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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Clinical Development (Dr. Hermann, Dr. Siebert-Weigel) and Early Phase Development (Dr. Locher), VIATRIS GmbH & Co. KG, Frankfurt am Main, Germany; MURO Pharmaceuticals, Department of Biostatistics, Tewksbury, Massachusetts (Dr. LaVallee); Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida (Dr. Derendorf, Dr. Hochhaus).
Address for reprints: Günther Hochhaus, PhD, Box 100494, JHMHC, College of Pharmacy, University of Florida, Gainesville, FL 32610-0494.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Loteprednol etabonate • pharmacokinetics • intranasal suspension formulations • endogenous cortisol • glucocorticosteroids
A number of studies were conducted to assess the activity of topical LE application on experimental models of inflammation.6-10 Results indicated that the efficacy of the soft steroid was superior to flurbiprofen and dexamethasone in several models of ocular inflammation. Interestingly, LE had no adverse effect on intraocular pressure in contrast to increases noted with other corticosteroids. The favorable pharmacological profile in these models of ocular inflammation led to development of ophthalmic products. LE formulated as a 0.5% suspension is currently marketed for topical treatment of inflammatory disorders of the eye and as a 0.2% suspension for treatment of seasonal allergic conjunctivitis (Lotemax® and Alrex®, Bausch & Lomb Pharmaceuticals).
Pharmacological evaluation in rat, pig, and guinea pig models of allergic rhinitis showed that intranasal LE administration reduced the magnitude of the vascular permeability response elicited by challenge antigens.11 Norway rats sensitized to ovalbumin were treated with intranasal LE prior to challenge with intranasally administered ovalbumin. Extravasation of intravenously administered Evans blue dye was monitored as a marker of vascular permeability. Results indicated that LE and beclomethasone caused similar inhibition of vascular permeability with respective IC50 values of 0.34 and 0.17 µmol/L. In the same model, dexamethasone was considerably less active (IC50 = 23 µmol/L). Intranasal LE showed dose-proportional efficacy in reducing antigen-induced rhinorrhea in Ascaris-sensitized domestic pigs. The effect of 0.5% nasal drops of LE was similar to 0.05% fluticasone propionate (FP) in blocking antigen-induced rhinorrhea in sensitized guinea pigs challenged with ovalbumin.
Intranasal LE was also comparable to betamethasone efficacy in experimental models of nonallergic rhinitis. The severity of vascular extravasation after nasally instilled acetic acid and arachidonic acid irritants in anaesthetized rats was reduced approximately 40% with 0.25% suspensions of LE or 0.1% betamethasone (data on file, VIATRIS GmbH & Co. KG).
Results in animal models of rhinitis, together with the clinical efficacy and safety profiles of ophthalmic LE, suggested that an LE nasal spray could provide a safe and effective therapeutic alternative to currently available nasal corticosteroids. This report describes results of the initial (i.e., first in man) repeated dose safety and pharmacokinetic investigation of LE nasal spray in healthy male subjects. Twenty-four-hour serum cortisol profiles were monitored as the most sensitive index of basal adrenal cortisol secretion. The randomized study compared two formulations of LE with placebo and with FP in parallel groups of healthy male volunteers. We decided to include not only a placebo group in the trial design but also FP, a powerful and clinically widely established topical corticosteroid, to facilitate an early head-to-head comparison of the local tolerability and systemic safety (i.e., potential inhibitory effects on the hypothalamic-pituitary-adrenal axis [HPAA]) of LE with currently established therapeutic standards.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Subjects were randomly assigned to four parallel treatment groups of 8 subjects each. The total treatment duration was 14 days. All subjects received two puffs of the following nasal spray formulations once daily into each nostril: LE 0.1% (400 µg/day), LE 0.2% (800 µg/day), FP 0.05% (Flonase®, 200 µg/day), and placebo (inactive ingredients of the LE formulation).
The assessment of 24-hour serum cortisol profiles was chosen as a well-accepted pharmacodynamic surrogate marker for systemic GCS exposure and resulting bioactivity in terms of suppression of cortisol secretion. We determined the basal (i.e., unstimulated) 24-hour cortisol profiles because it has been suggested that this approach would reflect HPAA-suppressive drug effects with higher sensitivity, as opposed to measures under stimulated conditions (e.g., with cosyntropin [ACTH]), since adrenocorticotropic hormone (ACTH) stimulation reflects the adrenal reserve under supra-physiological stimulation rather than basal secretion under physiological conditions. Eight subjects were assigned to each treatment group so that a potential adverse drug reaction with an incidence of at least 31% could be seen in at least 1 subject (with 95% probability).
The study was conducted at the Clinical Pharmacology Unit of VIATRIS GmbH & Co. KG (Frankfurt, Germany). Each subject gave written informed consent before participation in the study, which was approved by the independent ethics committee of the Landesärztekammer Hessen. The study was conducted in accordance with the Declaration of Helsinki (Somerset West Amendment, 1996) and the International Conference on Harmonization's guideline on good clinical practice.
For the purpose of pharmacokinetic and 24-hour serum cortisol profiling at study days -1, 1, and 14, subjects were confined to the clinical center at the VIATRIS Human Pharmacology Unit for 36-hour periods beginning at least 10 hours before the first blood samples were to be collected. Subjects were required to fast 10 hours before the start of blood sampling and continued fasting on study days 1 and 14 until 2 hours after study drug administration. Subjects received standardized meals and beverages during confinement in the clinical center and did not consume xanthine-containing food or beverages. In addition, subjects abstained from strenuous physical exercise, beginning from 48 hours before first study drug administration and throughout the entire course of the study. During the ambulatory days of the study (days 2-13), subjects reported each morning to the clinical center for scheduled safety assessments, adverse event (AE) documentation, and supervised nasal spray administrations.
Blood Sampling for 24-Hour Serum Cortisol Profiles and Analytical Methods
The 24-hour serum cortisol profiles were determined for each subject from a total of 13 blood samples collected at 2-hour intervals on the day before the first dosing (day -1; i.e., baseline) and after the last dose was given on day 14. Blood was collected in 4.5-mL tubes (Serum Monovette®, Sarstedt, Germany), allowed to clot for at least 30 minutes, and then centrifuged at 2300g for 10 minutes within 1 hour following blood withdrawal. Serum was frozen and stored at -20°C until analysis. Samples were analyzed by using a validated automatic analyzer system (Elecsys® 2010, Roche, Switzerland). Serum cortisol concentrations were determined by means of a specific and highly sensitive enzyme immunoassay (ECLIA, Roche, Switzerland) with a lower limit of quantification of 0.29 µg/dL and intra- and interassay coefficients of variation of 2.78% and 3.64%, respectively.
Pharmacokinetic Blood Sampling and Analytic Methods
To evaluate the pharmacokinetics of LE and FP, blood was collected in 7.5-mL tubes (NH4-heparin Monovette®, Sarstedt, Germany). Blood was collected immediately before dosing to screen for potential trough concentrations on study days 1, 5, 12, 13, and 14. After the last dose on study day 14, further samples were collected at 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours to allow for the description of complete plasma-level time curves after repeated dosing. The samples were centrifuged within 30 minutes (2300g, 10 min), and plasma was frozen and stored at -20°C until analysis. LE and FP concentrations were determined using validated analytical methods that included solid-phase extraction and analysis by high-performance liquid chromatography (HPLC) with tandem mass-spectrometric detection (LC-MS/MS). The assay limit of quantification (LOQ) for LE was 50 pg/mL, while the LOQ for FP was 5 pg/mL.
After addition of internal standard, protein in plasma samples was precipitated by addition of a 30:70 ethanol/water (v/v) mixture, and supernatant was separated by centrifugation. The supernatant was then transferred onto an SPE C18 extraction column (Supelco, Bellefonte, PA) preconditioned using ethanol and water. Adequate vacuum pressure was applied to ensure a dropwise flow rate from the column. The column was then washed with 1 volume of 25% aqueous ethanol, 1 volume of water, and then 2 mL of a 2:98 (v/v) ethyl acetate/n-heptane mixture. Finally, the analytes were eluted using 3 mL of a 35:65 (v/v) ethyl acetate/n-heptane mixture at a dropwise flow rate. The eluate was evaporated to dryness in a vacuum centrifuge and reconstituted in 50 µL (for LE) or 100 µL (for FP) of mobile phase. A volume of 40 or 80 µL was injected onto the HPLC/MS/MS system for determination of respective LE and FP concentrations.
The LC-MS/MS system consisted of a Micromass Quattro-LC-Z triple quadrupole mass spectrometer (Beverly, MA) equipped with an electrospray (ESI) ion source for the determination of LE or an atmospheric pressure chemical ionization (APCI) ion source for the detection of FP. The LC-MS/MS conditions for FP were previously described.12 The mobile phase for LE was 70:30 methanol/water (v/v) with 0.1% formic acid delivered at a flow rate of 0.3 mL/min by an LDC CM 3500 pump. The C18 reversed-phase analytical column (Waters, Symmetry 3.5-µm, 4.6 x 50 mm i.d.) was preceded by an adequate precolumn filled with reversed-phase C18 material. The source temperature was 120°C, with a probe temperature of 350°C for LE and 500°C for FP. The transitions selected for monitoring were m/z 466.79 to 264.97 for LE and m/z 499.23 to 295.24 for the internal standard. The collision gas was argon. Data analysis was performed using the Masslynx software. The calibration curves were plotted as the peak response (area ratio of analyte/internal standard) on the y-axis versus analyte concentration on the x-axis. The calibration curve ranged from 0.025 to 5 ng/mL for LE and 0.005 to 1 ng/mL for FP, with a coefficient of determination (r2) that consistently exceeded 0.99 for each of the 11 assay calibrations used in the study to evaluate concentrations of the two drugs.
Safety and Tolerability Assessments
Safety evaluations included the assessment and documentation of the subject's well-being throughout the study in terms of nature, severity, and incidence of adverse events; local tolerability; clinical laboratory assessments; vital signs assessments; and electrocardiograms (ECG). Hematology, blood chemistry, and urinalysis variables were assessed as criteria prior to study enrollment and at the beginning and end of the 14-day treatment period. Vital signs and ECG recordings were monitored throughout the study. Appearance and integrity of the anatomical structures of the nose, with particular reference to the nasal mucosa, were assessed by a board-certified specialist in otolaryngology who conducted anterior rhinoscopy before study medication was administered and under blinded conditions with respect to the individual treatments at the end of the dosing period on day 14.
Pharmacokinetic, Pharmacodynamic, and Statistical Analyses
The plasma concentration-time data for each subject were analyzed by standard noncompartmental pharmacokinetic methods. Parameters were calculated using standard commercially available KineticaTM (InnaPhase Corporation, Philadelphia, PA) software. The observed peak plasma concentration (Cmax) and time to peak concentration (tmax) were identified directly from the measured plasma concentrations, while area under the concentration-time curve (AUC0-t) values were calculated by using the trapezoidal rule, when Cn > Cn-1, or by using the log-linear method. The elimination rate constant (ke) was estimated from the terminal slope of the log concentration versus time profiles, while the elimination half-life (t1/2) was calculated as ln(2)/ke. AUC0-
was determined from the sum of AUC0-t, and the extrapolated area was calculated from the last detectable plasma sample (Clast) as Clast/ke.
The 24-hour cortisol AUCs were calculated using the trapezoidal rule for serum samples collected at baseline (i.e., day -1 before first dosing) and on day 14 of once-daily dosing with study medication. ANOVA models and independent sample t-tests were used to compare mean AUC values between the treatment groups on each day. Paired t-tests were used to assess whether there were significant changes in the AUC within-treatment groups from day -1 to day 14.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eight of the 32 subjects reported at least one adverse event, but all events were identified as mild and transient and resolved without medical intervention or sequelae. Results show no indication that adverse events had a disproportionate incidence for any treatment group. The adverse events were sneezing (1 subject in the LE 400-µg group), headache (1 subject in the LE 400-µg and LE 800-µg groups), rhinitis (1 subject in the LE 800-µg, FP 200-µg, and placebo groups), coughing (1 subject in the LE 800-µg and FP 200-µg groups), pharyngitis (1 subject in the FP 200-µg and placebo groups), and hematoma related to blood sampling (1 subject in the LE 400-µg group). Results from hematology, blood chemistry, and urinalysis showed no indication of any clinically significant change or underlying drug effect. Anterior rhinoscopy assessments did not show any changes in the appearance and integrity of the nasal mucosa. The only abnormality reported from nasal examinations after treatment was a deviated septum, which was previously identified prior to drug treatment.
Pharmacokinetics
Mean (± SD) LE plasma concentration-time profiles of both formulations and dosages are illustrated in Figure 1. The mean (± SD) pharmacokinetic parameters for each treatment are given in Table I.
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In general, there was considerable variability in each of the pharmacokinetic parameters.
LE plasma concentrations could be measured in the majority of subjects who received the 0.1% formulation (i.e., 400-µg dose) up to 2 hours, as well as in those who received the 0.2% formulation (i.e., 800-µg dose) up to 3 hours, while FP plasma concentrations could be quantified in 4 of 8 subjects up to 4 hours. In 1 subject of the LE 400-µg group, all plasma samples were below the limit of quantification of the LE assay (50 pg/mL); therefore, this subject was excluded from the pharmacokinetic analysis.
Trough plasma drug values of both the LE and FP treatments, measured from samples collected immediately before dosing on study days 1, 5, 12, 13, and 14, were below the limit of quantification in all subjects, which indicates a lack of LE and FP accumulation during the 2-week dosing period. These findings are consistent with the observed mean terminal half-lives of 2.2 ± 1.5 hours and 1.8 ± 1.0 hours for both LE treatments and 4.2 ± 1.8 hours for the 200-µg FP treatment. It is to be noted in this context that LE terminal half-lives were independent from dose and formulation and approximately twice as short relative to the observed mean FP terminal half-life, which was found in our study to be consistent with data from the literature.13
The times required to achieve maximum concentrations (tmax) indicate that both LE formulations and FP were rapidly absorbed into the systemic circulation, with maximum concentrations (Cmax) observed in 27 of 32 of the volunteers between 20 and 40 minutes. Maximum concentrations were observed at mean (± SD) times of 0.6 ± 0.3 hours, 0.9 ± 0.7 hours, and 0.8 ± 0.3 hours for daily LE 400-µg (0.1%), LE 800-µg (0.2%), and FP 200-µg (0.05%) doses, respectively. Peak LE concentrations from the 0.2% formulation yielding the 800-µg daily dose had a mean of 164 ± 54 pg/mL, which was only slightly greater than the mean peak concentration of 139 ± 57 pg/mL observed from the 0.1% formulation yielding the 400-µg daily dose. The mean peak concentration obtained after dosing with 200 µg/day of FP was approximately 10% of levels seen after dosing with the 800-µg dose of LE. This should be interpreted, however, in light of the fourfold difference in nominal doses administered.
The relative extent of systemic exposure for each treatment can be derived from the area under the curve values (AUC), as given in Table I. Because for the majority of subjects, the extrapolated portion of AUC0- values was more than 40% of the total areas, the AUC0-t values should be considered instead, which were on average 193 ± 87 pg/h/mL-1 for the LE 0.1% formulation (400-µg dose), 300 ± 183 pg/h/mL-1 for the LE 0.2% formulation (800-µg dose), and 40 ± 34 pg/h/mL-1 for the FP 0.05% formulation (200-µg dose).
Twenty-Four-Hour Serum Cortisol Profiles
The median 24-hour serum cortisol profiles for each of the four treatment groups, determined on baseline (day-1) and day 14 of treatment, are illustrated in Figure 2a-d, respectively. The mean 24-hour serum cortisol AUC values, calculated from individual serum profiles obtained at baseline and day 14, and the mean changes in AUC values are shown in Table II.
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There were no statistically significant changes in AUC between baseline and day 14 for any of the treatment groups. Although all subjects had normal basal morning serum cortisol values at screening, 6 of the total 32 recruited individuals (18.8%) were noted to have some remarkable baseline patterns in their 24-hour serum cortisol profiles in terms of one or two observed daytime peaks in addition to the morning peak. Of these subjects, 3, 2, and 1 of them were assigned to the FP, LE 800-µg, and LE 400-µg groups, respectively. This unbalanced assignment of subjects with remarkable baseline patterns to the different treatment groups is thought to be the mai reason for the observation that the mean 24-hour cortisol baseline AUC and the corresponding standard deviation were highest in the 200-µg FP group. This may have further contributed to the observation that the FP group showed the greatest numerical treatment-emergent change, with a mean decline in the 24-hour serum cortisol AUC of 49 mg/h/dL-1 (p = 0.18).
The mean change in both LE-treated groups over the course of the study was negligible, did not differ from placebo, and did not show any dose relationship.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The design and dose selection of the present study reflect many of these aspects and considerations. It is further to be noted that we considered it justified to embark with a 14-day repeated-dose treatment under close clinical surveillance, based on the already existing clinical experience with ophthalmic LE formulations and because in the preclinical program, LE showed no substantial deviations from other well-characterized GCS.
The results from this initial clinical evaluation of two LE intranasal doses indicate that both concentrations are well tolerated. Mild, spontaneously resolved events were noted in one-third of volunteers participating in the study. However, the nature and incidence of events, which included sneezing, headache, rhinitis, coughing, and pharyngitis, was not considered different between LE-treated, FP-treated, and placebo-treated groups. A relatively high incidence of reported events is typical for intensely monitored initial clinical investigations of new compounds, especially for trials with subjects confined to the clinical investigation site for periods longer than a single work day. Therefore, data from placebo-treated subjects are indispensable, and data from active control groups are very helpful in determining the causality and clinical significance of treatment-emergent adverse events in such initial clinical trials. Further evidence that both LE formulations were well tolerated is indicated by the absence of clinically significant abnormalities for hematology, blood chemistry, urinalysis, or anterior rhinoscopy in any of the four treatment groups.
Systemic side effects of potential clinical importance that are most commonly associated with long-term topical corticosteroid therapy are impaired release of endogenous cortisol, short-term growth reduction, and reduction of bone density. All of these systemically mediated side effects require the drug to enter the systemic circulation to exert the adverse effect. In the case of intranasal application, the drug could be directly absorbed into the systemic circulation or be swallowed and undergo oral absorption. Estimates for some formulations indicate that—due to a combination of incomplete deposition and mucociliary clearance of intranasally deposited drug substance—approximately 70% of an intranasal steroid dose escapes nasal absorption and is swallowed.14 Therefore, the limitation of oral bioavailability plays a major role in minimizing the potential for unwanted side effects of intranasal steroids. The oral bioavailability of FP has been reported very low at < 1% compared to other steroids available as intranasal formulations.15 Although no formal absolute oral bioavailability study is available up to now for LE, a very low oral bioavailability can be assumed because an early study in healthy male volunteers given a single 40-mg oral dose of LE (i.e., 50-fold of the highest intranasal dose applied in this study) detected only very low drug concentrations near the threshold of assay sensitivity (data on file, Prof. Nicholas Bodor). Consequently, it is conceivable to assume that any systemic exposure observed for both FP or LE should almost exclusively reflect the amount of drug that has been absorbed at the level of the nasal mucosa. For LE, the present study shows that the rate and extent of systemic availability depend not only on the drug itself but also on the formulation. This finding is in line with previous reports on other intranasal GCS formulations, such as the bioavailability of FP from an aqueous nasal spray, which was found to be eightfold higher relative to nasal drops.13 Similarly, distinct differences in the systemic bioavailability among different budesonide and triamcinolone acetonide formulations have been reported.13,14
Both the LE and the FP formulations used in this trial were aqueous suspensions. Thus, drug particles need to be dissolved at the surface of the nasal mucosa prior to absorption. Nasal absorption itself is likely to be an unsaturable first-order process.16 This renders the physicochemical properties of the drug molecule itself (e.g., lipophilicity) and the dissolution rate of the suspended drug particles as limiting determinants for the rate and extent of systemic exposure because both factors compete with the removal of the drug by the nasal mucociliary clearance.16 Drug and formulation properties, together with the mucociliary clearance, are therefore the major determinants of the fraction of dose escaping nasal absorption. These general considerations are confirmed for the tested LE preparations by the data from our study: when both LE formulations are compared, systemic absorption appears slightly more sustained and less complete from the 0.2% formulation than from the 0.1% formulation.
The pharmacokinetic results for FP from this study indicate peak concentrations of approximately 16 pg/mL, which occurred at about 1 hour after a 200-µg intranasal dose. These results, while showing considerable variability, are similar to other published studies identifying a Cmax of 18 pg/mL after a single 200-µgdose of FP. The investigators estimated a systemic availability of 5% for intranasal FP and attributed the low nasal bioavailability of FP primarily to the low dissolution rate of the drug due to its lipophilicity.13 The lipophilic nature of the molecule, however, is also responsible for a relatively large volume of distribution resulting in a prolonged terminal half-life of approximately 4 hours, as opposed to only 2 hours seen with both LE formulations. When the overall systemic exposure of the 0.2% LE formulation is adjusted for dose and compared with FP, Cmax is approximately threefold, and AUC0-t is approximately twofold.
Thus, consideration of systemic exposure alone would suggest that the order of systemic pharmacodynamic effects (i.e., 24-h serum cortisol suppression) identified for the present study would be 800 µg/day LE > 400 µg/day LE > 200 µg FP > placebo, assuming similar protein binding. As predicted, the placebo group showed virtually no change from baseline to day 14. Consistent cortisol profiles over the 14-day study period in the placebo group positively reflect study conduct.
The order of systemic pharmacodynamic activity for the various GCS-treated groups, however, was not closely related to measures of systemic exposure. Factors in addition to the overall systemic exposure that contribute to systemic bioactivity include receptor-binding affinity and plasma protein binding.16 A significant body of evidence suggests that the receptor-binding affinity (RBA) of a GCS correlates with its bioactivity/potency at the site of action. GCS receptor-binding studies indicate that LE has an RBA 1.5 to 4.3 times that of dexamethasone,4 while the RBA of FP was estimated as 18 times that of dexamethasone.17 This would translate to a difference in bioactivity between FP and LE by a factor 4 to 12, if the steroids have similar protein binding.
Initial examination of the mean changes in 24-hour serum cortisol profiles and the statistical outcome between baseline and day 14 of treatment with 400 µgand 800 µg LE or 200 µg FP suggests that, overall, none of the treatments may have suppressed normal function of the HPAA. It should be borne in mind, however, that the sensitivity to adverse systemic GCS effects shows large intersubject variability.18 For this reason, treatment-emergent remarkable individual changes may be more sensitive in early detection of the HPAA suppression potential of a particular GCS at a certain dose. If individual values are considered, 3 of 8 subjects treated with FP exhibited a remarkable treatment-emergent change of their individual 24-hour serum cortisol profiles, suggesting that these 3 individuals were the major contributors to the observed trend toward suppression in the FP group. Similar remarkable differences between baseline and day 14 cortisol profiles could be observed in 2 subjects of the LE 800-µg group and in only 1 subject of the LE 400-µg group. The placebo group did not show any subject with remarkable treatment-emergent changes of the individual 24-hour cortisol profiles. These findings suggest that the susceptibility of the 200-µg intranasal FP to significantly suppress the 24-hour cortisol secretion cannot be entirely ruled out by our study because the statistical power (i.e., the sample size) may have been too low to confirm real but relatively small differences in a highly variable measure. On the other hand, the possibility of a non-treatment-related difference between baseline and active treatment data due to an increased baseline value in this specific group (see Table II) is not unlikely. This is supported by the fact that most studies in the literature report a lack of suppression of serum and urinary cortisol by FP (for review, see Hochhaus et al16). On the other hand, a study by Wilson and Lipworth19 reported a statistically significant suppression of overnight urinary cortisol secretion that occurred after 4 days of treatment with 200 µg intranasal FP. The discrepancies of the literature data and the higher variability in the FP baseline values in our study seem to argue for a more conservative interpretation of the data, also suggesting no clear support for cortisol suppression by FP. Other more sensitive clinical parameters, such as growth retardation in children, should be included in future studies. For the LE data, however, it can be concluded that there was no evidence in our study that multiple intranasal doses of daily 400 µg and 800 µg LE would be susceptible to a clinically relevant suppression of serum cortisol because changes in both LE-treated groups over the course of the study were negligible, did not substantially differ from placebo, and did not show any dose relationship.
In conclusion, the findings of this study underline the importance of early and comprehensively addressing both pharmacokinetics and pharmacodynamics in the clinical development of new topical GCS to properly assess a reliable early estimate of systemic exposure and safety. Repeated once-daily dosing with 0.1% and 0.2% LE intranasal formulations in healthy male subjects was well tolerated up to daily doses of 800 µg and exerted no systemic inhibitory action on the HPAA in terms of 24-hour serum cortisol secretion. The uptake and systemic exposure appears more sustained and less complete from the 0.2% LE concentration. This principally favors this formulation for further clinical development because the ratio of local exposure at the target site (i.e., nasal mucosa) and undesired systemic exposure is distinctly higher as opposed to the 0.1% LE formulation. In summary, intranasal LE was well tolerated in healthy volunteer subjects. The pharmacokinetics assessment of LE after nasal administration of once-daily dosing over 14 days at doses of 400 and 800 µg/day revealed a relatively low systemic drug exposure, as indicated by the small AUC0-t and Cmax estimates and a short terminal half-life of about 2 hours. Pharmacokinetic parameters indicate a rapid decline of plasma drug levels, with little or no systemic accumulation of the study drug. No effects on 24-hour serum cortisol profiles were detected after repeated LE dosing, which is consistent with low systemic bioavailability of the drug.
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FOOTNOTES |
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The study was sponsored by ASTA Medica AG (predecessor of VIATRIS GmbH), Frankfurt am Main, Germany.
Submitted for publication November 26, 2003; Revised version accepted January 30, 2004.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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