Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024523 (malabsorption)
 7,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, a new oral microemulsion formulation of cyclosporin A (CsA)--Neoral (Sandoz, Basle, Switzerland)--with a higher bioavailability has become available. Ten stable paediatric renal transplant recipients with excessive variations in CsA trough levels with the original Sandimmun (Sandoz, Basle, Switzerland) preparation were switched to Neoral on a 1:1 basis. Pharmacokinetic studies revealed impaired absorption of Sandimmun in six patients. Compared with equal doses of Sandimmun, the 8-h area under the concentration-time curve increased from 1,422 to 2,657 ng x h/ml and the peak concentration rose from 319 to 824 ng/ml (P < 0.01). In six patients with Sandimmun malabsorption, conversion on a 1:1 basis led to a reduction in creatinine clearance which was reversible after dose reduction by 9%-25%. With trough levels at the lower end of the present target range, creatinine clearance stabilised around pre-conversion values.
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PMID:Improved absorption of cyclosporin A from a new microemulsion formulation: implications for dosage and monitoring. 779 18

The microemulsion-based formulation of cyclosporin (Neoral; referred to as the microemulsion formulation in this review) is a microemulsion preconcentrate which has been developed to overcome problems associated with the poor and unpredictable absorption of the standard oral formulation of this drug. These include marked intra- and interpatient variability in the extent of absorption, a poor correlation between trough blood concentrations of cyclosporin and total systemic exposure, and the need for regular monitoring of blood cyclosporin concentrations. In healthy volunteers and renal or liver transplant recipients, administration of the microemulsion formulation resulted in cyclosporin absorption which was significantly faster, more extensive and more predictable than that seen with the standard oral formulation. Furthermore, measurement of whole-blood trough cyclosporin concentrations provided a better estimate of systemic drug exposure in renal transplant recipients who received the microemulsion formulation than in those who received the standard formulation. Systemic exposure of cyclosporin delivered by the new formulation appears to be relatively unaffected by food intake. Initial data suggest that drug absorption from the microemulsion formulation is enhanced in comparison with that achieved from the standard formulation in liver transplant recipients undergoing biliary diversion or with cholestasis, although absorption from the new formulation does not appear to be completely independent of bile. Preliminary results from other groups that experience cyclosporin malabsorption from the standard formulation (patients with cystic fibrosis or diabetes, and children) are also encouraging. Clinical trials specifically designed to investigate the relative immunosuppressive efficacy of the microemulsion formulation have not been reported; further data are required to fully establish the relationship between the more rapid and extensive absorption of cyclosporin from the microemulsion formulation and the probability of graft rejection or adverse events (including nephrotoxicity and hypertension). However, no statistically significant differences have been noted between the 2 formulations in the incidence of these events in studies to date. The incidence of rejection in new renal or liver transplant recipients treated for a minimum of 3 months was approximately 31 to 50% in those receiving the microemulsion formulation and approximately 24 to 56% in those receiving the standard formulation. Thus, although confirmation of existing efficacy and tolerability data is required, the characteristic pharmacokinetic properties of the microemulsion formulation make it an attractive option for the oral delivery of cyclosporin in transplant recipients, offering more predictable and more extensive drug absorption than the standard formulation. The microemulsion formulation may be of particular benefit in patients who show poor absorption of cyclosporin from the standard oral formulation, such as liver transplant recipients with biliary diversion or cholestasis.
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PMID:Cyclosporin. A review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoral). 858 33

In conclusion, Neoral gives more consistent drug absorption, achieving better pharmacokinetic predictability. Among other advantages, this results in a close correlation between trough blood levels and drug exposure (AUC) so that trough blood levels can be used as a more meaningful monitoring parameter when using the new formulation. Studies have also now confirmed that absorption of Neoral is bile independent, making it more useful in the early postoperative period and in the setting of cholestasis and rejection. Furthermore, studies have now demonstrated that in patients who have problems absorbing Sandimmune such as patients with cystic fibrosis, pancreatitis, or Crohn's disease, conversion to Neoral results in correction of malabsorption of CyA. Issues that need to be addressed in the future will include long-term toxicity associated with maintaining high Cmax and AUC; whether the introduction of Neoral can result in steroid sparing; and whether the introduction of Neoral will result in a reduced incidence of acute and chronic rejection.
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PMID:Neoral in liver transplantation. 862 16

In conclusion, Neoral gives more consistent drug absorption, achieving better pharmacokinetic predictability. Among other advantages, this results in a close correlation between trough blood levels and drug exposure (AUC) so that trough blood levels can be used as a more meaningful monitoring parameter when using the new formulation. Studies have also now confirmed that absorption of Neoral is bile independent, making it more useful in the early postoperative period and in the setting of cholestasis and rejection. Furthermore, studies have now demonstrated that in patients who have problems absorbing Sandimmune such as patients with cystic fibrosis, pancreatitis or Crohn's disease, conversion to Neoral results in correction of malabsorption of CyA. More recent data suggests that induction with Neoral results in a marked reduction in the incidence of acute rejection and allows for withdrawal of steroids and normalization of blood glucose, serum triglyceride, and cholesterol even when withdrawal is done 1 year after transplantation. Despite the high Cmax and AUC, there appears to be no increased toxicity in patients treated with Neoral. Issues that need to be addressed in the future include long-term toxicity associated with maintaining high Cmax and AUC and confirmation that the use of Neoral results in a reduction of both acute and chronic rejection.
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PMID:Neoral therapy in liver transplantation. 876 6

Cyclosporine (Sandimmune; Novartis Pharmaceuticals UK Ltd) is an effective immunosuppressive drug, but its lipid formulation and variable absorption may expose children to the risk of rejection during episodes of gastroenteritis after liver transplantation. Neoral (Novartis) is a microemulsified form of cyclosporine that may be better absorbed. In this study, the pharmacokinetic profiles of Neoral and Sandimmune were compared in stable children after liver transplantation to evaluate whether Neoral is more predictably absorbed. Eight children, 6 boys and 2 girls, with a mean age of 4.5 years (range, 1.2-12) were studied between 4 and 12 months after liver transplantation. Pharmacokinetic profiles were performed on each child by using the same dose (mg/kg) of Neoral or Sandimmune. Tmax, Cmax, Ctrough, and the area under the curve (AUC) were calculated and side effects were documented in children taking either drug for more than 3 months. Mean peak cyclosporine levels were higher and were achieved significantly sooner with Neoral (Cmax 790.5 +/- 216.5 ng/mL, P =.06; Tmax 1.8 +/- 1.0 hr, P =.01) than with Sandimmune (Cmax 589.4 +/- 313 ng/mL, Tmax 2.5 +/- 1.7 hr), implying more rapid and better absorption. There was no significant difference in overall drug exposure (AUC) and 12-hour trough levels between the two formulations (P >.05). Children with Roux-en-Y loop biliary anastomosis taking Neoral, however, showed greater increases in AUC (mean increase = 37%) than those with duct-to-duct anastomosis (mean increase = 16%). There was no correlation between 12-hour trough level and AUC for either Neoral (r2 = 0.48) or Sandimmune (r2 = -0.08); however, for both drugs, AUC correlated very well with the 2-hour post-dose level (r2 = 0.68 and 0.7, respectively). Hirsutism was reported in 4 of 6 children on Neoral and may be associated with higher peak levels. Neoral is more consistently absorbed than Sandimmune in children after liver transplantation and may be more effective prophylaxis against rejection. Because of the increased peak levels and drug exposure, which may influence side effects, particularly in children with Sandimmune malabsorption, we recommend a 1:0.75 dose conversion ratio in patients being converted from Sandimmune to Neoral.
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PMID:Comparison of pharmacokinetics of Neoral and Sandimmune in stable pediatric liver transplant recipients. 1007 49