Dexamethasone

Dexamethasone is a synthetic glucocorticoid; it combines high anti-inflammatory effects with low mineralocorticoid activity. At high doses (e.g. 40 mg), it reduces the immune response.

Dexamethasone has been shown to induce multiple myeloma cell death (apoptosis) via a down-regulation of Nuclear Factor-κB activity and an activation of caspase-9 through second mitochondria-derived activator of caspase (Smac; an apoptosis promoting factor) release. Prolonged exposure was required to achieve maximum levels of apoptotic markers along with increased caspase-3 activation and DNA fragmentation.

Dexamethasone also down-regulated anti apoptotic genes and increased IκB-α protein levels. Dexamethasone apoptotic activity is enhanced by the combination with thalidomide or its analogues and with proteasome inhibitor (e.g. bortezomib).

Multiple myeloma is a progressive rare haematologic disease. It is characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein only (free immunoglobulin monoclonal κ and λ light chains).

Dexamethasone is a synthetic adrenocorticoid with approximately a 7 times higher anti-inflammatory potency than prednisolone and 30 times that of hydrocortisone. Adrenocorticoids act on the HPA at specific receptors on the plasma membrane. On other tissues the adrenocorticoids diffuse across cell membranes and complex with specific cytoplasmic receptors which enter the cell nucleus and stimulate protein synthesis. Adrenocorticoids have anti-allergic, antitoxic, antishock, antipyretic and immunosuppressive properties. Dexamethasone has only minor mineralocorticoid activities and does therefore, not induce water and sodium retention.

Dexamethasone has been shown to suppress inflammation by inhibiting oedema, fibrin deposition, capillary leakage, and phagocytic migration of the inflammatory response. Vascular Endothelial Growth Factor (VEGF) is a cytokine which is expressed at increased concentrations in the setting of macular oedema. It is a potent promoter of vascular permeability. Corticosteroids have been shown to inhibit the expression of VEGF. Additionally, corticosteroids prevent the release of prostaglandins, some of which have been identified as mediators of cystoid macular oedema.

Absorption

Oral administration

After oral administration, dexamethasone peak plasma levels are reached at a median of three hours. Bioavailability of dexamethasone is approximately 80%. There is a linear relationship between administered and bioavailable doses.

Dexamethasone is transported by the P-glycoprotein (also known as MDR1). Other MDR transporters may also have a role in dexamethasone transport.

IV / IM administration

After administration of Dexamethasone solution for injection, dexamethasone sodium phosphate is rapidly hydrolysed to dexamethasone. After an IV dose of 20 mg dexamethasone plasma levels peak within 5 minutes.

Ocular administration

When given topically to the eye, dexamethasone is absorbed into the aqueous humour, cornea, iris, choroid, ciliary body and retina. Systemic absorption occurs but may be significant only at higher dosages or in extended paediatric therapy. Up to 90% of dexamethasone is absorbed when given by mouth; peak plasma levels are reached between 1 and 2 hours after ingestion and show wide individual variations.

Distribution

Oral administration

Dexamethasone is bound by plasma proteins, principally albumin, up to about 80%, depending on the administered dose. At very high doses the majority of dexamethasone circulates unbound in the blood. The volume of distribution is approximately 1 l/kg. Dexamethasone crosses the blood-brain barrier and the placental barrier and passes into breast milk.

IV / IM administration

Dexamethasone is bound (up to 77%) by plasma proteins, mainly albumin. There is a high uptake of dexamethasone by the liver, kidney and adrenal glands.

Ocular administration

Tissue distribution studies in animals show a high uptake of dexamethasone by the liver, kidney and adrenal glands; a volume of distribution has been quoted as 0.58 l/kg. In man, over 60% of circulating steroids are excreted in the urine within 24 hours, largely as unconjugated steroid.

Biotransformation

Oral administration

A minor part of administered dexamethasone is excreted unchanged by the kidney. The major part is hydrogenated or hydroxylated in humans, the major metabolites being hydroxy-6-dexamethasone and dihydro-20-dexamethasone. 30 to 40% are conjugated to glucuronic acid or sulphated in the human liver and excreted in this form in the urine. Dexamethasone is metabolized via cytochrome P450 3A4 (CYP3A4). Other cytochrome P450 isoenzymes may also play a role in dexamethasone biotransformation.

IV / IM administration

Metabolism in the liver is slow and excretion is mainly in the urine, largely as unconjugated steroids.

Ocular administration

Dexamethasone sodium phosphate is rapidly converted to dexamethasone within the circulation. Up to 77% of dexamethasone is bound to plasma proteins, mainly albumin. This percentage, unlike cortisol, remains practically unchanged with increasing steroid concentrations. The mean plasma half-life of dexamethasone is 3.6 ± 0.9h.

Elimination

Oral administration

The plasma half-life of dexamethasone is approximately 250 minutes. Specific groups of patients No data are available on the biotransformation of dexamethasone in hepatically impaired patients. Smoking has no influence on dexamethasone pharmacokinetics. No differences were found in dexamethasone pharmacokinetics between subjects of European and Asian (Indonesian and Japanese) descent.

IV / IM administration

The plasma half-life is 3.5-4.5 hours but as the effects outlast the significant plasma concentrations of steroids the plasma half-life is of little relevance and the use of biological half-life is more applicable. The biological half-life of dexamethasone is 36-54 hours; therefore, dexamethasone is especially suitable in conditions where continuous glucocorticoid action is desirable.

Ocular administration

Dexamethasone also appears to be cleared more rapidly from the circulation of the foetus and neonate than in the mother; plasma dexamethasone levels in the foetus and the mother have been found in the ratio of 0.32:1.

Intravitreal injection

Plasma concentrations were obtained from a subset of 21 patients in the two RVO, 6-month efficacy studies prior to dosing and on days 7, 30, 60 and 90 following intravitreal injection of a single intravitreal implant containing 350 μg or 700 μg dexamethasone. Ninety-five percent of the plasma dexamethasone concentration values for the 350 μg dose group and 86% for the 700 μg dose group were below the lower limit of quantitation (0.05 ng/mL). The highest plasma concentration value of 0.094 ng/mL was observed in one subject from the 700 μg group. Plasma dexamethasone concentration did not appear to be related to age, body weight, or sex of patients.

Plasma concentrations were obtained from a subgroup of patients in the two DME pivotal studies prior to dosing and on days 1, 7, and 21, and months 1.5 and 3 following intravitreal injection of a single intravitreal implant containing 350 μg or 700 μg dexamethasone. One hundred percent of the plasma dexamethasone concentration values for the 350 μg dose group and 90% for the 700 μg dose group were below the lower limit of quantitation (0.05 ng/mL). The highest plasma concentration value of 0.102 ng/mL was observed in 1 subject from the 700 μg group. Plasma dexamethasone concentration did not appear to be related to age, body weight, or sex of patients.

In a 6-month monkey study following a single intravitreal injection of dexamethasone the dexamethasone vitreous humour C_max was 100 ng/mL at day 42 post-injection and 5.57 ng/mL at day 91. Dexamethasone remained detectable in the vitreous at 6 months post-injection. The rank order of dexamethasone concentration was retina>iris>ciliary body>vitreous humour>aqueous humour>plasma.

In an in vitro metabolism study, following the incubation of [¹⁴C]-dexamethasone with human cornea, iris-ciliary body, choroid, retina, vitreous humour, and sclera tissues for 18 hours, no metabolites were observed. This is consistent with results from rabbit and monkey ocular metabolism studies.

Dexamethasone is ultimately metabolised to lipid and water soluble metabolites that can be excreted in bile and urine.

The dexamethasone matrix slowly degrades to lactic acid and glycolic acid through simple hydrolysis, then further degrades into carbon dioxide and water.

Oral administration

Glucocorticoids have only weak acute toxicity. No chronic toxicity and carcinogenicity data are available. Genotoxicity findings have been shown to be artefactual. In reproductive toxicity studies in mice, rats, hamsters, rabbits and dogs, dexamethasone has led to embryo-fetal malformations such as increase in cleft palate and skeletal defects; decreases in thymus, spleen and adrenal weight; lung, liver, and kidney abnormalities; and inhibition of growth. Post-natal development assessment of animals treated prenatally presented decreased glucose tolerance and insulin sensitivity, behavioural alterations and decrease in brain and body weight. In males, fertility may be decreased through germ cell apoptosis and spermatogenic defects. Data on female fertility are contradictory.

IV / IM administration

In animal studies, cleft palate was observed in rats, mice, hamsters, rabbits, dogs and primates; not in horses and sheep. In some cases these divergences were combined with defects of the central nervous system and of the heart. In primates, effects in the brain were seen after exposure. Moreover, intra-uterine growth can be delayed. All these effects were seen at high dosages.

Ocular administration

Repeat dose topical ocular safety studies with dexamethasone in rabbits have shown systemic corticosteroid effects. Such effects are considered to be unlikely when dexamethasone eye drops are used as recommended.

Dexamethasone was clastogenic in the in vitro human lymphocyte assay and in vivo in the mouse micronucleus assay at doses in excess of those obtained following topical application. Conventional carcinogenicity studies with dexamethasone have not been performed.

Dexamethasone has been found to be teratogenic in animal models. Dexamethasone induced abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development.

Intravitreal injection

Effects in non-clinical studies were observed only at doses considered sufficiently in excess of the maximum dose for human indicating little relevance to clinical use. No mutagenicity, carcinogenicity, reproductive or developmental toxicity data are available for dexamethasone. Dexamethasone has been shown to be teratogenic in mice and rabbits following topical ophthalmic application. Dexamethasone exposure to the healthy/untreated eye via contralateral diffusion has been observed in rabbits following delivery of the implant to the posterior segment of the eye.