Cyclosporine microemulsion

The usual adult oral dose of cyclosporine ranges from 4 to 18 mg/kg per day in two divided doses.11 Appropriate selection of the starting dose usually depends on the organ type, the patient s preexisting disease states, and other concomitant immunosuppressive agents used. Cyclosporine microemulsion is available as 25 and 100 mg individually blister-packed capsules and... 

Keown, P, and D. Niese, Cyclosporine microemulsion increases drug exposure and reduces acute rejection without incremental toxicity in de novo renal transplantation. International Sandimmun Neoral Study Group. Kidney Int, 1998. 54(3) 938-44. 

Holt, D.W and Johnston, A. (1997) Cyclosporin microemulsion. A guide to usage and moni ira%Jugs,... 

Kramer BK, Montagnino G, Del Castillo D, Margreiter R, Sperschneider H, Olbricht CJ, Kruger B, Ortuho J, Kohler H, Kunzendorf U, Stummvoll HK, Tabernero JM, Muhibacher F Rivero M, Arias M European Tacrolimus vs Cyclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation 2 year follow-up results. Nephrol Dial Transplant 2005 20 968-973. 

Hoppu K, Jalanko H, Laine J, Holmberg C. Comparison of conventional oral cyclosporine and cyclosporine microemulsion formulations in children with a liver transplant. Transplantation 1996 62 66-71. 

Trompeter R, Filler G, Webb NJ, Watson AR, Milford DV, Tyden G et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002 17 141-9. 

Kaplan B, Meier-Kriesche HU, Napoli KL, Kahan BD. The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther 1998 63 48-53. 

In recent years there has been an increased interest in the utility of lipid-based delivery systems to enhance oral bioavailability (4). It is generally known that membrane permeability is directly correlated to a drug s water-lipid partition coefficient however, the systemic availability of highly lipophilic drugs is impeded by their low aqueous solubility. In an effort to improve this solubility-limited bio-availabiliy,formulators have turned to the use of lipid excipients to solubilize the compounds before oral administration. Several formulations are currently on the market, for example, Sandimmun/Neoral (cyclosporin microemulsion), Norvir (ritonavir), and Fortovase (saquinavir)... 

Cole E, Keown P, Landsberg D, Halloran P, Shoker A, Rush D, Jeffrey J, Russell D, Stiller C, Muirhead N, Paul L, Zaltzman J, Loertscher R, Daloze P, Dandavino R, Boucher A, Handa P, Lawen J, Belitsky P, Parfrey P, Tan A, Hendricks L. Safety and tolerability of cyclosporine and cyclosporine microemulsion during 18 months of follow-up in stable renal transplant recipients a report of the Canadian Neoral Renal Study Group. Transplantation 1998 65 505-510. 

A multicenter randomized comparative trial of tacrolimus in combination with azathioprine or mycofenolate mofetU (MMF) versus cyclosporin (microemulsion) with MMF after cadaveric kidney transplantation demonstrated that all regimens yielded similar acute rejection and graft survival rates at 1 year. The tacrolimus-MMF regimen was associated with the lowest rate of steroid-resistant rejection requiring antilymphocyte therapy. In addition, the tacrolimus-treated patients had lower incidence of hyperlipidemia, a side effect of particular concern in these patients [60]. 

Margareiter, R., and the European Tacrolimus vs Cyclosporin-Microemulsion Renal Transplantation Study Group (2000). A prospective, randomized multicentre study to compare the efficacy and safety of tacrolimus and cyclosporin-microemulsion in renal transplantation. Presented at Transplant (May 13-17, Chicago). Abstr. No. 8. 

Peld LG, Stablein D, Fivush B et al (1997) Renal transplantation in children from 1987-1996 the 1996 annual report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 1 146-162 Filler G, Webb NJ, Milford DV et al (2005) Four-year data after pediatric renal transplantation a randomized trial of tacrolimus vs. cyclosporin microemulsion. Pediatr Transplant 9 498-503... 

Barone, G., C.T. Chang, M.G. Choc, Jr., et al.. The pharmacokinetics of a microemulsion formulation of cyclosporine in primary renal allograft recipients. The Neoral Study Group. Transplantation, 1996.61(6) 875-80. 

Ku YM, Min DI, Flanigan M. Effect of grapefruit juice on the pharmacokinetics of microemulsion cyclosporine and its metabohte in healthy volunteers does the formulation difference matter J Clin Pharmacol 1998 38(10) 959 965. 

Cyclosporine absorption is incomplete and somewhat erratic, although a microemulsion formulation improves its consistency and provides 20-30% bioavailability. Grapefruit juice increases cyclosporine bioavailability by as much as 62%. Cyclosporine is metabolized by CYP3Aand consequently is subject to a large number of drug interactions (see Chapters 55 and 66). 

Mueller, E.A. et al. (1994a) Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation.Pharm. Res., 11 301-304. 

Ritschel, W.A. (1996) Microemulsion technology in the reformulation of cyclosporine the reason behind the pharmacokinetic properties of NeorSILin. Transplant., 10 364-373. 

Trull, A.K. et al. (1993) Cyclosporine absorption from microemulsion formulation in liver transplant recipient. Lancet, 341 433. 

Studies demonstrating that cyclosporine absorption is enhanced through reduction in the formulation particle size [18] have established that the bioavailability is improved by microemulsion formulation [35,36],... 

The new cyclosporine formulation (Sandimmun Neoral, Novartis Pharmaceuticals Corporation, East Hanover, NJ) is a self-microemulsifying drug delivery system, which consists of the drug in a lipophilic solvent (corn oil), hydrophilic cosolvent (propylene glycol) surfactant and an antioxidant [37]. Upon contact with GI fluids, Sandimmun Neoral readily forms a homogenous, monophasic microemulsion, which allows the absorption of the drug molecules. Unlike Sandimmun, the formation of this microemulsion is independent of bile salt activity, and indeed, studies have shown that the absorption of cyclosporine from the new formulation is much less dependent on bile flow [38] and is unaffected by food intake [39],... 

Improved pharmacokinetic behavior was also seen with the microemulsion in many other studies. Inter- and intraindividual variabilities of cyclosporine primary pharmacokinetic parameters (Cmax, /max, AUC, and terminal half-life) were compared following the administration of the two formulations to 24 healthy volunteers. Both inter- and intraindividual variabilities were significantly reduced with the microemulsion intraindividual variability ranged between 9% and 22% for the microemulsion, compared with 19%-41% for the standard formulation, and the interindividual variability values were 3%-22% and 20%-34%, respectively [40],... 

The pharmacokinetic dose proportionality and relative bioavailability of cyclosporine from the microemulsion formulation were compared to those of the regular formulation over the dosage range of 200 to 800 mg. The AUC for Sandimmun increased in a less than proportional manner with respect to dose, whereas that for Neoral was consistent with linear pharmacokinetics. In addition, the relative bioavailability of cyclosporine from the microemulsion formulation ranged from 174% at the 200 mg dose to 239% at the 800 mg dose compared to the regular formulation [41]. 

Cyclosporine A absorption was evaluated following oral administration of the regular Sandimmun soft gelatin capsule and the Neoral microemulsion formulation to patients with psoriasis. The Neoral formulation showed 32% increased mean AUC value, increased Cmax, decreased tmax and reduced variability between patients (Figure 6.4) [42],... 

FIGURE 6.4 Individual plasma cyclosporine A profiles following oral administration of Neoral microemulsion formulation (a) and the regular Sandimmun soft gelatin capsule (b) in psoriasis patients. (From Erkko, P., et al., Br. J. Dermatol., 136, 82, 1997. With permission.)... 

Ritschel, W.A., et al. 1990. Improvement of peroral absorption of cyclosporine A by microemulsions. Methods Find Exp Clin Pharmacol 12 127. 

Trull, A.K., et al. 1995. Absorption of cyclosporin from conventional and new microemulsion oral formulations in liver transplant recipients with external biliary diversion. Br J Clin Pharmacol 39 627. 

Kovarik, J.M., et al. 1994. Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci 83 444. 

Erkko, P., et al. 1997. Comparison of cyclosporin A pharmacokinetics of a new microemulsion formulation and standard oral preparation in patients with psoriasis. Br J Dermatol 136 82. 

Goa KL. Cyclosporin an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (neoral)l in organ transplantation. Drugs. 2001 61 1957-2016. 

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