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Extraneal

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Extraneal

CLINICAL PHARMACOLOGY

Mechanism of Action

Extraneal (icodextrin peritoneal dialysis solution) is an isosmotic peritoneal dialysis solution containing glucose polymers (icodextrin) as the primary osmotic agent. Icodextrin functions as a colloid osmotic agent to achieve

ultrafiltration during long peritoneal dialysis dwells. Icodextrin acts in the peritoneal cavity by exerting osmotic pressure across small intercellular pores resulting in transcapillary ultrafiltration throughout the dwell. Like other peritoneal dialysis solutions, Extraneal (icodextrin peritoneal dialysis solution) also contains electrolytes to help normalize electrolyte balance and lactate to help normalize acid-base status.

Pharmacokinetics of Icodextrin

Absorption

Absorption of icodextrin from the peritoneal cavity follows zero-order kinetics consistent with convective transport via peritoneal lymphatic pathways. In a single-dose pharmacokinetic study using Extraneal (icodextrin), a median of 40% (60 g) of the instilled icodextrin was absorbed from the peritoneal solution during a 12-hour dwell. Plasma levels of icodextrin rose during the dwell and declined after the dwell was drained. Peak plasma levels of icodextrin plus its metabolites (median Cpeak 2.2g/L) were observed at the end of the long dwell exchange (median T^ = 13 hours).

At steady-state, the mean plasma level of icodextrin plus its metabolites was about 5 g/L. In multidose studies, steady-state levels of icodextrin were achieved within one week. Plasma levels of icodextrin and metabolites return to baseline values within approximately two weeks following cessation of icodextrin administration.

Metabolism

Icodextrin is metabolized by alpha-amylase into oligosaccharides with a lower degree of polymerization (DP), including maltose (DP2), maltotriose (DPS), maltotetraose (DP4), and higher molecular weight species. In a single dose study, DP2, DPS and DP4 showed a progressive rise in plasma concentrations with a profile similar to that for total icodextrin, with peak values reached by the end of the dwell and declining thereafter. Only very small increases in blood levels of larger polymers were observed. Steady-state plasma levels of icodextrin metabolites were achieved within one week and stable plasma levels were observed during long-term administration.

Some degree of metabolism of icodextrin occurs intraperitoneally with a progressive rise in the concentration of the smaller polymers in the dialysate during the 12-hour dwell.

Elimination

Icodextrin undergoes renal elimination in direct proportion to the level of residual renal function. Diffusion of the smaller icodextrin metabolites from plasma into the peritoneal cavity is also possible after systemic absorption and metabolism of icodextrin.

Special Populations

Geriatrics

The influence of age on the pharmacokinetics of icodextrin and its metabolites was not assessed.

Gender and Race

The influence of gender and race on the pharmacokinetics of icodextrin and its metabolites was not assessed.

Clinical Studies

Extraneal (icodextrin peritoneal dialysis solution) has demonstrated efficacy as a peritoneal dialysis solution in clinical trials of approximately 480 patients studied with end-stage renal disease (ESRD).

Ultrafiltration, Urea and Creatinine Clearance

In the active-controlled trials of one to six months in duration, described below, Extraneal (icodextrin peritoneal dialysis solution) used once-daily for the long dwell in either continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) therapy resulted in higher net ultrafiltration than 1.5% and 2.5% dextrose solutions, and higher creatinine and urea nitrogen clearances than 2.5% dextrose. Net ultrafiltration was similar to 4.25% dextrose across all patients in these studies. Effects were generally similar in CAPD and APD.

In an additional randomized, multicenter, active-controlled two-week study in high average/high transporter APD patients, Extraneal (icodextrin peritoneal dialysis solution) used once daily for the long dwell produced higher net ultrafiltration compared to 4.25% dextrose. Mean creatinine and urea nitrogen clearances were also greater with Extraneal (icodextrin peritoneal dialysis solution) and ultrafiltration efficiency was improved.

In 175 CAPD patients randomized to Extraneal (icodextrin peritoneal dialysis solution) (N=90) or 2.5% dextrose solution (N=85) for the 8-15 hour overnight dwell for one month, mean net ultrafiltration for the overnight dwell was significantly greater in the Extraneal (icodextrin peritoneal dialysis solution) group at weeks 2 and 4 (Figure 1). Mean creatinine and urea nitrogen clearances were also greater with Extraneal (icodextrin peritoneal dialysis solution) (Figure 2).

Figure 1 - Mean Net Ultrafiltration for the Overnight Dwell

Mean Net Ultrafiltration for the Overnight Dwell - Illustration

Figure 2 - Mean Creatinine and Urea Nitrogen Clearance for the Overnight Dwell

Mean Creatinine and Urea Nitrogen Clearance for the Overnight Dwell - Illustration

In another study of 39 APD patients randomized to Extraneal (icodextrin peritoneal dialysis solution) or 2.5% dextrose solution for the long, daytime dwell (10-17 hours) for three months, the net ultrafiltration reported during the treatment period was (mean ± SD) 278 ± 192 mL for the Extraneal (icodextrin peritoneal dialysis solution) group and -138 ± 352 mL for the dextrose group (p < 0.001). Mean creatinine and urea nitrogen clearances were significantly greater for Extraneal (icodextrin peritoneal dialysis solution) than 2.5% dextrose at weeks 6 and 12 (p < 0.001).

In a six-month study in CAPD patients comparing Extraneal (icodextrin peritoneal dialysis solution) (n=28) with 4.25% dextrose (n=31), net ultrafiltration achieved during an 8-hour dwell averaged 510 mL for Extraneal (icodextrin peritoneal dialysis solution) and 556 mL for 4.25% dextrose. For 12-hour dwells, net ultrafiltration averaged 575 mL for Extraneal (icodextrin peritoneal dialysis solution) (n=29) and 476 mL for 4.25% dextrose (n=31). There was no significant difference between the two groups with respect to ultrafiltration.

In a two week study in high average/high transporter APD patients (4-hour D/P creatinine ratio > 0.70 and a 4-hour D/D0 ratio < 0.34, as defined by the peritoneal equilibration test (PET)), comparing Extraneal (icodextrin peritoneal dialysis solution) (n=47) to 4.25% dextrose (n=45), after adjusting for baseline, the mean net ultrafiltration achieved during a 14 ± 2 hour dwell was significantly greater in the Extraneal (icodextrin peritoneal dialysis solution) group than the 4.25% dextrose group at weeks 1 and 2 (p < 0.001, see Figure 3). Consistent with increases in net ultrafiltration, there were also significantly greater creatinine and urea nitrogen clearances and ultrafiltration efficiency in the Extraneal (icodextrin peritoneal dialysis solution) group (p < 0.001, see Figure 3).

Figure 3 - Mean Net Ultrafiltration, Creatinine and Urea Nitrogen Clearances and Ultrafiltration Efficiency for the Long Dwell in High Average/High Transporter Patients

Mean Net Ultrafiltration, Creatinine and Urea Nitrogen Clearances and Ultrafiltration Efficiency for the Long Dwell in High Average/High Transporter Patients - Illustration

Peritoneal Membrane Transport Characteristics: After one year of treatment with Extraneal (icodextrin peritoneal dialysis solution) during the long dwell exchange, there were no differences in membrane transport characteristics for urea and creatinine. The mass transfer area coefficients (MTAC) for urea, creatinine, and glucose at one year were not different in patients receiving treatment with Extraneal (icodextrin peritoneal dialysis solution) or 2.5% dextrose solution for the long dwell.

Last reviewed on RxList: 4/29/2011
This monograph has been modified to include the generic and brand name in many instances.

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