, Volume 63, Issue 19, pp 2079-2105
Date: 17 Sep 2012

Icodextrin

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Summary

Abstract

Icodextrin (Extraneal®) is a high molecular weight glucose polymer developed specifically for use as an alternative osmotic agent to dextrose during the once-daily long-dwell exchange in peritoneal dialysis (PD).

Isosmotic 7.5% icodextrin solution induces transcapillary ultrafiltration (UF) by a mechanism resembling ‘colloid’ osmosis (unlike hyper-osmolar dextrose-based solutions, which induce UF by crystalline osmosis). In addition, absorption of icodextrin from the peritoneal cavity is relatively slow compared with that of dextrose; this results not only in UF of longer duration, but also a lower carbohydrate load compared with medium (2.5%) and strong (4.25%) dextrose exchanges.

In randomised clinical trials of up to 2 years in duration, administration of icodextrin for the long (8- to 16-hour) overnight exchange in continuous ambulatory peritoneal dialysis (CAPD) or daytime exchange in automated peritoneal dialysis (APD) produced net UF which exceeded that with 1.5% and 2.5% dextrose solutions (thereby improving fluid balance), and was equivalent to that with 4.25% dextrose solution. Icodextrin also increased peritoneal clearances of creatinine and urea nitrogen compared with 2.5% dextrose solution. The increase in UF volume with icodextrin was enhanced in CAPD patients with high peritoneal membrane permeability (i.e. high and high-average transporters), maintained in the small number of patients followed-up for 2 years and sustained during episodes of peritonitis. Icodextrin reduced the percentage of patients with net negative UF in contrast to 1.5% and 2.5% dextrose and, in noncomparative studies, extended PD technique survival in patients who had failed dextrose-based dialysis. The use of icodextrin was also associated with some symptomatic improvements and health-related quality of life advantages, and no adverse effect on patient survival, compared with dextrose, although confirmation of these findings is ideally required in appropriately designed studies.

The tolerability of icodextrin was generally similar to that of dextrose-based solutions in controlled clinical trials, although there was an approximate three-fold increase in the risk of new skin rash (5.5% vs 1.7%). However, reports of severe cutaneous hypersensitivity reactions remain rare; this possibility should not preclude the use of the polymer.

Conclusion: 7.5% icodextrin solution offers the first feasible alternative to conventional dextrose solutions for the once-daily long-dwell exchange in PD. It is effective, generally well tolerated and appears to be most useful in situations of reduced or inadequate UF with dextrose, including in high and high-average transporters, during episodes of peritonitis and patients who have failed dextrose-based dialysis.

Pharmacodynamic Properties

Icodextrin, a starch-derived, water-soluble, glucose polymer (average molecular weight 16.8kDa) linked predominantly by α1–4 glucosidic bonds, induces trans-capillary ultrafiltration (UF; removal of excess fluid from the plasma) by a mechanism resembling ‘colloid’ osmosis. Thus, icodextrin-based peritoneal dialysis (PD) solutions can be iso-osmotic with respect to normal plasma, unlike hyper-osmotic dextrose-based solutions, which produce UF by crystalline osmosis.

Intraperitoneal administration of PD solution containing 7.5% icodextrin provides sustained UF throughout the once-daily long-dwell exchange (8–16 hours) in patients treated with continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD); the effect on UF is immediate with the first exchange. UF volumes with icodextrin are equivalent to those with ‘strong’ (4.25%) dextrose solutions; compared with ‘weak’ (1.5%) and ‘medium’ (2.5%) dextrose solutions, icodextrin increases UF and improves fluid balance. Interestingly, in a 4-month randomised multicentre trial, treatment with icodextrin, but not 1.5% dextrose, was associated with a significant 5% reduction in left ventricular hypertrophy, an effect that was unrelated to changes in volume status or blood pressure.

Due to the relatively slow rate of absorption of icodextrin from the peritoneal cavity (which accounts for the prolonged UF effect) the carbohydrate load per exchange is lower than that with 2.5% and 4.25% dextrose solutions. Beneficial effects of icodextrin on insulin sensitivity and plasma lipids (significant reductions in total and low-density lipoprotein cholesterol levels) compared with dextrose have also been observed in some studies. These reports notwithstanding, the incidences of hyperglycaemia (5% vs 4%) and hypercholesterolaemia (2% vs 2%) were similar for icodextrin and dextrose in a pooled analysis of data from controlled clinical trials.

Preclinical data suggesting that icodextrin may be a more biocompatible osmotic agent than dextrose have recently received some clinical support. Specifically, icodextrin appeared to have a less deleterious effect on membrane function, especially compared with 2.5% and 4.25% dextrose, in a 2-year prospective study in 177 anuric APD patients. However, neither icodextrin nor 1.5–4.25% dextrose solutions had clinically meaningful effects on peritoneal membrane characteristics during 1–2 years of treatment in randomised studies of nonanuric CAPD patients.

Pharmacokinetic Properties

Icodextrin is absorbed at a constant rate from the peritoneal cavity, mostly via lymphatic pathways. The amount of icodextrin absorbed thus depends on the dwell time; it represents approximately 40% of the administered dose after a 12-hour exchange. Up to 80% of the absorbed icodextrin dose is eventually metabolised, first by circulating α-amylases and then by tissue maltases, into glucose; the remaining 20% is eliminated via the urine (in direct proportion to the level of residual renal function) or in the dialysate.

The plasma profile of icodextrin and its three main metabolites (maltose, maltotriose, and maltotetraose) fits a simple one-compartment model assuming zero-order absorption and first-order elimination. Peak plasma concentrations are reached at the end of a 12-hour dwell and decline to baseline levels within 3–7 days following a single icodextrin exchange. Concentrations of the main icodextrin metabolites in the dialysate also rise during the dwell, either as a result of diffusion from the plasma (maltose) or intraperitoneal metabolism of other, minor metabolites (in the case of maltotriose and maltotetraose), although this has no effect on the osmolality of the solution.

The steady-state plasma concentration of icodextrin plus its main metabolites (typically 5–6 g/L) is reached within 7–10 days, with the metabolites accounting for approximately 40% of the total measured polymers. Maltose accumulation is avoided by limiting the use of icodextrin to the once-daily long-dwell exchange.

Therapeutic Efficacy

The effects of 7.5% icodextrin solution used once daily for the long-dwell exchange in PD have been compared with those of standard dextrose solutions in several clinical trials of up to 2 years in length. These trials include four pivotal, multicentre, randomised studies: three (versus 1.5% and 4.25% dextrose in CAPD [n = 209], 2.5% dextrose in CAPD [n = 175] and 2.5% dextrose in APD [n = 39]) evaluating the short-term (≤6 months) UF efficacy of icodextrin; and one (versus 2.5% dextrose in CAPD or APD [n = 278]) assessing the long-term (1-year) effects of the polymer on patient survival and health-related quality of life (HR-QOL).

The effects of icodextrin on UF and small solute (e.g. creatinine, urea nitrogen) clearances were broadly similar when administered for the long overnight exchange (8–16 hours) in patients undergoing CAPD or the long daytime exchange (12–16 hours) in patients receiving APD. The increase in UF volume with icodextrin was maintained in a small number of patients (12 CAPD, 7 APD) foliowed-up for 2 years and preserved during episodes of peritonitis. Net UF during the long-dwell exchange with icodextrin was significantly greater than that with 1.5% and 2.5% dextrose solutions, and was similar to that with 4.25% dextrose solution. Icodextrin also reduced the percentage of patients with net negative UF in contrast to 1.5% and 2.5% dextrose. In a double-blind study in 175 patients undergoing CAPD, the average net UF during the 1-month treatment period was 1.7 times higher with icodextrin than with 2.5% dextrose (587 vs 356mL; p < 0.001); the greatest relative benefit with icodextrin was seen in high and high-average transporters. In addition, the average peritoneal clearances of creatinine and urea nitrogen were 1.1 times higher with icodextrin than with 2.5% dextrose (4 vs 3.5 mL/min and 4.5 vs 4.1 mL/min, respectively; p ≤ 0.001).

Available data suggest that CAPD patients receiving icodextrin for 6–12 months experience some symptomatic improvements and HR-QOL advantages compared with those receiving dextrose. Overall, perceived HR-QOL declined in a double-blind study in 278 patients receiving CAPD or APD, although the deterioration was less in patients treated with icodextrin, with 30% considering themselves to be much better now than 1 year ago compared with only 4% of those receiving 2.5% dextrose (p < 0.05). Similarly, available data suggest that treatment with icodextrin does not, on the whole, adversely affect patient survival and, furthermore, may extend PD technique survival in patients with UF failure who are on the point of transferring to haemodialysis.

Tolerability

Pooled data from controlled clinical trials (n = 840) suggest that, while in general icodextrin is as well tolerated as conventional dextrose-based solutions, it is three times more likely to cause new skin rash (5.5% vs 1.7%). A total of 265 patients were randomised to icodextrin in two pivotal multicentre, randomised, double-blind studies conducted in North America; of these, eight (3%) discontinued the polymer because of rash or exfoliative dermatitis. There have also been several reports of serious cutaneous hypersensitivity reactions occurring in clinical practice, although these remain rare overall. Pharmacovigilance data provided by the manufacturer suggest that most skin eruptions (incidence rate ≈2.5%) are mild, while more than half are self-limiting.

Use of icodextrin was not associated with an increased frequency of peritonitis or exit-site infections in large-scale clinical trials. There have, however, been several reports of icodextrin-associated aseptic peritonitis attributed to contamination of some batches of the manufactured product with peptidoglycan.

Body weight was little changed during 6–12 months of treatment with icodextrin or dextrose, with the notable exception of a significant (p < 0.05) 2.3kg increase with dextrose in the 1-year double-blind study in 278 patients receiving CAPD or APD. Overall, oedema occurred with a similar frequency in patients treated with icodextrin or dextrose in controlled clinical trials (6% vs 5%). Slight decreases in plasma sodium and chloride levels are attributed to a dilutional effect of icodextrin metabolites in the plasma, as are small increases in osmolality and alkaline phosphatase levels. However, these laboratory changes are not clinically significant.

Dosage and Administration

PD solution containing 7.5% icodextrin is indicated as a single daily exchange for the long (8- to 16-hour) dwell during CAPD or APD for the management of end-stage renal failure. It is contraindicated, however, in patients with a known allergy to cornstarch and those with glycogen storage disease.

Patients and physicians should follow all the normal procedures and precautions regarding intraperitoneal administration of dialysis solutions. In particular, not more than one long-dwell icodextrin exchange should be performed in a 24-hour period.

Importantly, plasma glucose levels in insulin-dependent diabetic PD patients must be measured using glucose-specific tests to avoid interference by icodextrin and its metabolites (resulting in erroneously high estimates of glycaemia). Icodextrin and its metabolites also interfere with enzymatic-based plasma amylase activity assays (resulting in inaccurately low values).

Various sections of the manuscript reviewed by: S.J.H. Bredie, Department of General Internal Medicine, University Medical Centre St Radboud, Nijmegen, The Netherlands; E. Goffin, Department of Nephrology, Universite Catholique de Louvain, Brussels, Belgium; R. Gokal, Manchester Royal Infirmary, Manchester, England; E. Imai, Department of Nephrology, Osaka Prefectural General Hospital, Osaka, Japan; C.H. Schröder, Department of Pediatric Nephrology, Wilhelmina Children’s University Hospital, Utrecht, The Netherlands; W. Van Biesen, Renal Division, University Hospital Ghent, Ghent, Belgium; M. Wilkie, Sheffield Kidney Institute, Sheffield, England; G. Woodrow, Renal Unit, Leeds General Infirmary, Leeds, England.
Data Selection
Sources: Medical literature published in any language since 1980 on icodextrin, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘icodextrin’. EMBASE search terms were ‘icodextrin’. AdisBase search terms were ‘icodextrin’. Searches were last updated 21 August 2003.
Selection: Studies in patients undergoing continuous ambulatory peritoneal dialysis or automated peritoneal dialysis who received icodextrin for the once-daily long-dwell exchange. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Icodextrin, glucose polymer, peritoneal dialysis, ultrafiltration, pharmacodynamics, pharmacokinetics, therapeutic use.