Pharmacokinetics of intranasal corticosteroids

Transcription

1 Pharmacokinetics of intranasal corticosteroids Stanley J. Szefler, MD Denver, Colo Topical administration of corticosteroids can reduce the total dose of corticosteroid required to treat the patient and minimize side effects. This logic has led to the development of intranasal corticosteroids (INCS) for allergic and perennial rhinitis. The second generation of these compounds includes beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. There is evidence that the INCS are effective in rhinitis; however, there is concern about the potential for these compounds to cause growth suppression. In one study, beclomethasone dipropionate significantly reduced growth in children; however, treatment of children with mometasone furoate nasal spray for 1 year showed no signs of growth suppression. It is evident that the differences among INCS lie in their pharmacokinetics. Structural differences among the various INCS influence their metabolism. The goal of INCS therapy is to have a high ratio of topical to systemic activity. The drug delivery device, absorption of the drug, and drug distribution all contribute to effective topical activity of an INCS. In addition, individual drug metabolism and elimination (half-life and drug clearance) also contribute to the therapeutic index of a drug. Overall, the second-generation INCS cause minimal systemic effects at recommended doses. (J Allergy Clin Immunol 2001;108:S26-31.) Key words: Beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, corticosteroids, half-life, hypothalamicpituitary-adrenal axis, intranasal corticosteroids, mometasone furoate, triamcinolone acetonide From the University of Colorado Health Sciences Center and the National Jewish Center Medical and Research Center. Dr Szefler is on the Respiratory Medication Advisory Panel for Schering- Plough. Reprint requests: Stanley J. Szefler, MD, 1400 Jackson St Annex Bldg, Room J 209, Denver, CO Copyright 2001 by Mosby, Inc /2001 $ /0/ doi: /mai S26 Abbreviations used BDP: Beclomethasone dipropionate BUD: Budesonide CL: Clearance rate FLU: Flunisolide FP: Fluticasone propionate HPA axis: Hypothalamic-pituitary-adrenal axis INCS: Intranasal corticosteroid MF: Mometasone furoate TAA: Triamcinolone acetonide Corticosteroids are natural and synthetic compounds that are structurally related to hydrocortisone and that bind to a single class of endogenous corticosteroid receptors involved in anti-inflammatory activity. 1,2 The corticosteroids alter the transcription of genes that increase the synthesis of anti-inflammatory mediators and decrease the synthesis of proinflammatory mediators. 1 Additionally, corticosteroids interfere with the influx of inflammatory cells. 1 Among the therapeutic indications for intranasal corticosteroids (INCS) are seasonal and perennial allergic rhinitis. Allergic rhinitis is a hypersensitivity to inhaled allergens, with symptoms including congestion, rhinorrhea, sneezing, and nasal itching. 3-5 The activity of INCS alters the course of both the early and late phases of allergic rhinitis. 4,6,7 Other therapeutic uses of INCS include nonallergic rhinitis, 6-8 chronic rhinosinusitis, 6,9 rhinitis medicamentosa, 10 and nasal polyposis. 6,7 Corticosteroids are currently available as intravenous, oral, inhaled, intranasal, and dermatologic preparations. 1,4,11 With their introduction in the 1950s, corticosteroids were administered systemically for the treatment of allergic rhinitis. 12 However, chronic systemic administration of corticosteroids was associated with serious adverse events. These adverse events include growth suppression, suppression of hypothalamic-pituitaryadrenal (HPA) axis function, changes in skin such as acne, skin thinning and bruising, and alterations in bone metabolism that may lead to a net decrease in bone mass. 13,14 Therefore, topical administration was explored to localize the corticosteroid effect, reduce the total corticosteroid dose required, and minimize side effects. Rapidly metabolized INCS, with high topical potency and low systemic bioactivity, were introduced for perennial rhinitis in 1974 and found to be as effective as corticosteroids administered systemically. 6 These secondgeneration INCS include beclomethasone dipropionate (BDP), budesonide (BUD), flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TAA). 4,15 Although these INCS represent improvements relative to earlier topical corticosteroids, they do vary from one to the other in potency and systemic bioactivity. Mometasone furoate (MF), the most recently introduced INCS, is equal in potency to FP, considered the most potent to date, and has almost undetectable systemic availability. 4 Although using INCS reduces systemic side effects, local side effects can occur. These local effects include epistaxis, nasal crusting, dryness, and nasal septum perforation The more frequently observed of these is light epistaxis. The risk of side effects is minimized if the patient is properly trained in the use of INCS. 3

2 J ALLERGY CLIN IMMUNOL VOLUME 108, NUMBER 1 Szefler S27 USE OF INCS IN CHILDREN There has been a rise in INCS usage with the recognition that long-term treatment is beneficial for seasonal and perennial rhinitis. 3,21 Although the use of INCS to treat allergic rhinitis is generally thought to be associated with minimal serious adverse events in adults, increased longterm use in children has raised concerns about the potential for pediatric-specific effects, such as growth suppression A 1-year study showed that use of 168 µg BDP aqueous nasal spray twice daily resulted in a significant suppression of growth in children compared with placebo. 25 However, other similar studies have shown no suppression of bone growth in children after 1 year of treatment with the recommended pediatric dose of MF nasal spray (100 µg daily) 26 or with BUD (200 µg twice daily). 27 STRUCTURE-ACTIVITY RELATIONS The basic chemical structure of the corticosteroids is composed of 3 rings of 6 carbons each and 1 of 5 carbons (Fig 1). There are a few features that are common to all anti-inflammatory corticosteroids. These include the ketone oxygen at position 3, the unsaturated bond between carbons 4 and 5, the hydroxyl at position 11, and the ketone oxygen at carbon 20. Prednisone is converted to the active anti-inflammatory agent prednisolone by reducing the 11-keto oxygen to an 11-β-hydroxyl. Prednisolone and the INCS differ from cortisol in having a double bond between carbons 1 and 2. This double bond increases the corticosteroid activity by 4-fold relative to cortisol while reducing mineralocorticoid activity. Several of the INCS have halogen groups added to positions 6 and 9. The addition of fluorine at position 9 on the dexamethasone molecule increases its corticosteroid activity by 25-fold, whereas the addition of a methyl group at position 16 decreases mineralocorticoid activity. The greatest variation among the corticosteroids takes place off of carbon ring D at positions 16, 17, and 21. These modifications usually increase topical activity while minimizing systemic adverse effects. For MF, the 21-chloro 17(2 furoate) group increases the topical anti-inflammatory activity. The chloride at position 21 makes MF resistant to degradation by esterases, and the addition of the chloride at position 9 increases the affinity for the corticosteroid receptor. PHARMACOKINETICS Pharmacokinetics are those processes that ultimately determine the concentration of the drug at the receptor site. The intrinsic kinetic properties of a corticosteroid are described by several parameters. The volume of distribution (V) is the fluid volume required to contain the entire drug at the same concentration existing in the blood and is a measure of relative tissue uptake. Clearance (CL) is the rate of elimination by all routes relative to the concentration of drug in the blood and is a measure of the elimination capacity. The half-life (t1 ) is the relation between V and CL and is the time it takes for the plasma concentration to be reduced by 50%. Factors included in t1 are the time to reach steady state and the decay rate from steady-state concentrations. Bioavailability (F) is the amount of drug that reaches the systemic circulation. In the case of drugs that are administered locally, such as the INCS, the term systemic availability is more appropriate. A reference formulation is used to calculate the extent of systemic availability. The term absolute systemic availability is used when intravenous dosing is used as the standard. These kinetic properties are described as the absorption, distribution, metabolism, and excretion (ADME) properties of the drug. Although INCS are applied topically, a significant portion can be absorbed systemically, as described below. The goal of INCS design is to achieve a high ratio of topical to systemic activity because this increases the potential for desired therapeutic effects relative to undesired systemic effects (therapeutic ratio). 13,28 DELIVERY DEVICE Delivery devices have evolved to meet specific requirements for efficacious and tolerable delivery of INCS. The Freon-propelled aerosols first used to deliver INCS distributed the drug poorly Metered-dose pump sprays were used to deliver FP solubilized in polyethylene glycol and propylene glycol, although this approach caused nasal stinging. 6 Aqueous pump sprays and pure powder formulations are now the more common methods of delivery 6 because the intranasal distribution of drug is more favorable than with a pressurized aerosol Delivery of aqueous suspensions by pump spray provides better drug deposition at the ciliated mucous membrane rather than the nonciliated anterior when compared with pressurized aerosol. 6,31 Studies with TAA indicate greater systemic levels when administered in an aqueous rather than aerosol formulation for allergic rhinitis. 32 Actual quantitative comparisons of drug delivered by different devices are complicated by the large amounts of drug deposited in the nozzle of pressurized aerosols. 6 However, there appears to be approximately the same degree of symptom reduction by pressurized aerosols and aqueous pump sprays. 6,33 After intranasal administration, there is nasociliary clearance of the drug into the throat. Lipworth and Seckl 34 estimate that approximately 80% of the drug is available for absorption at the nasal mucosa. A recent study that used positron emission tomography to monitor intranasal administration of TAA aqueous nasal spray demonstrated clearance of drug from the frontal cavity toward the throat (with a maximum of 8% of the dose in the sinuses at any one time). It also indicated that significant amounts of drug (10% to 20%) remained in the target areas of the frontal cavity and turbinates for up to 1.5 hours. 35 However, it was not clear how much of the TAA was absorbed from the nasal mucosa into the systemic circulation and how much was swallowed.

3 S28 Szefler J ALLERGY CLIN IMMUNOL JULY 2001 FIG 1. Diagram of structures of prednisolone and other synthetic corticosteroid (GC) derivatives. Ring D is most modified among GC. Tables indicate differences among GC. TABLE I. Systemic availability (F) after intranasal administration Drug Dose F (%) Budesonide µg 102 Flunisolide µg 49 Fluticasone propionate µg 1.8 Mometasone furoate µg <.1 ABSORPTION There are two aspects of absorption regarding the INCS. One is topical absorption at the target site (the nose) that determines therapeutic efficacy and the other is systemic absorption. Systemic absorption either occurs from the fraction of INCS swallowed and subsequently absorbed through the gastrointestinal tract or from the fraction absorbed into the blood at the nasal mucosa. The amount of drug reaching target tissues and exerting a therapeutic effect relative to the amount reaching the systemic circulation is a measure of safety for topically applied drugs, such as the INCS. Some corticosteroids (eg, BUD) are well absorbed through the nasal mucosa directly into the systemic circulation. 36 In contrast, FP and MF are believed to be poorly absorbed into the systemic circulation because of their lipophilicity. When the area under the concentration-time curve after intranasal administration is compared with that for intravenous administration, the absolute systemic availability can be calculated (Table I). For both FP 37 and MF, 38 the systemic availability is very low. The estimates of systemic availability are based on a fraction of study subjects for whom drug concentrations were detectable. It is important to remember that in many cases, the plasma concentration of the drug was below the limit of quantification of the assay used (50 ng/l). The following examples illustrate the nuances of determining plasma concentrations of corticosteroid after intranasal administration. After administration of 440 µg of TAA aqueous nasal spray to children 6 to 12 years of age, a peak plasma drug concentration of 890 pg/ml is achieved in about 1 hour. 39 TAA absorption may be slightly lower in adults because 800 µg achieved a peak plasma concentration of 430 ng/ml. 40 In contrast, in studies with intranasal FP in adults, plasma concentrations were below the limit of detection (50 pg/ml) after single doses of 200 µg and under 100 pg/ml for a majority of subjects after a single dose of 800 µg. 37 In the same study, plasma concentrations of FP were above 100 pg/ml for half the subjects after 200 µg twice daily for 5 days. In a study with MF, the plasma concentration was below the limit of detection of 50 ng/ml in 99% of samples taken from 48 children treated with MF (50 to 200 µg daily) after 1 and 7 days of treatment. 41 In studies with FLU, 42 TAA, 32 and FP, 37 there is no substantial difference in absorption of these drugs from healthy and inflamed nasal mucosa. DISTRIBUTION Once in the systemic circulation, many corticosteroids are highly bound by plasma albumin. The degree of plas-

4 J ALLERGY CLIN IMMUNOL VOLUME 108, NUMBER 1 Szefler S29 ma protein binding for several corticosteroids has been determined, including TAA (71%), FLU (80%), BDP (87%), BUD (88%), and FP (90%), with data for MF unavailable. 43 Binding to plasma proteins, primarily albumin, is generally greater with the more lipophilic corticosteroids. The volume of distribution is a classic pharmacokinetic parameter derived from intravenous drug administration. It reflects the tissue distribution of the drug, with higher amounts indicating greater amounts of drug either protein bound or in peripheral tissue outside of the systemic circulation. As the lipophilicity of a corticosteroid increases, so does the volume of distribution (V). Representative values for the volume of distribution for INCS are presented in Table II. Fluticasone has an unusually large volume of distribution, in keeping with its high lipophilicity. 43 METABOLISM As stated previously, cortisone and prednisone are converted to active forms (cortisol and prednisolone) by reducing the ketone at position 11. BDP is a prodrug metabolized by many tissues, including the nose, into the more active metabolite, beclomethasone monopropionate (BMP). 1,34,43 Compared with a corticosteroid receptor affinity of 1 for dexamethasone, the relative binding affinity of BDP is 0.53, whereas that of the metabolite, BMP, is almost 25-fold greater (13). 43 In a study that compared the relative binding affinities of MF, FP, BUD, and TAA with dexamethasone (dexamethasone binding affinity was defined as 100), all of the corticosteroids had greater binding affinity than did dexamethasone. MF showed the highest affinity for the corticosteroid receptor with a relative binding affinity of 1235, followed by FP at 813, BUD at 258, and TAA at Systemic absorption of the swallowed portion of the dose may be inactivated by the first-pass effect (ie, metabolism of the drug by the liver before entering the systemic circulation). Rapid inactivation in the gastrointestinal tract minimizes systemic activity from the swallowed portion. As a result, the oral bioavailability of FP is low because of poor absorption from the gastrointestinal tract and an extensive first-pass metabolism. 7 MF also undergoes extensive metabolism in the liver 4 ; consequently, systemic absorption is extremely low. ELIMINATION Standard pharmacokinetic parameters for the corticosteroids after intravenous administration are presented in Table II. The CL is similar for most of the second-generation INCS (Table II) and is close to the rate of hepatic blood flow, which would be the maximum clearance for drugs primarily metabolized by the liver. 43 Because the therapeutic activity of these drugs is topical, the rapid clearance of any drug absorbed into the systemic circulation contributes to a high therapeutic index. A higher clearance also leads to a lower steady-state level after the administration of multiple doses. TABLE II. Pharmacokinetic parameters after intravenous administration Drug V (L/kg) CL (L/min) t1 2 (h) Triamcinolone acetonide Budesonide Flunisolide Fluticasone propionate Mometasone furoate 4 NA NA 5.8 Volume of distribution was calculated by terminal rate constant except for budesonide and fluticasone propionate, which use moment analysis. NA, Not available. Half-life (t1 ) is a function of clearance rate and volume (V). After multiple doses of a drug, the plasma concentration rises until it reaches a steady-state concentration. As a general rule, it takes about 5 half-lives for a drug to reach its steady-state concentration during repeated dosing. 43 The greatest half-life value currently reported is for FP (7.8) (Table II); MF has the second-greatest half-life (5.8), followed by BUD (2.3), FLU (1.6), and TAA (1.5). BUD exists as a 1:1 mixture of R and S epimers that differ in their CL and V but not their t1.45,46 Most pharmacokinetic analyses are performed on healthy adults, and few data exist for children. When the pharmacokinetic parameters of BUD were investigated in children (10 to 13 years of age), the t1 (1.5 hours) was shorter and the weight-adjusted CL was approximately 50% higher than those values previously reported for adults. 46 The authors postulate that this finding may be the result of a higher hepatic blood flow in children. Assuming that this suggestion is correct, more rapid systemic elimination in children compared with adults would be expected for other high clearance drugs, 46 including the other second-generation INCS. The elimination half-life has been measured after intranasal administration for some of the second-generation INCS. For BUD, the t1 after intranasal administration (2.9 hours) 36 is similar to that after intravenous administration (2.3 hours; Table II). However, the intranasal t1 for TAA (4.0 hours in healthy adults) 40 appears to be longer than the intravenous t1 (1.5 hours). The longer t1 after intranasal administration has been explained by prolonged absorption caused by limited aqueous solubility. 40 Despite the prolonged, intranasal t1 administration of 800 µg TAA daily does not result in TAA accumulation. 40 IMPLICATIONS FOR PHARMACODYNAMICS Pharmacokinetic parameters such as systemic availability, clearance, and half-life can be used to assess the relative systemic exposure to INCS. The expectation that low systemic exposure results in minimal adverse systemic effects has been examined by monitoring sensitive systemic indexes, such as HPA axis effects. The secondgeneration INCS causes minimal systemic effects at recommended doses, 47 with the possible exception of FP, which showed significant suppression of overnight uri-

5 S30 Szefler J ALLERGY CLIN IMMUNOL JULY 2001 nary cortisol when compared with TAA and BDP. 48 Reviews of intranasal administration of BDP, BUD and FLU, 49 FP, 7 and MF 4 indicate no detectable effects on measures of HPA axis function at recommended doses, which is in agreement with rapid hepatic metabolism of these INCS. Therefore the improved pharmacokinetic parameters of the second-generation INCS maximize efficacy relative to systemic availability (Tables I and II) CONCLUSIONS The second generation of INCS have a substantially improved therapeutic index compared with intravenous and oral corticosteroids; however, there are still some differences among them. The local administration of drugs with high topical activity and rapid hepatic metabolism results in an effective dose in the nose combined with relatively limited systemic exposure. 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