Cyclosporine formulations

Any change in cyclosporine formulation should be made cautiously and under the advisement of a physician—Patients should be given detailed dosage instructions... 

FIGURE 11.7 Comparison of marketed lipid-based cyclosporine formulations, Sandimmune (Olive oil SEDDS) and Neoral (Hydrolyzed Corn oil SMEDDS) in patients. (Adaptedfrom Constantinides, P.P. (1995) Pharm. Res., 12 1561-1572.)... 

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],... 

The current proprietary cyclosporin formulation, Sandimmun Neoral, is a microemulsion formulation. Although the formulation details of the Neoral formulation are not generally available, the relative bioavailabilities of the Neoral formulation and the initial Sandimmun formulation have been reported. In a dose linearity study, the relative bioavailability of the Neoral formulation compared with the Sandimmun formulation varied from 1.74 at a 200-mg dose to 2.39 at an 800-mg dose, illustrating the usefulness of the microemulsion formulation and suggesting an approximate twofold increase in bioavailability from the microemulsion formulation [74], Further studies showed that the absorption of cyclosporin from the Neoral formulation was significantly less variable [75] and less dependent on bile flow [76] than oral Sandimmun and that its absorption was unaffected by food [77], In terms of its apparent lack of reliance on bile for absorption, it is not known whether cyclosporin is absorbed from the formulation directly or just requires much lower bile salt concentrations to facilitate absorption. 

On the other hand, bioinequivalence of cyclosporine formulations, and of other drugs that have a narrow therapeutic index, could have serious therapeutic consequences. 

Sorbitan monooleate, polysorbate 80, and unsaturated polyglycolyzed glycerides (Labrafils) are components in the cyclosporin formulations Gengraf and Sandimmune. Bexarotene is a benzoic acid derivative, which is a selective activator of the retinoid X receptor indicated for the treatment of T-cell lymphoma, and is solubilized in a mixture of Polysorbate 20 and PEG 400 (in combination with povidone and BHA as an antioxidant) in 75 mg Targretin soft gelatin capsules. 

Olyaei AJ, deMattos AM, Bennett WM. Switching between cyclosporin formulations. What are the risks Drug Saf 1997 16(6) 366-73. 

Kovarik JM, Kalbag J, Figueiredo J, Rouilly M, O Bannon LF, Rordorf C. Differential influence of two cyclosporine formulations on everolimus pharmacddnetics a clinically relevant pharmacokinetic interaction. J CUn Pharmacol (2002) 42,95-9. 

The glucan synthase inhibitor caspofungin (intravenous formulation) is new on the market for the treatment of invasive aspergillosis in patients whose disease is refractory to, or who are intolerant of, other therapies. During the clinical trials fever, infused vein complications, nausea, vomiting and in combination with cyclosporin mild transient hepatic side effects were observed. Interaction with tacrolismius and with potential inducer or mixed inducer/inhibitors of drug clearance was also seen. 

Klyashchitsky, B. A., Owen, A. J., Nebulizer-compatible liquid formulations for aerosol pulmonary delivery of hydrophobic drugs glucocorticoids and cyclosporine,... 

Patients suffering from cystic fibrosis often use various aerosolized drugs. To reduce the viscosity of the mucus in the airways, recombinant human deoxyribonuclease is used. This enzyme is the first recombinant protein that has been developed for specific delivery to the lungs via the airways. It has a local action on the mucus in the airways and its absorption is minimal. Another drug that decreases the viscosity of the mucus is acetylcysteine. Aerosolized antibiotics are a further group of therapeutics that is widely used by cystic fibrosis patients. Solutions of antibiotics like tobramycin or colistin are used in nebulizers to prevent exacerbation of the disease. Pentamidine has been used for the prophylaxis of Pneumocystis pneumonia in patients infected with HIV virus, while chronic rejection of lung transplants provided a reason to develop an aerosol formulation of cyclosporine A. 

Levy GA. C2 monitoring strategy for optimising cyclosporin immunosuppression from the Neoral formulation. BioDrugs 2001 156 279-90. 

Answer Cyclosporine is an immunosuppressant drug used to prevent transplant rejections. Though an oral formulation is available, it has low bioavailability (very httle reaches the systemic circulation as intact drug). Diltiazem will inhibit cytochrome P450 3A4 in the gut. CYP3A4 is the... 

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). 

Posaconazole is the newest triazole to be licensed in the USA. It is available only in a liquid oral formulation and is used at a dosage of 800 mg/d, divided into two or three doses. Absorption is improved when taken with meals high in fat. Posaconazole is rapidly distributed to the tissues, resulting in high tissue levels but relatively low blood levels. Visual changes have not been reported, but drug interactions with increased levels of CYP3A4 substrates such as tacrolimus and cyclosporine have been documented. 

Sandimmune is the original formulation of cyclosporine used in clinical transplantation. Erratic absorption of the formulation has limited its use in transplant recipients. Many long-term transplant recipients continue on Sandimmune . The formulation has been supplanted by the micro-emulsion formula of cyclosporine. 

Cyclosporine (amount affected by coadministration schedule and formulation). 

If an emulsion formulation utilizes excipients within limits approved for human use, then the toxicity of the formulation is unlikely to be higher than that of the drug. However, if unapproved excipients are used (e.g., to increase drug solubility) or if excipients are used in quantities much larger than those approved for human use, extensive toxicity testings should be carried out before investigation in humans. On the other hand, there may be cases where formulating in an emulsion will decrease toxicity (e.g., cyclosporine and amphotericin B) (Table 10.4). 

Gonz ez, R.C.B. et al. (2002) Improved oral bioavailability of cyclosporin Ain male wistar rats comparison of a Solutol HS 15 containing self-dispersing formulation and a microsuspeihstoA. Pharm., 245 143-151. 

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

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

Murine Pharmocokinetics and Biodistribution of Cyclosporine A in a PEO-b-PCL Micelle Formulation and the Cremophor Preparation (Sandimmune , Novartis Pharmaceuticals)... 

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