Single‐dose study to compare the pharmacokinetics of HFA flunisolide and CFC flunisolide

Single-Dose Study to Compare the Pharmacokinetics of HFA Flunisolide and CFC Flunisolide ARNO NOLTING,1 SURYANARAYANA SISTA,2 WATTANAPORN ABRAMOWITZ1 1

Department of Pharmacokinetics, Forest Laboratories Incorporated, Harborside Financial Center, Plaza Three, Suite 602, Jersey City, New Jersey 07311 2

Biovail Technologies, Ltd., 3701 Concorde Parkway, #800, Chantilly, Virginia 20151-1126

Received 1 March 2001; revised 5 September 2001; accepted 10 September 2001

ABSTRACT: The hydro¯uoroalkane (HFA) formulation of the inhaled corticosteroid ¯unisolide is a modi®cation of the original chloro¯uorocarbon (CFC) formulation. HFA ¯unisolide replaces CFC with an HFA propellant and uses a built-in spacer in its pressurized metered-dose inhaler. The average HFA ¯unisolide particle size is 1.2 mm compared with 3.8 mm for the CFC formulation. The smaller particle size improves lung targeting, allowing a reduction in the HFA ¯unisolide dose relative to CFC ¯unisolide while maintaining comparable ef®cacy. In a study of 12 healthy men, pharmacokinetic parameters were determined after single doses of 1000 mg CFC ¯unisolide delivered without a spacer, 340 mg HFA ¯unisolide delivered through a spacer, and 516 mg HFA ¯unisolide delivered without a spacer. A standard noncompartmental analysis of the concentration data was performed and mean ( S.D.) pharmacokinetic values were reported. Peak plasma concentrations (observed Cmax) were similar for the three treatments. Area under the curve up to the time corresponding to the last measurable concentration (AUC0±tlast) was similar for the CFC and HFA ¯unisolide, plus spacer groups (4.4  1.6 ng
h/mL and 5.0  4.2 ng
h/mL, respectively); however, AUC0±tlast for the HFA ¯unisolide without spacer group was comparatively lower than for the CFC group (3.5  1.6 ng
h/mL). Observed Cmax and AUC0±tlast for 6b-OH ¯unisolide, the ®rst-pass metabolite of ¯unisolide and an indicator of oropharyngeal deposition, were signi®cantly higher in the CFC ¯unisolide group than in either HFA ¯unisolide group. ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:424±432, 2002

Keywords:

aerobid; asthma; ¯unisolide

INTRODUCTION Asthma is a chronic disease with in¯ammation occurring throughout the airways involving both central and peripheral bronchi.1±3 An advantage of newer asthma medications may involve intrinsic pharmacokinetic properties that may improve delivery of drug to both the large and small airways. Correspondence to: Arno Nolting (Telephone: 201-386-2013; Fax: 201-524-9711; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 91, 424±432 (2002) ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association

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Chloro¯uorocarbon (CFC) ¯unisolide is an inhaled corticosteroid approved for the treatment of asthma as prophylactic therapy. A reformulated ¯unisolide inhaler has been developed that substitutes a hydro¯uoroalkane (HFA) for the CFC propellant. Concerns about the harmful environmental effects of CFC led to a 1987 international agreement calling for the gradual elimination of this compound from commercial use.4 In the treatment of asthma, this mandate has also provided the impetus to devise new inhaler technologies for improving delivery of aerosols to the respiratory tract.5

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PHARMACOKINETICS OF HFA AND CFC FLUNISOLIDE

The physical properties of HFA and CFC propellants differ in that HFA ¯unisolide exists in solution and results in small aerosol droplets, with respirable particles averaging 1.2 mm in uniform size, while the CFC formulation exists as a suspension with an average particle size of 3.8 mm.6 The smaller particle size of HFA ¯unisolide may contribute to better penetration in both the large and small airways of the lungs, resulting in asthma control at correspondingly lower doses as compared with CFC ¯unisolide.7±9 The improved formulation of HFA ¯unisolide, with built-in spacer, more than triples the amount of drug deposited in the lungs, up to 68.3%10 compared with 19.7% in CFC formulation. Oral deposition is reduced to 25.0% as compared with the 79.9% in CFC formulation. In a pharmacokinetic study of HFA and CFC ¯unisolide in healthy volunteers, no signi®cant differences in dose-adjusted peak plasma concentration (observed Cmax) were observed.6 Another study found cortisol suppression, an indicator of systemic absorption, was comparably low among asthmatic patients receiving HFA or CFC ¯unisolide.11 Inhaled asthma medications are routinely given via a pressurized metered-dose inhaler (pMDI). The pMDI used to deliver HFA ¯unisolide has been redesigned with a built-in spacer, as recommended in current asthma treatment guidelines published by the National Institutes of Health.12 Spacers are known to reduce oropharyngeal deposition of inhaled corticosteroids.13±15 Less drug in the mouth and throat decreases oral bioavailability, which is expected to have several advantages, including minimizing both local corticosteroid side effects (such as candidiasis14) and systemic adverse effects, depending on the degree of hepatic ®rst-pass metabolism.16±18 Thus, HFA ¯unisolide may offer several advantages over CFC formulation in the treatment of asthma. The objective of this present single-dose study was to compare the pharmacokinetic and tolerability pro®les of HFA ¯unisolide, given through a pMDI with or without spacer, and CFC ¯unisolide in healthy volunteers.

MATERIALS AND METHODS Subjects Twelve healthy men volunteered for the study. Subjects were screened for eligibility within

425

2 weeks before admission to the clinical site. At screening, prospective subjects gave a complete medical history and underwent a physical examination (including electrocardiography and spirometry) and clinical laboratory testing. All subjects had to meet the following inclusion criteria: males 18 to 35 years of age in good health; nonsmoker; normal vital signs; and forced expiratory volume in 1 s (FEV1)  80% of the predicted value. Reasons for exclusion from the study included: known hypersensitivity to ¯unisolide or other corticosteroid; upper or lower respiratory tract infection during the 4 weeks before screening; other clinically signi®cant medical condition(s); or history of chronic respiratory illness with symptoms of upper or lower respiratory tract infection. In addition, all volunteers had to provide written informed consent.

Study Design and Procedures The study protocol was approved by the Institutional Review Board of International Medical Technical Consultants, Inc. (Lenexa, KS). The study was an open-label, randomized, three-way crossover, single-dose trial. The 12 subjects enrolled in the study were randomly assigned to receive one of three treatments and then were crossed over to the remaining treatments. All subjects received each of the following single-dose administrations: four puffs (250 mg/ puff) of CFC ¯unisolide delivered without a spacer (Aerobid; Forest Laboratories, Inc., New York, NY), 1,000 mg total dose (treatment A); four puffs (85 mg/puff) of HFA ¯unisolide delivered via pMDI with built-in (Bespak) spacer, 340 mg total dose (treatment B); and four puffs (129 mg/puff) of HFA ¯unisolide delivered via pMDI without spacer, 516 mg total dose (treatment C). The ¯unisolide doses administered to the subjects were based on in vitro measurements of the amounts ex-device after actuation. The slight differences in the HFA ¯unisolide ex-device doses (85 mg/puff for HFA ¯unisolide with spacer vs. 129 mg/puff for HFA ¯unisolide without spacer) were due to the changes in the design of the two HFA formulations (different actuators and presence or absence of spacer device). There was a 3 day washout period between treatments; each treatment was administered at 8 A.M. Subjects were housed in a smoke-free environment from approximately 7 P.M. the night before a treatment was going to be administered until approximately 12 h after the JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002

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8 A.M. dose. Thus, there were three overnight stays for each subject who completed the study. The evening before and 1 h prior to administration of the ®rst dose, subjects were taught how to use the inhalation device in the presence of trained personnel to assure consistent inhalant delivery across doses. The training procedure followed the technique described in the User and Service Manual for the Aerosol Inhalation Monitor (AIM) device (Vitalograph, Ltd., Buckingham, UK). The inhalation device was primed within 30 min of administration of the ®rst dose. During their stays at the clinical site, subjects were restricted to xanthine- and alcohol-free diets for 48 h before dosing and throughout the study until the last blood samples were collected for each regimen. Subjects were required to fast for 10 h before and at least 2 h after dosing. A maximum of 271 mL of blood (including 20 mL before and after the study) was collected from each subject. Serial 7 mL blood samples were taken for analysis of plasma ¯unisolide and 6b-OH ¯unisolide. 6b-OH ¯unisolide is an inactive metabolite of ¯unisolide generated during ®rst-pass metabolism. Blood samples were drawn [BD Vacutainer tubes with K2EDTA (Franklin Lakes, NJ)] at 0 (predose), 5, 10, 20, and 30 min and at 1, 2, 4, 6, 8, and 12 h after 8 A.M. administration of the study drug. Cumulative 12 h urine collections were taken at the clinical center following each single-dose administration. Plasma levels of ¯unisolide, 6b-OH ¯unisolide, and hydrocortisone were quantitated using highperformance liquid chromatography (LC)/mass spectrometry (MS)/MS. From 0.5 mL of plasma, ¯unisolide, 6b-OH ¯unisolide, and hydrocortisone were isolated with solid-phase extraction with ¯unisolide-d6 as the internal standard. For hydrocortisone, a deuterated analogue was used as the internal standard. The ®nal eluate was evaporated to dryness in a vacuum centrifuge and then reconstituted in a water/methanol/tri¯uoroacetic acid mixture before being injected into the LC/ MS/MS system for analysis. For both ¯unisolide and 6b-OH ¯unisolide, the standard curve concentrations ranged from 0.1 (lower limit of quantitation) to 50 ng/mL. For hydrocortisone, the standard curve concentrations ranged from 5.0 (lower limit of quantitation) to 500 ng/mL. Standard curves were linear with correlation coef®cients greater than or equal to 0.99. Recoveries ranged from 98.2 to 118.6% for ¯unisolide, 102.2 to 115.2% for 6b-OH ¯unisolide, and 87.2 to 117.0% for hydrocortisone. Intraday reproduciJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002

bility ranged from 4.8 to 13.5% for ¯unisolide, 3.4 to 11.7% for 6b-OH ¯unisolide, and 1.9 to 14.1% for hydrocortisone. Interday reproducibility was approximately 8% or less for ¯unisolide, 6b-OH ¯unisolide, and hydrocortisone. Urine samples were extracted by organic phase extraction with methylene chloride as the organic solvent. The limit of quantitation was 1 ng/mL. Standard curves were linear with correlation coef®cients of 0.99 in the concentration range of 1 to 100 ng/mL. Recoveries ranged from 75.1 to 81.4% for ¯unisolide and 44.4 to 46.1% for 6b-OH ¯unisolide. Intraday and interday reproducibility was less than or equal to 6.4% for ¯unisolide and for 6b-OH ¯unisolide. Pharmacokinetics Plasma concentration versus time data were used to estimate pharmacokinetic parameters, including observed Cmax, time to reach peak plasma concentration (Tmax), and area under the (concentration-time) curve (AUC). These parameters were estimated using the WinNonlin nonlinear regression program (Scienti®c Consulting, Inc., USA). Observed Cmax was determined observationally as the peak concentration for each subject. Tmax was determined as the time corresponding to observed Cmax. Values for C0 (extrapolated) were determined by linear regression of the logarithmically transformed observed concentration values back to time point 0. Area under the curve up to the time corresponding to the last measurable concentration (AUC0±tlast) was calculated by numeric integration using the linear trapezoidal rule. The value of the elimination rate constant, lZ, was determined using WinNonlin, applying a noncompartmental analysis technique that focused on the terminal linear phase of semilogarithmic plots of the individual plasma concentration-time data. Elimination half-life (T1/2) was calculated using the following equation: T1/2 ˆ 0.693/lZ. Area under the curve up to time in®nity (AUC0±1) was computed according to the equation, AUC0±1 ˆ AUC0±tlast ‡ Clast/lZ with Clast as the last measurable concentration and tlast as the corresponding time point. Urinary concentrations of ¯unisolide and the 6b-OH metabolite determined from 12 h collections were used to calculate mean total amounts excreted in urine (Aexcreted). Statistical Test An analysis of variance (ANOVA) was performed on pharmacokinetic parameters using general

PHARMACOKINETICS OF HFA AND CFC FLUNISOLIDE

linear model procedures of the statistical analysis system. The ANOVA model included the variables sequence, subject (nested in sequence), period, and treatment. Because subjects were nested within sequence, the sequence effect was tested by the mean squared value for a subject (nested in sequence) from the ANOVA output as an error term, and all other main effects were tested by the residual error term. Comparisons between treatment C and treatment A, as well as between treatment B and treatment A, were carried out by two-sample t-tests where the residual error term from the ANOVA model was used as the error term.

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RESULTS Patient Disposition and Characteristics Twelve healthy men were entered into the study, and 11 completed treatment; one subject withdrew from the study for personal reasons. Demographic data describing these 11 subjects included a mean age of 23.6 years, ranging from 18 to 35 years (S.D. ˆ 5.4); a mean weight of 79.0 kg, ranging from 65.9 to 90.9 kg (S.D. ˆ 6.3); and a mean height of 176.6 cm, ranging from 165 to 185 cm (S.D. ˆ 6.4). Out of the 11 subjects who completed the study, nine were Caucasian, one was Hispanic, and one was Asian.

Adverse Events

Pharmacokinetics

Adverse events were documented as reported spontaneously by the subjects. Subjects were asked as to their well being each time vital signs were taken. All adverse events were recorded in case report forms and evaluated for possible relationship to the drug by the principle investigator.

In Figure 1, mean ¯unisolide plasma concentrations are plotted against time for the three ¯unisolide treatments on a semilogarithmic scale. No differences in the ¯unisolide concentration data after the three treatments were noted. Plasma concentrations exhibited simple ®rst-order kinetics for all treatments. Mean pharmacokinetic

Figure 1. Semilogarithmic plot of the mean ¯unisolide plasma concentrations (ng/mL) after administration of all treatments. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002

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Table 1. Pharmacokinetic Parameters (Mean  S.D.) of Flunisolide After Single Doses of HFA Flunisolide (With and Without Built-in Spacer) or CFC Flunisolide

Parameter Observed Cmax (ng/mL) C0(extrapolated) (ng/mL) AUC0±tlast (ng
h/mL) AUC0±1 (ng
h/mL) Tmax (h) T1/2 (h) Aexcreted (mg)

Treatment A

Treatment B

Treatment C

CFC Flunisolide

HFA Flunisolide With Spacer

HFA Flunisolide Without Spacer

Comparison (B vs A)

Comparison (C vs A)

2.53  1.19 2.91  0.15 4.41  1.59 5.12  1.00 0.18  0.16 1.56  0.31 1.70  0.89

3.25  2.66 3.72  2.70 4.99  4.20 5.82  4.27 0.09  0.03 1.43  0.23 1.98  2.29

2.02  1.03 2.31  0.95 3.46  1.60 4.15  1.35 0.17  0.16 1.93  0.36 1.29  0.85

NS NS NS NS S NS NS

NS NS S NS NS S NS

NS, not signi®cant and S, signi®cant (p < 0.05). S.D., standard deviation.

parameters ( S.D.) for ¯unisolide following all treatments are shown in Table 1. Observed Cmax and extrapolated C0(extrapolated) were similar for the three treatments. Values for AUC0±tlast were similar for CFC and HFA ¯unisolide delivered with a built-in spacer. AUC0±tlast was comparatively lower for a single dose of HFA ¯unisolide delivered without a spacer.

Figure 2 is a plot of mean 6b-OH ¯unisolide plasma concentrations versus time for each of the three treatments on a semilogarithmic scale. Signi®cantly higher 6b-OH ¯unisolide concentrations were observed from 0.5 to 6 h after CFC compared to HFA ¯unisolide delivered with a built-in spacer. Mean pharmacokinetic parameters ( S.D.) for 6b-OH ¯unisolide following

Figure 2. Semilogarithmic plot of the mean 6b-OH ¯unisolide plasma concentrations (ng/mL) after administration of all treatments. *Signi®cant difference (p < 0.05) for comparison of CFC versus HFA ¯unisolide with spacer and for comparison of CFC versus HFA ¯unisolide without spacer. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002

PHARMACOKINETICS OF HFA AND CFC FLUNISOLIDE

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Table 2. Pharmacokinetic Parameters (Mean  S.D.) of 6b-OH Flunisolide After Single Doses of HFA Flunisolide (With and Without Built-in Spacer) or CFC Flunisolide

Parameter Observed Cmax (ng/mL) C0(extrapolated) (ng/mL) AuC0±tlast (ng
h/mL) AUC0±1 (ng
h/mL) Tmax (h) T1/2 (h) Aexcreted (mg)

Treatment A

Treatment B

Treatment C

CFC Flunisolide

HFA Flunisolide With Spacer

HFA Flunisolide Without Spacer

Comparison (B vs A)

Comparison (C vs A)

0.75  0.16 2.91  0.15 3.03  0.77 3.75  0.83 1.23  0.52 3.10  0.71 50.50  16.89

0.28  0.17 3.72  2.70 1.12  0.98 2.30  1.06 1.15  0.53 5.06  1.90 19.69  13.82

0.36  0.08 2.31  0.95 1.38  0.29 2.18  1.26 1.27  0.61 3.97  1.19 24.21  8.21

S NS S S NS S S

S NS S S NS NS S

NS, not signi®cant and S, signi®cant (p < 0.05). S.D., standard deviation.

all treatments are shown in Table 2. Observed Cmax and AUC values for 6b-OH ¯unisolide after a single dose of HFA delivered with a spacer were signi®cantly lower than for HFA ¯unisolide delivered without a spacer or for CFC ¯unisolide. Urinary measurements found the level of excreted 6b-OH ¯unisolide after a single dose of HFA ¯unisolide delivered with a spacer to be signi®cantly lower than after a single dose of CFC ¯unisolide. Urinary levels of ¯unisolide after singledose administration of HFA ¯unisolide without a spacer were elevated when compared with HFA ¯unisolide with a spacer. These data indicate a lower oropharyngeal deposition of ¯unisolide when delivered with HFA ¯unisolide and a built-in spacer. No statistical differences were found in the mean pharmacokinetic parameters ( S.D.) for hydrocortisone following all treatments. The AUC0±tlast (ng
h/mL) for CFC ¯unisolide, HFA ¯unisolide with spacer, and HFA ¯unisolide without spacer was reported as 827  260, 770  185, and 881  236, respectively. Adverse Events No serious adverse events were reported and none of the subjects discontinued the study because of adverse events. Two subjects reported a total of eight adverse events during the study: four were mild, two were moderate, and two were severe. Four adverse events (dizziness, nausea, and two reports of rhinitis, all termed mild) were reported following inhalation of four puffs of HFA ¯unisolide delivered at a dose of 85 mg/puff through the built-in spacer. In addition, one case each of severe dizziness, severe headache, mod-

erate pharyngitis, and moderate vomiting were reported following inhalation of four puffs at 129 mg/puff of HFA ¯unisolide without spacer.

DISCUSSION In this study of 12 healthy males, peak ¯unisolide plasma concentrations were similar after a single dose of CFC ¯unisolide and after single doses of HFA ¯unisolide delivered with or without a builtin spacer. Similar systemic exposure to ¯unisolide, as measured by the AUC values, was observed when reducing the administered dose of ¯unisolide by approximately 66% from 250 mg/ puff (CFC ¯unisolide) to 85 mg/puff (HFA ¯unisolide). Because most of the ¯unisolide deposited in the lung will eventually be absorbed into the systemic circulation, similar systemic exposure to ¯unisolide at one-third of the dose was due to changing from a CFC-based to an HFA-based formulation, together with the inherent changes in physical characteristics and the inclusion of a spacing device with the HFA ¯unisolide formulation. At the doses studied, signi®cant differences were observed in the pharmacokinetic properties of the ®rst-pass metabolite of ¯unisolide, 6b-OH ¯unisolide. Observed Cmax and AUC0±tlast values for 6b-OH ¯unisolide were signi®cantly higher in the CFC ¯unisolide group than in either HFA ¯unisolide group; the 6b-OH metabolite is an inactive form of ¯unisolide. First-pass metabolism of ¯unisolide is high, with an estimated 93% of circulating drug converted in the liver,19 primarily to the 6b-OH ¯unisolide metabolite.20,21 Thus, the observed differences in 6b-OH ¯unisolide AUC values were due to differences in JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002

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oropharyngeal deposition of ¯unisolide, which was converted to 6b-OH ¯unisolide and subsequently absorbed into the systemic circulation. Therefore, less oropharyngeal deposition occurred for HFA ¯unisolide delivered with or without a spacer than for CFC ¯unisolide, as evidenced by the lower levels circulating and the lower excreted amounts of 6b-OH ¯unisolide. Although inhaled corticosteroids act locally to reduce airway in¯ammation, some of the active compound enters the circulation, where it becomes systemically available. One route for systemic exposure of inhaled corticosteroids is by swallowing any drug that had been deposited in the mouth and throat. A number of adverse effects are associated with the use of exogenous systemic corticosteroids. They can retard bone growth, cause cataracts, inhibit immunity, and suppress hypothalamic-pituitary-adrenal (HPA) axis activity.22 HPA axis suppression, usually detected by measuring levels of endogenous cortisol, can inhibit stress response, making an individual vulnerable to infection or complications during surgery. Flunisolide has a relatively short circulating half-life among inhaled corticosteroids.22 The present study found that the T1/2 of HFA ¯unisolide ranged from 1.43 to 1.93 h after CFC and HFA treatment doses. This is consistent with previous estimates after CFC ¯unisolide administration.23 Observed Cmax, AUC, and T1/2 are important pharmacokinetic parameters for evaluating the safety of inhaled corticosteroid formulations, because they provide information on the relative systemic availability of the corticosteroid. The relatively short T1/2 of ¯unisolide indicates that the medication that is likely to have contributed to the low observed Cmax and AUC0±tlast values does not remain in circulation; this result indicates low systemic absorption (see Tables 1 and 2). The doses of HFA ¯unisolide were lower than the approved dose of CFC ¯unisolide used in the present study. A reduction in the dose of inhaled corticosteroids may be one of a number of bene®ts for HFA formulations beyond those currently observed with CFC formulations.7,9 A preliminary clinical study investigated the use of lower doses of HFA ¯unisolide compared with the CFC formulation in patients with asthma. It found that the ef®cacy of HFA formulation was similar at onethird the corresponding dose of CFC formulation.8 The HFA ¯unisolide formulation used in this study incorporates two signi®cant modi®cations JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002

that distinguish it from the CFC formulation. The ®rst design change consists of replacing the CFC propellant with an HFA propellant, resulting in a signi®cant effect on the physical properties of corticosteroid particles emitted from the pMDI.7 The previous CFC formulation of ¯unisolide was delivered as a suspension, whereas the new HFA ¯unisolide formulation is a solution. The change from suspension to solution is associated with a reduction in the median aerosol particle size (3.8 to 1.2 mm)6; this may help improve the respirable dose of HFA ¯unisolide compared to the CFC formulation. In addition, the smaller particles should have better access to the small airways of the lungs, which, it has been suggested, enhances corticosteroid ef®cacy24 and may suppress in¯ammation more effectively at the lung periphery.25,26 The other design change entails incorporating a built-in spacer into the pMDI used to deliver HFA ¯unisolide. Studies indicate that oropharyngeal deposition of inhaled corticosteroids may be reduced dramatically by using a spacer or holding chamber.19,27,28 Such a reduction in mouth and throat deposition is likely to have contributed to the low observed Cmax for 6b-OH ¯unisolide observed after a single dose of HFA ¯unisolide via pMDI with a spacer in the present study (see Table 2). Without a spacer, the lung deposition of CFC suspension is limited to 19.7%, with much of the dose deposited in the oropharynx where it can contribute to both local and systemic adverse effects.14,16Although cortisol levels of ¯unisolide remain the same with both formulations, HFA ¯unisolide at one-third the dose of CFC ¯unisolide results in more of the dose being deposited in the lung. In conclusion, the present study observed some different pharmacokinetic parameters for HFA ¯unisolide compared with CFC ¯unisolide. These differences suggest a low systemic exposure for both HFA ¯unisolide and its major metabolic product after administration. The reduced exposure of HFA ¯unisolide is likely the result of this formulation's smaller particle size that may allow improved lung targeting and reduced dosing relative to CFC formulation. Furthermore, a built-in spacer enhances the pharmacokinetic characteristics of HFA ¯unisolide.

ACKNOWLEDGMENTS This work was supported by a grant from Forest Laboratories, Inc., New York, NY.

PHARMACOKINETICS OF HFA AND CFC FLUNISOLIDE

REFERENCES 1. Wagner EM, Liu MC, Weinmann GG, Permutt S, Blecker ER. 1990. Peripheral resistance in normal and asthmatic subjects. Ann Rev Respir Dis 141: 584±588. 2. Kraft M, Pak J, Martin RJ, Irvin CG. 1998. Elevated peripheral airway resistance (PAR) in nocturnal asthmatics (NA) is due to differing contributions from the airway and parenchyma. Am J Respir Crit Care Med 157:A629. 3. Irvin CG, Pak J, Martin RJ. 2000. Airway-parenchyma uncoupling in nocturnal asthma. Am J Respir Crit Care Med 161:50±56. 4. The 1987 Montreal Protocol on Substances that Deplete the Ozone Layer: as adjusted and amended by the second Meeting of the Parties (London, 27± 29 June 1990), and by the fourth Meeting of the Parties (Copenhagen, 23±25 November 1992), and further adjusted by the seventh Meeting of the Parties (Vienna, 5±7 December 1995), and further adjusted and amended by the ninth Meeting of the Parties (Montreal, 15±17 September 1997). Available at http//www.unep.org/ozone/mont_t.htm. Accessed January 16, 2001. 5. Leach CL. 1998. Improved delivery of inhaled steroids to the large and small airways. Respir Med 92(Suppl A):3±8. 6. Data on ®le, Forest Laboratories. 7. Shaw RJ. 1999. Inhaled corticosteroids for adult asthma: impact of formulation and delivery device on relative pharmacokinetics, ef®cacy and safety. Respir Med 93:149±160. 8. Richards JC, Pitcairn GR, Sista S, Mahashabde S, Abramowitz W, Newman SP. 1998. A scintigraphic study to assess the deposition of ¯unisolide delivered by HFA and CFC metered dose inhalers. In: Dalby RN, Byron PR, Farr SJ, editors. Respiratory drug delivery, 6th ed. Buffalo Grove: Interpharm Press, pp. 405±406. 9. Busse WW, Brazinsky S, Jacobson K, Stricker W, Schmitt K, VandenBurgt J, Donnell D, Hannon S. 1999. Ef®cacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. J Allergy Clin Immunol 104:1215±1222. 10. Newman SP, Richards JC, Hirst PH, Nolting A, Pitcairn G, Mahashabde S, Abramowitz W. 2001. Deposition and pharmacokinetics of ¯unisolide delivered from pressurized inhalers containing non-CFC and CFC propellants. J Aerosol Med, in press. 11. Corren J, Nelson H, Greos L, Bensch G, Goldstein M, Wu J, Wang S, Newman K. 2001. Effective control of asthma with hydro¯uoroalkane (HFA) ¯unisolide delivered as an extra®ne aerosol in asthma patients. Ann Allergy Asthma Immunol, in press.

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12. National Asthma Education and Prevention Program. 1997. Expert panel report 2: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health. Publication No. 97±405. 13. Newman SP, Millar AB, Lennard-Jones TR, MoreÂn F, Clarke SW. 1984. Improvement of pressurised aerosol deposition with Nebuhaler spacer device. Thorax 39:935±941. 14. Toogood JH, Baskerville J, Jennings B, Lefcoe NM, Johansson S-A. 1984. Use of spacers to facilitate inhaled corticosteroid treatment of asthma. Am Rev Respir Dis 129:723±729. 15. Dempsey OJ, Wilson AM, Coutie WJR, Lipworth BJ. 1999. Evaluation of the effect of a large volume spacer on the systemic bioactivity of ¯uticasone propionate metered-dose inhaler. Chest 116:935± 940. 16. Brown PH, Blundell G, Greening AP, Crompton GK. 1990. Do large volume spacer devices reduce the systemic effects of high dose inhaled corticosteroids? Thorax 45:736±739. 17. Farrer M, Francis AJ, Pearce SJ. 1990. Morning serum cortisol concentrations after 2 mg inhaled beclomethasone dipropionate in normal subjects: effect of a 750 ml spacing device. Thorax 45:740± 742. 18. Lipworth BJ. 1996. Pharmacokinetics of inhaled drugs. Br J Clin Pharmacol 42:697±705. 19. Dickens GR, Wermeling DP, Matheny CJ, John W, Abramowitz W, Sista SM, Foster T, Choudhury S. 2000. Pharmacokinetics of ¯unisolide administered via metered dose inhaler with and without a spacer device and following oral administration. Ann Allergy Asthma Immunol 84:528±532. 20. Teitelbaum PJ, Chu NI, Cho D, ToÈkeÂs L, Patterson JW, Wagner PJ, Chaplin MD. 1981. Mechanism for the oxidative de¯uorination of ¯unisolide. J Pharmacol Exp Ther 218:16±22. 21. Chaplin MD, Rooks W II, Swenson EW, Cooper WC, Nerenberg C, Chu NI. 1980. Flunisolide metabolism and dynamics of a metabolite. Clin Pharmacol Ther 27:402±413. 22. Lipworth BJ. 1999. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 159:941±955. 23. MoÈllmann H, Derendorf H, Barth J, Meibohm B, Wagner M, Krige M, Weisser H, KnoÈller J, MoÈllmann A, Hochhaus G. 1997. Pharmacokinetic/ pharmacodynamic evaluation of systemic effects of ¯unisolide after inhalation. J Clin Pharmacol 37:893±903. 24. Laube BL. 1996. In vivo measurements of aerosol dose and distribution: clinical relevance. J Aerosol Med 9(Suppl 1):S77±S91. 25. Goldin JG, Tashkin DP, Kleerup EC, Greaser LE, Haywood UM, Sayre JW, Simmons MD, Suttorp M, Colice GL, Vanden Burgt JA, Aberle DR. 1999. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002

432

NOLTING, SISTA, AND ABRAMOWITZ

Comparative effects of hydro¯uoroalkane and chloro¯uorocarbon beclomethasone dipropionate inhalation on small airways: assessment with functional helical thin-section computed tomography. J Allergy Clin Immunol 104:S258±S267. 26. Tashkin DP, Goldin JG, Kleerup EC. 2000. Evaluation of small airways and the impact of inhaled steroidsÐsize does matter. In: Wenzel SE, editor.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002

Asthma and the small airways. New York: American Thoracic Society, pp. 7±16. 27. EdsbaÈcker S. 1999. Pharmacological factors that in¯uence the choice of inhaled corticosteroids. Drugs 58(Suppl 4):7±16. 28. Newman SP. 1991. Aerosol physiology, deposition, and metered dose inhalers. Allergy Proc 12:41± 45.