Determinants of glucocorticoid dosing

INTRODUCTION — Natural and synthetic glucocorticoids (also called steroids) can be used for a variety of disorders. These agents are most commonly given in pharmacologic doses to manage conditions that require the suppression of inflammation. Less often, they are used to establish the diagnosis and cause of Cushing's syndrome and for hormone replacement in adrenal insufficiency and congenital adrenal hyperplasia.

The determinants of glucocorticoid dosing include:

●Pharmacokinetics of the different drug preparations

●Effects of underlying disorders on drug kinetics

●Interactions of glucocorticoids with concurrently administered non-glucocorticoid drugs

This topic will review the factors that affect glucocorticoid dosing. A detailed discussion of the structure, absorption, metabolism, and biologic activities of glucocorticoids is presented separately. (See "Pharmacologic use of glucocorticoids".)

BIOEQUIVALENCE AND BIOAVAILABILITY — The different preparations of glucocorticoids are largely bioequivalent (ie, have the same rate of absorption). As an example, most commercially available prednisone tablets are bioequivalent, independent of tablet strength (eg, 1, 2, 5, 10, 20 mg) [1], and the systemic bioavailability of prednisone and prednisolone are similar. Although the rectal and oral absorption of methylprednisolone are variable (relative bioavailability of 50 to 90 percent), such preparations are also bioequivalent [2,3]. Glucocorticoid bioavailability does not appear to be affected, although preeclampsia and gestational hypertension may increase cortisol metabolism (without affecting neonatal birth weight) [4].

Different formulations of glucocorticoid preparations are being developed to improve delivery of these drugs (eg, palmitate large porous particles, oral dissolvable film formulations, nanosuspensions in soft contact lenses, multidose dry powder inhalers), which may improve the usefulness of glucocorticoids [5-8].

Incomplete bioavailability of glucocorticoids has occasionally been noted in certain patients. As an example, in one study 20 percent of patients given methylprednisolone showed poor bioavailability (23 to 65 percent), compared to only 1 of 12 patients given prednisone [9].

The dosing equivalents, relative antiinflammatory and mineralocorticoid activity, and duration of action of the different glucocorticoid preparations, shown in the table (table 1), are discussed separately. (See "Pharmacologic use of glucocorticoids".)

Inhaled glucocorticoids — The bioavailability of inhaled glucocorticoids varies with the physical properties of the particular agent. Eighty percent of inhaled glucocorticoids are swallowed, with the remainder deposited in the lungs. When deposited in the lungs, the more lipophilic compounds (such as fluticasone and beclomethasone) are retained longer in lung tissue.

The absorption of inhaled glucocorticoids also varies with the specific agents. Drugs that are highly lipophilic are relatively poorly absorbed orally (less than 11 percent). By comparison, agents which are not lipophilic (such as budesonide) are somewhat better absorbed orally (less than 20 percent). Since all of the drug deposited in the lung eventually enters the systemic circulation, overall absorption of inhaled glucocorticoids varies between 20 and 40 percent of the administered dose [10].

DISPOSITION — Prednisone is rapidly metabolized via reduction to prednisolone; the elimination of prednisone is approximately 13 times faster than prednisolone [11]. In contrast to cortisol, the endogenously produced glucocorticoid, the synthetic glucocorticoids bind less or minimally to cortisol-binding globulin (CBG, transcortin). Prednisolone has about 60 percent, prednisone 5 percent, and methylprednisolone, dexamethasone, betamethasone, and triamcinolone have less than 1 percent of the affinity of cortisol for CBG. (See "Pharmacologic use of glucocorticoids".)

Clearance — The clearance of prednisolone is 210 mL/min per 1.73 m², with an elimination half-life of approximately three hours. Clearance decreases with age; as an example, children less than 12 years of age have a 33 percent higher clearance than older children and adults [9].

Glucocorticoids exhibit dose-dependent kinetics. Total prednisolone clearance increases by 75 percent as the intravenous dose increases from 5 to 40 mg [12,13]. Free prednisolone clearances also change with administered dose, but to a lesser degree and require larger doses to demonstrate such kinetics [14]. The clinical consequence of these properties is that a somewhat greater, nonlinear drug effect is observed at prednisolone doses over 40 mg compared to doses between 10 to 20 mg.

Clearances also vary with the time of day. Both prednisolone and methylprednisolone clearance is lower (18 to 28 percent) in the morning than the evening [15,16]. This property, in combination with the disruption of the usual cortisol diurnal rhythm with exogenous glucocorticoids, may result in variations in efficacy when glucocorticoids are administered at different times during the day [17,18]. In one study, for example, the efficacy of prednisolone was assessed in seven asthmatic patients in whom the drug was given at 8 AM and 3 PM, and at 3 PM and 8 PM [19]. The earlier dosing regimen was more effective in improving nocturnal pulmonary function and symptoms.

Distribution in breast milk — Glucocorticoids are excreted in small amounts in human milk. In one study, approximately 0.23 percent of a 5 mg prednisolone dose was found in breast milk [20].

DISEASES AND ALTERED PHYSIOLOGIC STATES — The pharmacokinetics of glucocorticoids vary with certain diseases and pathophysiologic conditions.

Asthma — There are no clinically important pharmacokinetic differences between asthmatic patients and healthy subjects [21].

Cystic fibrosis — The bioavailability of prednisolone appears to be unaffected by cystic fibrosis, but the total prednisolone clearance was increased by over 50 percent [22]. As a result, more frequent dosing may be necessary.

End-stage kidney disease — Among patients treated with hemodialysis, the clearance of total prednisolone is dose-dependent, while the clearance of unbound prednisolone is constant [23]. Hemodialysis also removes significant amounts of methylprednisolone, thereby resulting in a 32 percent reduction in plasma half-life relative to those without ESKD [24]. However, these changes are not sufficient to require a dose adjustment. The removal rate of unbound cortisol in patients treated with peritoneal dialysis is similar to those without ESKD [24,25].

Hyperthyroidism — The clearance of prednisolone is increased in hyperthyroidism. In one small study, total prednisolone clearance was increased by 58 percent and nonrenal clearance (principally hepatic) was increased by 84 percent [26]. There were also small changes in absorption and binding.

Inflammatory bowel disease — The overall kinetics of prednisolone do not appear to be affected by inflammatory bowel disease (IBD). One study, for example, found that total and unbound kinetics of prednisolone were unchanged in active and inactive IBD, although the unbound fraction was increased in active disease [27].

Nephrotic syndrome — Patients have low serum concentrations of albumin and cortisol-binding globulin. However, although their bound and therefore total glucocorticoid concentrations are reduced, the physiologically important unbound (free) serum concentrations of prednisone and prednisolone are similar to nonnephrotic individuals.

Perhaps because of the differences in protein-binding, nonrenal clearance is higher and renal clearance is lower in patients with nephrotic syndrome than in those without nephrotic syndrome [28]. The total prednisolone clearances are higher in nephrotic patients, since the increase in nonrenal clearance is of greater magnitude than the reduction in renal clearance.

Obesity — Obesity can affect the uptake, storage, and metabolism of glucocorticoids, although results are somewhat contradictory.

●In one study, the volume of distribution and clearance of prednisone in a person with obesity weighing more than 133 percent of ideal body weight was 20 to 30 percent higher than in a person without obesity [29].

●Another report indicated that each 1 percent higher baseline body mass index (BMI) was associated with a 2.9 percent decline in wake-up and total area under curve (AUC) cortisol, suggesting that a higher BMI suppresses cortisol [30].

●By contrast, two other reports that examined the metabolism of methylprednisolone and dexamethasone found that clearance among patients with obesity was decreased by about 40 percent when compared with those without obesity [31,32]. One of these studies also examined pharmacodynamic measures of glucocorticoid activity, particularly histamine and T cell responses [31]. Although not statistically significant, there was a clear trend toward an enhanced effect in obese subjects at the same mg/kg dose.

Dosing of glucocorticoids in a person with obesity should be based upon the ideal, rather than total, body weight.

Pregnancy — Little active prednisolone crosses the placenta to the fetus, since the placenta inactivates the drug. However, dexamethasone clearance is increased approximately twofold when compared to nonpregnant women, probably due to enzyme induction [33]. A more detailed discussion of the effects of glucocorticoids on the fetus during pregnancy can be found elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids'.)

When an effect on the fetus is desired, for example to speed fetal lung maturity in situations where premature delivery is anticipated, fluorinated glucocorticoids are used because these cross the placenta and have pharmacologic effects on the fetal organs. Dexamethasone and betamethasone are often used in this setting. Use of antenatal betamethasone is associated with a lower risk of neonatal death than is dexamethasone [34].

Severe liver disease — In the presence of severe liver disease, the activation of prednisone via metabolism to 6-beta-hydroxyl compounds may be impaired, potentially affecting the efficacy of glucocorticoid therapy [35]. (See "Pharmacologic use of glucocorticoids".)

Patients who undergo liver transplantation because of hepatic C viral infection should receive the lowest dose of glucocorticoids following transplantation that is feasible. The cumulative glucocorticoid dose is correlated closely with post-transplantation hepatitis-C viral load and with mortality rates [36].

DRUG INTERACTIONS

Systemic glucocorticoids — Glucocorticoids undergo metabolism in the liver and other tissues by cytochrome P450 3A4 (CYP 3A4) and other transformations. In vitro data suggest that dexamethasone, methylprednisolone and prednisolone are also substrates of P-glycoprotein membrane efflux transporters. Medications that strongly inhibit or induce CYP 3A4 and/or P-glycoprotein transporters may significantly alter the glucocorticoid serum concentration [37,38].

●Medications that increase the systemic glucocorticoid concentration include estrogen derivatives, such as oral contraceptives [39-42] and strong inhibitors of CYP 3A4 (table 2) including some antibiotics (eg, clarithromycin, ritonavir, telaprevir, telithromycin) [43-45], and antifungals (eg, posaconazole, voriconazole) [38,46,47].

●Medications that reduce the systemic glucocorticoid concentration include aluminum/magnesium containing antacids, which decrease prednisone bioavailability due to decreased oral absorption [48,49], and strong inducers of CYP 3A4 (eg, carbamazepine, phenobarbital, phenytoin and rifampin) [50-55].

However, a number of agents often used with glucocorticoids appear to have no substantial interaction with them. These include azathioprine, methotrexate, histamine₂ antagonists (eg, famotidine, cimetidine, ranitidine), proton pump inhibitors (eg, omeprazole, pantoprazole, rabeprazole), and diazepam [50,56-60].

The major drug interactions with systemic glucocorticoids, a summary of effect(s), and management suggestions are listed in the table (table 3). For additional interactions, see the Lexicomp drug interactions program included with UpToDate.

Inhaled or intranasal glucocorticoids — Inhibitors of CYP 3A4 may impair the metabolism of glucocorticoids administered intranasally or by inhalation and may increase the serum concentration associated with these methods of administration. Use caution when combining high-dose intranasal or inhaled glucocorticoids with strong CYP 3A4 inhibitors (table 2). This is discussed elsewhere. (See "Pharmacotherapy of allergic rhinitis" and "Major side effects of inhaled glucocorticoids", section on 'Medication interactions'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)

SUMMARY AND RECOMMENDATIONS

●The determinants of glucocorticoid dosing include pharmacokinetics of the different drug preparations, effects of underlying disorders on drug kinetics, and interactions of glucocorticoids with concurrently administered non-glucocorticoid drugs. (See 'Introduction' above.)

●The different preparations of glucocorticoids are largely bioequivalent (ie, have the same rate of absorption). The systemic bioavailability of prednisone and prednisolone are similar; the rectal and oral absorption of methylprednisolone are variable (relative bioavailability of 50 to 90 percent). Incomplete bioavailability of glucocorticoids has occasionally been noted. The bioavailability of inhaled glucocorticoids varies with the physical properties of the particular agent. (See 'Bioequivalence and bioavailability' above and 'Inhaled glucocorticoids' above.)

●The dosing equivalents, relative antiinflammatory and mineralocorticoid activity, and duration of action of the different glucocorticoid preparations, shown in the table (table 1), are discussed separately. (See "Pharmacologic use of glucocorticoids".)

●Prednisone is rapidly metabolized via reduction to prednisolone. In contrast to cortisol, the endogenously-produced glucocorticoid, the synthetic glucocorticoids bind less or minimally to cortisol-binding globulin. Prednisolone has an elimination half-life of approximately three hours; clearance decreases with age and varies with time of day. Kinetics are dose-dependent. Only small amounts are excreted in breast milk. (See 'Disposition' above and 'Clearance' above and 'Distribution in breast milk' above.)

●The pharmacokinetics of glucocorticoids vary with certain diseases and pathophysiologic conditions, including cystic fibrosis, end-stage kidney disease and hemodialysis, hyperthyroidism, nephrotic syndrome, obesity, pregnancy, and severe liver disease. (See 'Diseases and altered physiologic states' above.)

●Significant interactions with glucocorticoids have been documented for the medications listed in the table (table 3); a change of less than 30 percent is not likely to be clinically significant. Agents often used with glucocorticoids that appear to have no substantial interaction with them include azathioprine, cyclosporine, methotrexate, cimetidine, ranitidine, theophylline, and diazepam. (See 'Drug interactions' above.)

●Drugs that reduce the systemic glucocorticoid concentration include large doses of aluminum/magnesium hydroxide, which decrease bioavailability, and most anticonvulsants, which enhance glucocorticoid metabolism. Drugs that raise the systemic glucocorticoid concentration include some oral contraceptives, and certain antibiotics and antifungal agents; these drugs decrease metabolizing enzymes. (See 'Drug interactions' above.)