to PD
patients is particularly important for the treatment of peritonitis.
Clinicians need to know that the administered drug is compatible with both the
PD solution and its container. A detailed literature search on drug
compatibility and stability was performed and results of all published
stability studies are presented for all drugs, PD solutions, and containers
studied. These data will aid clinicians managing PD patients and provide a
resource to demonstrate which drugs have been shown to be stable in various PD
solutions and solution containers. This is important information to assist
clinicians in applying effective treatments, in particular, for
peritonitis.
KEY WORDS: Solutions; drug; stability; compatibility; intraperitoneal; adsorption; container.
Peritoneal dialysis (PD) is an effective form of renal replacement therapy and has been used widely across the world since its introduction in 1978. As an alternative treatment modality for end-stage renal disease in addition to hemodialysis, PD experienced rapid world-wide growth, as its simple technology enabled therapy in the home. Intraperitoneal (IP) administration of drugs is an important aspect of PD therapy and has been used for drugs such as insulin, heparin, and, in particular, antibiotics.
Peritonitis is a complication of PD therapy but, with advances in connectology and patient training methods, the rate of peritonitis has fallen considerably (1) and many patients will remain peritonitis free. However, peritonitis remains an issue since it can result in short-term morbidity and can be associated with long-term membrane damage (2). Prompt diagnosis and treatment of peritonitis is essential and the International Society for Peritoneal Dialysis (ISPD) guidelines give clear recommendations for prevention, investigation, and antibiotic therapy for peritonitis (3). In the clinical setting of peritonitis, it is important that the prescriber has evidence that the prescribed antibiotics are compatible with the PD solution and its container, and so more likely to be clinically effective. Around the world a variety of PD solutions are used in terms of both the solution itself (buffer: lactate, lactate/bicarbonate, bicarbonate; osmotic agent: glucose, icodextrin, amino acids) and the container material (PVC, polyolefin). The ISPD guidelines give summary guidance with respect to antibiotic regimes but, as stability studies have for most drugs been limited to the standard PD solutions, the authors recommended further research on drug stability in PD solutions (3). Indeed, due to significant differences in the constitution of the current PD solutions in terms of buffers, osmotic agents, and especially pH, stability data cannot simply be extrapolated from one PD solution to another.
The most recent review of drug stability in PD solutions dates from 1995 (4). The present review bundles all published stability data on antibiotics and other common drugs administered IP via PD solution, providing healthcare professionals with a reference document to support their decisions in the treatment of peritonitis. In addition, this review gives important background information on drug compatibility, which should not only ensure proper interpretation of the data presented but also benefit the quality of the design of future compatibility studies.
INTRAPERITONEAL DRUG ADMINISTRATION
Many different drugs have been administered IP in PD therapy, for local (e.g., antibiotics) and systemic (e.g., insulin) effects. The IP route is the recommended route for administration of antibiotics in the treatment of peritonitis (5). Intraperitoneal antibiotics for peritonitis are preferable to intravenous and oral administration because of the resulting very high local levels of antibiotics that are well above the minimum inhibitory concentration for sensitive organisms (3). In addition, antibiotics with a high molecular weight, high protein-binding capacity, and high lipid solubility are characterized by limited diffusion into the peritoneal cavity, rendering them ineffective when given intravenously or orally (6). A practical advantage of the IP route is that it avoids venipuncture and can be safely done by the patient at home after appropriate training (3).
Despite the numerous advantages of the IP administration of drugs via PD solutions, important considerations are to be taken into account with respect to drug stability and compatibility. Indeed, in contrast with intravenous additives, IP additives are exposed to the complex matrix of a PD solution and to external heating, which is inherent to the PD technique. Ideally, the dialysis bag is warmed in its overpouch to body temperature on a heating plate designed for this purpose. Then the overpouch is removed and the drug is added aseptically to the dialysis bag via the medication port and mixed thoroughly with the solution. Subsequently, the freshly prepared solution is instilled and, in case of intermittent dosing of an antibiotic, allowed to dwell for at least 6 hours to ensure adequate absorption of the antibiotic into the systemic circulation (3). In actual practice, however, the time of exposure of the drug or antibiotic to these stressful conditions is often much longer. Failure to know the compatibility of the IP administered drug and the PD solution can result in significant underdosing of the drug and/or exposure of the patient to possibly toxic drug decomposition products, as in the case of ceftazidime, which is degraded mainly into the toxic compound pyridine (7).
This review covers all drugs that have been administered via PD solution in a PD therapy setting and includes all antibiotics that have IP dosing recommendations in the ISPD guidelines (Tables 1, 2, 3, 4). Drug names of the latter are listed in italics in the Tables. Table 1 lists reports on IP administration of drugs that can be used in the PD setting but for which no stability data have been reported (3,8–22). Reports on IP use of drugs specifically related to chemotherapy were excluded. Table 1 contains references to pharmacokinetic studies, prospective randomized open trials and clinical trials, case reports, and ISPD recommendations of antibiotic regimes for the treatment of peritonitis.
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DEFINING STABILITY AND COMPATIBILITY
In the current literature, the terms "stability" and "compatibility" are often used interchangeably, causing confusion on the exact meaning of these terms. In the current United States Pharmacopeia (USP30-NF25), stability is defined as "the extent to which a product retains, within specified limits, and throughout its period of storage and use (i.e., its shelf life), the same properties and characteristics that it possessed at the time of its manufacture" (23). The stability definition can be applied to the drug (drug stability) and to the PD solution (diluent stability). As product limits may vary for different drugs and the pharmacopeial limits may be subject to regional differences (e.g., USP, BP, EP), the generally accepted drug stability criterion of a maximum of 10% drug decomposition will further be applied in this review (24).
Compatibility is a broader concept and includes drug stability and diluent stability, minimal adsorptive behavior of the drug (minimal drug–container interaction), and, in the case of drug combinations, minimal drug–drug interactions. Incompatibility is often but not necessarily accompanied by perceptible physical signs. Particulate formation, haze, precipitation, color change, or gas evolution are all visual signs of incompatibility. In addition to visual signs of incompatibility, a change in pH of the PD solution during the course of the study can indicate a chemical incompatibility. Thus, despite its frequent generalized use, stability is only one particular aspect of compatibility. Consequently, a drug that is compatible with the PD solution is, per definition, stable in the PD solution, while a drug that is stable in a PD solution is not necessarily compatible with it. In interpreting drug compatibility data, the reader should keep in mind that many published articles provide only partial evaluations and do not examine all aspects of a drug's compatibility.
IMPACT OF CONTAINER MATERIAL ON COMPATIBILITY
Lately, new container materials are being used. The type of container material can have a significant impact on drug compatibility due to potentially large differences in degree of drug adsorption. Generally, the polar PVC container material adsorbs drugs more readily than the nonpolar polyolefin container material (9). However, drug adsorption is a complex process that also depends on time, temperature, pH, and composition of the PD solution. In addition to adsorption, different container materials may also influence the drug degradation rate, albeit in a less pronounced manner (25). Insulin adsorption is a classic example of drug adsorption to container material, yet clinical studies and clinical practice demonstrate that insulin can be successfully administered via PD solutions (26–28). The percentage of insulin adsorbed to PVC material increases with time and temperature and decreases with increasing insulin concentrations (29). While no significant differences in adsorption of insulin are observed between PVC and polyolefin containers (30), adsorption to glass surfaces is much faster and more pronounced (29). Recently, Voges et al. demonstrated that insulin agglomeration (31), which occurs with increasing pH, was concomitant with increased adsorption (30). Generally, if adsorption occurs, the adsorption behavior of any drug seems similar to that of insulin in terms of time, temperature, and concentration. In contrast with insulin, however, other drugs tend to adsorb more readily and to a larger extent to the polar PVC container material than to a nonpolar polyolefin material. In compatibility studies, the difference between the target concentration and the effective initial concentration obtained after adding the drug to the PD solution is a good indication for adsorption. However, this difference is often ascribed to the approximate nature of the compounding procedure (e.g., concentration range specified by the manufacturer; syringe variability) or to volume overfills of the dialysis bags. While small differences can indeed be attributed to the difference between the nominal volume of the PD solution and the overfill volume (generally <4%), much larger differences can be expected to be a result of significant adsorption of the drug to the container material, which requires further investigation. In comparison to drug degradation, the drug adsorption process is much faster and can already be seen during the mixing procedure (29).
To conclude, if the stability of a drug has been studied in glassware or in a different container, no firm statements can be made on the compatibility of the drug and the PD solution in its original container. An understanding of the degree of drug adsorption may allow a compensatory increase of the dose in clinical practice if no excessive degradation of the drug takes place.
DESIGN OF COMPATIBILITY STUDIES
A drug compatibility study should be designed in a way that mimics end-user conditions as closely as possible. This applies to the drug formulation, drug concentration range, PD solution, and container material, as well as light and temperature conditions during storage. When using temperature-controlled rooms, the relative humidity should be described. The temperature profile recorded in a 2.5-L dialysis bag is very dependent on the heating conditions (e.g., hot plate, 25% or 75% relative humidity) used to simulate the transfer from room temperature to body temperature and has a large impact on drug stability. As mentioned above, at time zero of the drug concentration determination, vigilance to differences between target concentration and effective initial concentration is needed. Therefore, the actual initial concentration of the drug obtained after dosing should be clearly stated and not reported solely as being 100%. During the course of the study, the stability of the drug should be monitored by a properly validated, stability-indicating analytical method.
In addition to drug adsorption and drug stability, the impact of the drug on the solution should be verified by monitoring the pH, color, and particulate matter level of the PD solution.
STABILITY-INDICATING ANALYTICAL METHODS
Historically, early drug stability studies performed in PD solutions made use of microbiological methods (e.g., killing assay, diffusion method, turbidimetric method) to determine stability. This may not be surprising, as the first drugs studied in PD solutions were actually antibiotics and, consequently, monitoring bactericidal activity was a logical choice. Moreover, in clinical practice, the antimicrobial activity of the administered antibiotic is what actually matters. Among the microbiological methods described in the literature, one can differentiate between reports that present the bactericidal activity graphically as killing curves (expressed as percentage of survivors as a function of time) (32,33) or as a titer of sensitive micro-organisms (34), and those presenting antimicrobial activity, using the diffusion disk method, as a percentage of the initial activity (35–37). While bioassays can be sensitive, they are subject to wide variability, in part due to toxic drug degradation products that can interfere with determinations of the antimicrobial activity of the drug. For instance, the major degradation product of cefotaxime, desacetylcefotaxime, was reported to retain 10% – 50% of the antimicrobial activity of cefotaxime, depending on the sensitivity indicator micro-organism challenged (38). Thus, a microbial method is not only unable to differentiate between the intact drug and the drug degradation products, the overall potency determined is also strongly dependent on the indicator organism used. Paradoxically, microbial methods are often considered trustful due to their direct indication of antibiotic activity. To conclude, microbiological methods are not reliable in determining the drug stability of an antibiotic.
Currently, the high-performance liquid chromatography (HPLC) method that offers stability-indicating potential seems to have become the method of choice in stability studies. A recurring flaw in stability studies, however, is the failure to demonstrate the stability-indicating capability of the analytical method (i.e., the power to detect and separate the intact drug in the presence of its decomposition products). Since including this parameter in the selection criteria for Tables 2, 3, 4 would exclude too many otherwise acceptable quality studies, preference was given by denoting the stability-indicating assays with the "SI" superscript. The practitioner should consider this factor in the interpretation of the presented data. Unfortunately, despite the effort of Trissel in 1983 to improve the quality of stability studies (39), and the subsequent emphasis on the need for stability-indicating analytical methods in 1988 (40), many papers still lack this essential information. A forced degradation by exposure of the intact drug to extremes of pH, temperature, heat, oxygen, and light, followed by demonstration of separation of the drug decomposition products from the intact drug should be part of any HPLC validation protocol.
Finally, one should be careful when using popular immunoassays (e.g. ELISA, EMIT) that should not be considered stability-indicating, unless demonstrated otherwise, due to cross-reaction possibilities between the decomposition products and the antibody (40).
DRUG COMPATIBILITY AND DRUG STABILITY DATA IN PD SOLUTIONS
A literature search was performed on drug compatibility and drug stability in PD solutions using the PubMed and Web of Science search engines to download data from the Medline and the Science Citation Index Expanded database respectively. Primary key word searches included the following terms: "compatibility," "dialysate," "dialysis," "drug," "intraperitoneal," "peritoneal," "stability," and their combinations. Literature in languages other than English, French, or German was excluded. Reports limited to an abstract were also excluded as they contain only limited information. Since stability and compatibility are relative concepts requiring qualifiers of time and conditions (39), strict selection criteria were applied to the literature data. A complete description of the materials, test conditions, and methods was considered a requirement (i.e., the name and concentration of the drug studied; the name, type, and concentration of the PD solution; the actual temperature and the assay used to quantify the concentration of the drug). An exception was made for reports in which the lacking information could be deduced from the limited product information provided. As a time-zero determination of drug concentration is an essential reference point in a stability study, reports limited to graphical presentation of bactericidal activities or other formats that do not allow extrapolation of concentrations were also excluded. Finally, only data from studies that were performed in commercially available PD solutions in their original containers were included. Applying these criteria to the literature data, the following papers were excluded: Refs. (9), (32–34), and (41–43).
Among the data gathered, only in two papers were all aspects of drug compatibility investigated (30,44). In only 38% of the reports, in addition to drug stability, was diluent stability examined by both visual inspection and pH monitoring (30,38,44–54). Moreover, many studies lacked the use of blank PD solution as a reference. Indeed, a change in pH of the PD solution during the study can be attributed to a drug–diluent interaction only if, in the absence of the drug, no change in pH is observed under identical storage conditions. Finally, in only five studies was drug adsorption to the container material discussed (30,44,55–57). Except for these reports, the drug stability durations in the Tables do not include the potentially important loss caused by the initial adsorptive behavior of the drug. Moreover, two studies clearly demonstrate the significant impact that drug adsorption can have on drug availability (56,57).
The above observations highlight the limitations of the current literature data and indicate that future studies in PD solutions should address all aspects of drug compatibility.
Table 2 lists stability data of drugs studied as single additives to PD solutions in PVC containers (30,35–38, 45–50,52,54–71). For drugs for which stability differs with concentration and/or PD solution formulation, corresponding stabilities are given; otherwise, the reported stability is applicable to all combinations. In cases where there was more than 10% drug decomposition at the first data point, the remaining concentration is given in brackets.
For drug stability in solutions packaged in two-chambered bags, it is indicated whether the stability data concerns the mixed or the unmixed solution. Indeed, two-chambered bag products require mixing of the two compartments to obtain a mixed solution before infusion into the peritoneal cavity (72,73). The concentrates typically have pH values that are different from the mixed solution. As extremes of pH can drastically impact the drug degradation rate (74), one should always ascertain if the stability data apply to mixed or unmixed solution.
Table 3 lists stability data of drugs studied as single additives to PD solutions in polyolefin containers (30,44). As the container material of a PD solution plays an important role in drug compatibility and should therefore always be considered when interpreting stability data, the references are presented in separate Tables according to the container material.
Table 4 lists drugs that have been studied as combinations (36,37,51–54,60,64,75). Generally, the stability of individual drugs was not significantly affected by drug–drug interactions in PD solutions (i.e., the stability of individual drugs combined in a PD solution equals the stability of the individual drugs separately in that PD solution). Various glycopeptides, aminoglycosides, and cephalosporins can be mixed in the same dialysis solution bag without loss of bioactivity (Table 4); however, care should be taken to avoid combining the drugs in their concentrated form. Vancomycin and ceftazidime, for instance, are physically incompatible at high concentrations, resulting in immediate precipitation, but they can be safely used in combination when diluted in PD solution (76). Therefore, it is recommended that separate syringes be used for antibiotics that are to be admixed (3). Aminoglycosides and penicillins should never be used in combination due to chemical incompatibility resulting in inactivation of the aminoglycoside (77).
Finally, addition of heparin in concentrations ranging from 500 to 1000 U/L has negligible effect on the stability of various antibiotics admixed in PD solutions (36,47,50,54). Similarly, the addition of insulin does not affect the antimicrobial activity of many antibiotics (36).
CONCLUSIONS
Intraperitoneal administration of various drugs via PD solutions confers multiple advantages in PD therapy. To ensure effective treatment, the prescriber needs to know whether the administered drug is compatible with the PD solution and its container. A variety of PD solutions are used across the world, in terms of both the solution itself and the container material. The majority of the data on drug stability in PD solutions available today are limited to standard PD solutions and do not cover the complete set of antibiotics with dosing recommendations in the ISPD guidelines. Due to significant differences in the composition of current PD solutions and drug–container interactions, drug compatibility data generally cannot be extrapolated from one solution to another or from one container material to another. Moreover, the majority of the studies investigated only one aspect of drug compatibility, namely, drug stability. However, other drug compatibility aspects, drug adsorption in particular, can significantly impact drug potency. Therefore, complete drug compatibility studies should be performed on each drug administered intraperitoneally and for each PD solution. The availability of up to date, high quality, drug compatibility data will advance PD therapy by allowing treatment that is more effective for patients.
Received 28 March 2008; accepted 12 May 2008.
REFERENCES
This article has been cited by other articles:
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  C. Van Ende, M. Tintillier, C. Cuvelier, G. Migali, and J.M. Pochet Intraperitoneal Meropenem Administration: a Possible Alternative to the Intravenous Route Perit. Dial. Int., March 1, 2010; 30(2): 250 - 251. [Full Text] [PDF]
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