Elsevier

Drug Discovery Today

Volume 11, Issues 17–18, September 2006, Pages 846-854
Drug Discovery Today

Review
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Disease, destination, dose and delivery aspects of ciclosporin: the state of the art

https://doi.org/10.1016/j.drudis.2006.07.015Get rights and content

Since its discovery in 1971, ciclosporin has revolutionized organ transplantation and the treatment of autoimmune disorders. The wide array of applications resulting from its clinical efficacy warrant unique administration strategies and varying doses, times of exposure and extents of distribution, depending on target tissue. The poor biopharmaceutical characteristics of low solubility and permeability makes this uphill task even more challenging for the drug delivery scientist. Efforts underway have explored various body routes employing approaches like emulsions, microspheres, nanoparticles, liposomes, iontophoresis and penetration enhancers. This review attempts a brief holistic view of the ‘four Ds’ (disease, destination, dose and delivery) surrounding this immunomodulator drug.

Section snippets

Mechanism of action

Ciclosporin effectively suppresses T-cell-dependent immune reactions (those underlying transplant rejection and some forms of autoimmunity). Ciclosporin forms a complex with cyclophilin, a cytoplasmic receptor protein present in T lymphocytes, and this complex further binds to calcineurin and inhibits Ca2+-stimulated dephosphorylation of the cytoplasmic component of the nuclear factor of activated T cells (NFAT). As a result, the translocation of the NFAT from the cytoplasm to the nucleus of

Dose

Ciclosporin can be administered orally as a liquid-filled capsule or as an oily solution, which is diluted in fruit juice before administration. Concomitant administration of grapefruit or grapefruit juice must be avoided because certain components in grapefruit (bergamottin and 6′,7′-dihydroxybergamottin), inhibit cytochrome P450 3A4 enzyme, leading to increased blood level of ciclosporin, which can results in toxicity 11, 12. The dose of ciclosporin varies depending on the transplanted organ

Therapeutic monitoring of ciclosporin

Because ciclosporin is a critical-dose drug with a narrow therapeutic range and variable absorption characteristics, its dosage must be titrated by monitoring of blood levels [13]. Trough ciclosporin level (C0; blood samples drawn before the next oral dose) has been conventionally used to determine Neoral® dosing. However, trough estimates do not help in predicting accurate dose, so the risk of toxicity or organ rejection cannot be ignored [14].

Estimates of drug exposure using the full area

Biopharmaceutical hurdles

Any drug should have an optimum balance between its hydrophilicity and lipophilicity to permeate and penetrate across various biological lipoproteinaceous barriers so that it gets absorbed and transported to the desired site of action. Ciclosporin is poorly soluble (6.6 μg/ml) in an aqueous medium [19], but is easily soluble in organic solvents. Ciclosporin lacks functional groups that are ionizable in a pharmaceutically useful pH range and therefore manipulation of pH does not enhance its

Delivery approaches for ciclosporin

Systemic administration of ciclosporin is an effective therapy for the prevention of graft rejection as well as most of the immunoregulatory skin and eye disorders. However, the long term systemic administration of ciclosporin required for the adequate control of local autoimmune diseases (Table 1) often leads to adverse effects. Nevertheless, most of these disorders can be effectively controlled by local administration of the ciclosporin formulations, which reduces the body burden of the drug

Conclusion and future perspectives

Drug delivery technologies have successfully negotiated the difficulties associated with low solubility and permeability of ciclosporin and have enhanced its bioavailability and effectiveness for most routes of administration. Biodegradable polymeric nanoparticles seem to be the most promising candidates for oral delivery and have not only improved its oral bioavailability, but also enhanced the overall therapeutic efficacy by targeting the lymphatic system and providing a sustained release of

Acknowledgement

MNVRK acknowledges financial support in the form of a research grant from Department of Biotechnology, Government of India (BT/PR5097/BRB/10/369/2004).

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