n an increased ultrafiltration volume per gram of absorbedcarbohydrate compared to hyperosmolar glucose solutions.
12.3 Pharmacokinetics
Absorption
Absorption of icodextrin from the peritoneal cavity follows zero-order kinetics consistent with convective transportvia peritoneal lymphatic pathways. In a single-dose pharmacokinetic study using EXTRANEAL, a median of 40%(60 g) of the instilled icodextrin was absorbed from the peritoneal solution during a 12-hour dwell. Plasma levels oficodextrin rose during the dwell and declined after the dwell was drained. Peak plasma levels of icodextrin plus itsmetabolites (median Cpeak 2.2 g/L) were observed at the end of the long dwell exchange (median Tmax = 13 hours).
At steady-state, the mean plasma level of icodextrin plus its metabolites was about 5 g/L. In multi-dose studies,steady-state levels of icodextrin were achieved within one week. Plasma levels of icodextrin and metabolites returnto 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 (DP3), maltotetraose (DP4), and higher molecular weight species. In a singledose study, DP2, DP3 and DP4 showed a progressive rise in plasma concentrations with a profile similar to that fortotal icodextrin, with peak values reached by the end of the dwell and declining thereafter. Only very small increasesin blood levels of larger polymers were observed. Steady-state plasma levels of icodextrin metabolites wereachieved 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 thesmaller 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 thesmaller icodextrin metabolites from plasma into the peritoneal cavity is also possible after systemic absorption andmetabolism 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.
Drug Interactions
Insulin
A clinical study in 6 insulin-dependent diabetic patients demonstrated no effect of EXTRANEAL on insulinabsorption from the peritoneal cavity or on insulin’s ability to control blood glucose when insulin was administeredintraperitoneally with EXTRANEAL. However, appropriate monitoring of blood glucose should be performed when
initiating EXTRANEAL in diabetic patients and insulin dosage should be adjusted if needed [see Drug Interactions(7)].
Heparin
In vitro studies demonstrated no evidence of incompatibility of heparin with EXTRANEAL.
Antibiotics
Compatibility has been demonstrated with vancomycin, cefazolin, ceftazidime, gentamicin, and netilmicin.
However, aminoglycosides should not be mixed with penicillins due to chemical incompatibility.
Minimum Inhibitory Concentration (MIC)
No formal clinical drug interaction studies have been performed. In vitro studies with EXTRANEAL and thefollowing antibiotics have demonstrated |
