Aerosol Delivery of Ergotamine Tartrate Via a Breath-Synchronized Plume-Control Inhaler in Humans

By Armer, T A Shrewsbury, S B; Newman, S P; Pitcairn, G; Ramadan, N

Key words: Breath-synchronized plume-control inhaler – Ergotamine tartrate – Migraine – Pulmonary drug delivery ABSTRACT

Objective: To compare systemic delivery of ergotamine tartrate (ET) via a breath-synchronized, plume-control inhaler (BSPCI) (Tempo ET*) with a sublingual ergot preparation and a commercial inhaler.

Methods: Study 1 determined plasma ET concentrations in seven healthy subjects after administration of ET by a 2 mg tablet (Lingraine[dagger]) and a BSPCI delivering 258 [mu]g of ET. Study 2 determined plasma ET concentrations in 16 healthy subjects after administration via an ET metered dose inhaler (ME) (Medihaler[double dagger]) delivering 2052 [mu]g of ET and a BSPCI delivering 129 [mu]g of ET. Gamma scintigraphy with ^sup 99m^Tc validation was used to quantify lung deposition.

Results: For both studies, ET C^sub max^ was higher with the BSPCI (study 1: sublingual ET 134 pg/mL at 37 min; BSPCI 3743 pg/mL at 3 min; study 2: metered-dose inhaler 1109 pg/mL at 4 min; BSPCI 1210 pg/mL at 2.5 min). Mean dose normalized AUC was several-fold higher with the BSPCI compared with sublingual ET and ME dosing. Lung deposition of ET with the BSPCI was 33.5, 8.9, 11.4, and 13.2% for whole, central, intermediate, and peripheral lung, respectively, with a 1.5 peripheral : central ratio.

Conclusion: Based on these open-label studies, the BSPCI allows rapid delivery of potentially therapeutic plasma concentrations of ET at approximately 1/15th the dose of comparators.

Introduction

Despite the recognized burden of migraine and attention focused on the development of new therapeutic classes of treatment over the last decade, notably the introduction of the triptans, migraine attacks remain difficult to treat effectively and often require an office or emergency room visit1-4. In patients with refractory pain, only a few drugs for which there is good supportive data are effective, including dihydroergotamine (DHE)5. The majority of drugs for treating acute migraine are administered orally, but when at- home therapy fails, parenteral administration is often utilized. Although migraine sufferers prefer oral administration over nasal or injectable therapy, they are willing to trade inconvenience of administration for treatments that are fast and effective when pain becomes severe6.

Ergots are a proven effective therapy for acute migraine, in particular when administered intravenously (IV) as DHE5,7,8. Of the commercially available ergots, DHE is preferred because of its effectiveness in migraine relief, associated low recurrence rates, and favorable safety profile9. Other routes of administration for ergots exist, but these have erratic and somewhat unpredictable pharmacokinetic properties that create therapeutic difficulties such as unpredictable clinical response or unexpected adverse events. Therefore, the development of an ergot formulation which is easy to administer, safe, and effective, might be therapeutically advantageous. Earlier studies showed that a therapeutic response to ergotamine (ET) was associated with plasma concentrations of at least 200 pg/mL within 1 h of administration10,11.

Aerosol drug delivery by pressurized metered-dose inhaler (pMDI) remains popular but problematic. High in vivo dose variability, excessive oropharyngeal deposition, and reduced peripheral airway deposition have limited the utility of conventional pMDIs in delivery of narrow therapeutic window drugs, including ergot alkaloids for treating migraine7,8,12,13. To overcome these limitations, we developed the breath-synchronized, plume-control inhaler (BSPCI) (Tempo ET*), containing ET as a prelude to advancing an effective pulmonary inhalation route of administration for DHE. The BSPCI utilizes a breath-activated, synchronized trigger, which discharges the metered dose into a small, integral, ‘flow control chamber’ where the aerosol plume is slowed to around 1/10th of its discharge speed, spun into a vortex to increase residence time, and buffeted by sidewall airflows to prevent sidewall deposition (Figures 1 and 2). The increased residence time allows evaporation of the propellant, leaving a high proportion of respirable drug particles in the emitted plume. The breath-synchronized trigger of the BSPCI device can be preset to discharge the plume at a particular range in the inspiratory cycle (exchange volume) independent of peak flow rate or inspiratory volume. This enables targeting of different drug products and formulations to a particular lung region: deep lung (if discharged early in inspiration, suitable for systemic delivery or alveolar or lung parenchymal disease) or more central airways (if discharged late, suitable for upper or lower conducting airway disease).

Figure 1. The flow control chamber of the breath-synchronized, plume-control inhaler (BSPCI) at the start of inhalation

This paper reports results from two proof-of-concept studies conducted to assess the deposition characteristics and plasma concentrations of ET delivered by a BSPCI. The objective of study 1 was to compare the plasma concentrations of ET after administration via a BSPCI or a commercially available sublingual ET tablet. The effects of ET delivered by a BSPCI on pulmonary function also were assessed. Data from this single-dose study were used for dose selection and study design for study 2. Study 2 compared a BSPCI with ME pMDI to determine systemic absorption of inhaled ET and to determine total and regional lung deposition of inhaled ET using gamma scintigraphy.

Figure 2. Plume control during canister discharge (immediately following firing of synchronized trigger)

Methods

The protocol describing the two studies was reviewed and approved by an appropriately constituted Independent Ethics Committee. All study subjects provided signed consent before participating in the studies. The studies were conducted in accordance with the Declaration of Helsinki and subsequent amendments and with ICH Guidelines for Good Clinical Practice, 1996.

Study drugs

In both studies, the inhaled drug product consisted of a suspension of ET particles in fluorocarbon propellant, held in a standard aluminum MDI canister fitted with a metered-dose valve. BSPCI canisters contained ET suspended in pure HFA 227 propellant, and were provided by Primedica (Cambridge, MA, USA). For the BSPCI, the canister containing ET was inserted into a BSPCI tuned to trigger at approximately 30 L/min for a 3.0 L inhalation achieving a peak flow rate of 60 L/min. The ME canisters contained ET suspended in a CFC propellant. The ME canisters and commercial actuators were manufactured by 3M and sourced from Pharmaceutical Profiles, Nottingham, UK. No modification was made to the propellant, formulation, valve or aluminum canister for the BSPCI or for ME for study 1. For study 2, the BSPCI formulation was radiolabeled by the addition of the radionuclide ^sup 99m^Tc, using methods similar to that described for radiolabeling other pressurized metered-dose inhaler formulations14.

Study 1: Pharmacokinetic assessment of ET systemic levels when delivered via BSPCI compared to sublingual tablet

Study 1 was a randomized, open-label, two-way, cross-over, proof- of-concept study comparing the plasma concentration of ET after administration of a sublingual dose of ET or an inhaled dose of ET (BSPCI). Seven healthy male subjects, 18-65 years of age, were selected to participate and six completed both arms of study 1. Subjects were randomized to receive either a single 2 mg sublingual ET tablet or a 258-[mu]g dose from the BSPCI (six consecutive actuations, each of a nominal 43 [mu]g). Six actuations were required because the device was designed to allow for dosage flexibility and titration for individual patients. Prior to administration of the aerosol, subjects practiced the inhalation maneuver with the aid of a BSPCI device containing an empty canister fitted with a metering valve. Prior to receiving study drug, subjects were instructed on proper technique for using the inhalers and practiced until they were able to perform to the satisfaction of the investigator. The BSPCI synchronous trigger was set to discharge early in the inspiratory cycle, corresponding to approximately 20% exchange volume (30 L/min for a 3.0 L inhalation achieving a peak flow of 60 L/min). After each inhalation of ET via the BSPCI, subjects held their breath for 10 seconds and then exhaled through a filter for collection of expired aerosol.

In order to evaluate the flow characteristics of the BSPCI device, a record of each dosing inhalation was made using a Respitrace device (Ambulatory Monitoring Inc, Ardsley, NY, USA) set to record the inhalation. The Respitrace device was calibrated using an 800 mL Spirobag (Ambulatory Monitoring Inc, Ardsley, NY, USA). Inhaled volume, duration of inhalation, average inhaled flow rate, and breath-holding pause were calculated from the inhalation. After a minimum 48-h washout period, subjects then received the alternate crossover treatment.

Pulmonary function tests were performed to assess the effects of ET delivered via the BSPCI. Tests were performed prior to dosing, and at 30min and 14 h post-dose. Forced expiratory volume in 1 s (FEV^sub 1^), forced vital capacity (FVC), and peak expiratory flow (PEF) were determined using a Vitalograph Compact Spirometer (Vitalograph Ltd, Maids Moreton, UK). Study 2: Scintigraphic and pharmacokinetic assessment of BSPCI and ME

This was a randomized, open-label, two-way, crossover study. Sixteen healthy male subjects, 18-65 years of age, were selected to participate and 12 subjects completed both arms of study 2. Subjects were randomized to receive ET by inhalation from either a BSPCI or ME. Before initiating this study, preliminary work had demonstrated that three actuations from the BSPCI would deliver a radiolabeled ET fine particle dose (FPD) of 105 [mu]g to the lungs, which was similar to the 103 [mu]g unlabeled ET FPD delivered by six actuations of ME. Additionally, it was confirmed that radiolabeling the ET canisters for use in the BSPCI with ^sup 99m^Tc did not affect the particle size distribution compared to unlabeled ET, and therefore the gamma scintigraphic demonstration of deposition of labeled ET in the lung was a valid marker of ET lung deposition.

Prior to administration of ET via the BSPCI, each subject practiced using the BSPCI trainer device as in study 1. Subjects randomized to treatment with ME practiced the inhalation maneuver with the aid of a placebo pMDI. The last maneuver for the ME device was recorded using a Vitalograph Compact spirometer, while the radiolabeled maneuvers (third actuation) for the BSPCI were made using a Respitrace device set to record the inhalation. All inhalation maneuvers were performed in a seated position and at a target flow rate of 30 L/min. Inhaled volume, average inhaled flow rate, and breath-holding pause were calculated from the inhalation. After a 10-second breath-holding pause, subjects exhaled through a filter to trap any residual aerosol particles. When the investigator was satisfied that a subject could reproducibly perform the correct inhalation, the practice device was replaced with an active device. The ME device was discharged by the investigator as inspiratory flow rate reached approximately 30 L/min to approximate the flow rate achieved with the BSPCI.

Ergotamine tartrate was inhaled by each subject on one occasion from each device, with a 4-day minimum wash-out period between administrations. When using the BSPCI, subjects inhaled three actuations (two unlabeled and one radiolabeled). Each actuation delivered a nominal 43-[mu]g dose for a total of 129 [mu]g ET, 105 [mu]g delivered to the lung. Subjects randomized to ME were administered six actuations (342 [mu]g nominal delivered dose/ actuation) from the ME for a total of 2052 [mu]g ET, of which 103 [mu]g were delivered to the lung.

The final, third actuation of ET from the BSPCI was radiolabeled, and scintigraphic imaging was performed to determine lung deposition of ET immediately following administration from the radiolabeled ET- containing device. Comparisons of ET delivery to systemic circulation via BSPCI and ME were based on pharmacokinetic analyses. Scintigraphy was only performed on BSPCI delivery of ET as an understanding of the intrapulmonary distribution of ET via ME was not the primary objective for this work. Scintigraphic images were recorded using a General Electric Maxicamera (General Electric Co, Milwaukee, WI, USA), with a 40 cm field of view and fitted with a low-energy parallel-hole collimator. The following views were obtained: posterior chest, anterior chest, right lateral of the oropharynx, and anterior and posterior abdomen (if necessary to record activity beyond the previous field of view).

Any images required to capture activity on items external to the body using scintigraphic data from the BSPCI device were analyzed in accordance with methods described by Snell and Ganderton14. Posterior lung ventilation scans were performed using the a radioactive inert gas ^sup 81m^Kr (omitted if subject had a ventilation scan within the past 5 years). All images were recorded on a Micas V computer system (Park Medical, Farnborough, UK). Quantitative data were downloaded into a customized spreadsheet. The lung outlines from the ^sup 81m^Kr ventilation scans were used to define the edges of the lung fields on the aerosol views. Lungs were digitally divided into central, intermediate, and peripheral regions of interest. Regions of interest were also drawn around the oropharynx, esophagus, and stomach (including small intestine). Counts obtained were corrected for background activity, radioactive decay, and tissue attenuation. In regions where anterior and posterior images were recorded, the geometric mean counts of the two images were used to correct for tissue attenuation. Any activity detected on the mouthpiece of the exhalation filter was analyzed as a separate region of interest, and the counts were added to those of the oropharynx. The counts in each area were expressed as a percentage of the metered dose (sum of all body, BSPCI device, and exhalation filter counts). In order to determine the mass of drug ([mu]g) that was deposited in the lungs over the three actuations, percentages obtained for the lungs, oropharynx, and exhaled air filter were summed and the percentages converted to delivered dose. Data were then re-calculated as a percentage of the nominal dose (43 [mu]g) and extrapolated to three actuations.

Scintigraphic data obtained included: (1) percentage of metered dose in the whole lung, and central, intermediate, and peripheral lung regions, (2) percentage of metered dose deposited in the oropharynx, (3) percentage of metered dose retained on the actuator, and (4) percentage of metered dose in exhaled air. The percentages of deposition were then converted to: the amount of drug ([mu]g) in the whole lung, and central, intermediate, and peripheral lung regions, the amount of drug ([mu]g) deposited at the oropharynx and lung regions, and (3) the amount of drug ([mu]g) in exhaled air. The ratio of peripheral: central (P: C) lung region deposition (lung penetration index), which indicates the relative proportions of drug delivered to peripheral versus central lung regions, was calculated.

In order to compare the effects of ET inhalation via the BSPCI and ME devices, pulmonary function tests were performed prior to dosing, 30min post-dose, and at discharge (14 h post-dose). FEV^sub 1^, FVC, and PEF were determined using the Micro Medical Microloop Spirometer (Micro Medical Ltd, Chatham, Kent, UK).

Analysis of plasma ET concentrations

For both studies, plasma ET concentrations were assessed to compare systemic absorption of ET. Venous blood samples were collected pre-dose, at 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 30, and 45 min, and at 1, 2, 3, 4, 6, 8, and 12 h after complete dose administration. The first 1 mL of blood collected was discarded, and the remaining 6 mL was aspirated into lithium-heparin monovette tubes. The total blood collected from each subject, including pre- and post-study evaluations was 306 mL. Samples were centrifuged at approximately x 1140 g for 15 min at 2 [degrees]C. Plasma fractions were transferred to polystyrene tubes and shipped on dry ice for laboratory analysis. Plasma samples were assayed for ET by Simbec Research (Merthyr Tydfil, UK). ET was extracted from basified plasma by solvent extraction along with a closely-related internal standard. Following clean-up of the sample using back extraction, LC- MS-MS with multiple reaction monitoring of characteristic parent-to- product ion transitions was used for quantitation over the calibration range of 10-10 000pg/mL. The precision of the ET assay was reflected by inter-day coefficients of variation of 4.41, 4.29, and 4.45%, while the accuracy was determined to be 100.0, 102.3 and 91.6% at 10, 500, and 10 000pg/mL concentrations respectively. The concentrations of ET in plasma were determined using a Perkin Elmer Sciex API III Plus biomolecular mass analyzer (Perkin Elmer Sciex, Ontario, Canada).

Statistical analysis

In study 1, mean plasma concentrations at 1 min, 1 h and 6h, together with the pharmacokinetic parameters AUC^sub (0-12h)^, C^sub max^ and T^sub max^ were determined to provide statistical comparisons between ET delivered by the BSPCI and ET 2 mg sublingual tablet treatments (using a paired t-test or for T^sub max^, Wilcoxon’s signed ranks test). In study 2, the pharmacokinetic parameters, AUC^sub (0-[infinity])^, C^sub max^ and T^sub max^ and t^sub 1/2^ were determined to enable comparisons between ET delivery via the BSPCI and the ME pMDI (using paired t-tests or for T^sub max^, Wilcoxon’s signed ranks test). References to significant differences indicate a p < 0.05. Scintigraphic data were presented as mean and coefficient of variation.

Results

Study 1: Pharmacokinetic assessment of ET absorption via BSPCI compared to sublingual tablet

Of the six male subjects completing both arms of study 1, the mean age was 42.4 years and the mean weight was 84.2 kg. The ET dose delivered by inhalation with the BSPCI was calculated to be 258 [mu]g. The mean inhaled volume for the six subjects was 3.3 L, while the mean average inhaled flow rate was 29.1 L/min. The mean durations of inhalation and breath-holding were 6.8 and 8.3 s, respectively.

The plasma ET concentration and pharmacokinetic data after dosing via sublingual tablet and BSPCI are summarized in Table 1. The pharmacokinetics seen after sublingual and BSPCI dosing showed significantly greater C^sub max^. and AUC^sub (0-12h)^ following BSPCI dosing (p = 0.0004 and 0.006, respectively). The mean dose normalized plasma C^sub max^ ratio (BSPCI/sublingual tablet) was 329 in those subjects completing both arms of the study. Similarly, the mean dose normalized AUC^sub (0-12h)^ ratio (BSPCI/sublingual tablet.) was 217. T^sub max^ was achieved much earlier and more consistently after BSPCI dosing, at a median of 3 min (range 1-5 min) compared with 37 min (range 1-480 min) after sublingual dosing (although this was statistically ambiguous, p = 0.075, using Wilcoxon’s signed ranks test). Plasma ET concentrations after receiving the 2-mg tablets were often below the lower limit of quantification (BLQ 10.82 pg/mL) which prevented an accurate determineation of terminal half-life and calculation of AUC^sub (0- [infinity])^ for the sublingual data, hence comparisons between the two datasets were made using AUC^sub (0-12h)^. Since measurable amounts of ET were detectable in plasma samples from at least four of the six subjects receiving the 2 mg sublingual tablets at 1 min, 1 h, and 6 h post-dose, plasma concentrations in subjects treated with tablet and by BSPCI are reported at those time points (Table 1). At 1 min, 1 h, and 6 h post-dose, plasma ET concentrations were approximately 77, 9, and 2.3 times greater in BSPCI treated- subjects than in sublingual-treated subjects.

Pulmonary function tests showed that the mean pre-dose and post- dose FEV^sub 1^ values for the six subjects receiving ET via the BSPCI were similar (3.8 and 3.7 L, respectively).

Study 2: Scintigraphic assessment of inhaled ET

Of the 12 subjects completing both arms of study 2, mean age was 44.5 years and mean weight was 79.3 kg. The results of lung deposition of ET assessed for the final actuation using the BSPCI are provided in Tables 2-4. The mean percentage of ET dose delivered to the lung from a single actuation from the BSPCI was 33.5%, and the mean percentage of ET delivered to the central, intermediate, and peripheral lung regions were 8.9, 11.4, and 13.2%, respectively (Table 2). Figure 3 displays a representative scintigraphic image of ET distribution via the BSPCI. The percentage deposition for lungs, oropharynx, and exhalation filter was summed and expressed as the percent of delivered dose and then converted to the amount of drug ([mu]g) deposited in the various regions. Based on a nominal emitted BSPCI dose of 43 [mu]g/actuation over three actuations, the mean calculated peripheral deposition of ETwas 23 [mu]g (53.5% of the nominal dose), the mean central deposition was 15.7 [mu]g (36.5% of the nominal dose) and the mean peripheral/central lung region deposition ratio (P/C ratio) was 1.5 (Table 2).

Table 1. Mean and coefficient of variation (%CV) for ergotamine pharmacokinetics in subjects receiving sublingual tablet or via a breath-synchronized, plume-control inhaler (BSPCI) delivery of ergotamine tartrate at 1 min, and 1 and 6 h post-dose (study 1)

Following three actuations, the mean percentage of the metered dose of ET in the oropharynx was 40.4%, the mean percentage in exhaled air was 0.4%, and the mean percentage retained in the BSPCI actuator was 25.8% (Table 3). The mass of ET deposited in the oropharynx and exhalation filter was 69.4 [mu]g and 0.7 ug, respectively. The mean mass of ET deposited in the BSPCI actuator was 44.3 [mu]g. The pre-dose, 30-min post-dose, and discharge pulmonary function measurements for subjects treated with the BSPCI and ME are shown in Table 4. The mean FEV, at all time points was numerically similar for the BSPCI and ME devices. No evidence of bronchoconstriction was observed in any subject.

Plasma pharmacokinetics of ET are summarized in Table 5. In those subjects completing both arms of the study the median T^sub max^ of 2.5 min (range 1-6 min) in subjects treated with the BSPCI was significantly shorter compared with 4 min (range 3-10 min) with ME (p = 0.016, Wilcoxon’s signed ranks test). While plasma concentrations at T^sub max^ were similar (p = 0.5) following BSPCI (1001 pg/mL) compared with ME dosing (1109pg/mL), the mean concentrations were significantly lower for BSPCI-treated subjects than ME-treated subjects at 1 h (102 vs. 270 pg/mL, p = 0.002) and 6h (31 vs. 111 pg/mL, p = 0.0002) post-dose, respectively. This suggests that ET is more slowly absorbed from the ME formulation, which is supported by the significantly longer mean residence time (MRTlast) of 3.9 h vs. 2.6 h for ME vs. BSPCI treatments (p = 0.0006). The prolongation of absorption from the ME treatment was not sufficient to result in an alteration of terminal half-life, which did not significantly differ (p = 0.99) between the ME and BSPCI formulations (4.0 vs. 4.0h). The terminal half-life was longer than has been reported following IV dosing (1.86h)15 and IM dosing (2.34h)15 but similar to that seen after rectal dosing (3.35 h)16.

Table 2. Mean and coefficients of variation (%CV) of the percentage of metered dose and mass of ergotamine tartrate ([mu]g) deposited in whole lung and central, intermediate, and peripheral lung zones delivered by a breath-synchronized, plume-control inhaler (BSPCI) (n = 12 subjects)

Table 3. Mean and coefficient of variation (%CV) of the percentage of metered dose and mass of drug ([mu]g) deposited in the oropharynx and the exhalation filter and the mass of drug remaining on the breath-synchronized, plume-control inhaler (BSPCI) device

Table 4. Mean and coefficient of variation (%CV) of forced expiratory volume (FEV^sub 1^) values at pre-dose, 30 min post- dose, and pre-discharge (14 h post-dose) for ergotamine via pMDI and a breath-synchronized, plume-control inhaler (BSPCI)

Figure 3. Representative scintigraphic image of ET distribution via the breath-synchronized, plume-control inhaler (BSPCI)

Mean dose-normalized plasma C^sub max^ ratio (BSPCI/ ME) was 19.7 in those subjects completing both arms of the study. Similarly mean relative bioavailable fraction (Frel) for BSPCI was 6.9 using ME dosing as the reference (calculated from the individual CL/F values summarized in Table 5). The absolute bioavailable fraction (F) of BSPCI was estimated to be approximately 30% using IV data from migraine patients15 in which clearance was reported to be 0.68 L/kg/ h. Using the same reference data, F for the ME was estimated to be approximately 5%. However, ET shows a 3-4-fold higher intersubject variability in clearance15,17 and thus F cannot be estimated with a high accuracy unless IV studies are performed in the same subjects.

Table 5. Mean and coefficient of variation (%CV) for ergotamine pharmacokinetics in subjects receiving aerosol delivery by ergotamine pMDI and a breath-synchronized, plume-control inhaler (BSPCI) (study 2)

Table 6. Mean (standard error) ET plasma levels following a breath-synchronized, plume-control inhaler (BSPCI), ET pMDI, and sublingual ET administration: combined data from both studies

Combined data from both study 1 and study 2 are shown in Table 6, which illustrates the mean ET plasma concentrations following BSPCI, ME, and sublingual administration over 180 min post-dose.

Discussion

Migraine is a common and often debilitating disease, reported along with acute psychosis, dementia, and quadriplegia as one of the four conditions causing the highest levels of individual disability3. It is estimated that 30 million Americans suffer from migraine, a fact that accounts for significant morbidity, direct healthcare costs, and indirect cost to the economy as a result of lost productivity1,2,18. Ergots have long been used to treat migraine effectively; indeed, DHE has been marketed since 1946 and may be better tolerated than ET9. However, the efficacy of ergots has been offset by dose-limiting side-effects, and only parenteral administration offers reliable bioavailability. Other less invasive routes of administration have low bioavailability or require complex dosing regimens that limit acceptance. Previous attempts to offer an inhaled dosage form with ET met with some success, but the delivered dose had a low fraction of respirable particles and variable lung deposition typical of early pMDIs. A large portion of the dose was lost to oral deposition where the bioavailability was very low, necessitating high administered doses to achieve therapeutic blood levels, which have been reported to be >200pg/mL11.

Over the last two decades much migraine-specific research has been conducted, driven by the successful development and registration of several triptans that are more selective than the older ergots. However, predicting success with any one triptan within or between patients is difficult: 2-h pain relief rates vary between 39 and 67%, and 2-h pain-free rates vary between 22 and 40% among the various triptans19.

One approach has been to identify and develop new classes of drugs for the treatment or prophylaxis of acute migraine (e.g., calcitonin gene-related peptide). An alternative approach has been to reformulate products previously established as effective in an attempt to overcome the disadvantages of earlier formulations. Although antiemetics (e.g., prochlorperazine) and NSAIDs (e.g., naproxen) have been favored by some, re-formulating the effective ergots, either alone or in combination, including DHE which may have a more favorable safety profile because of more selective receptor binding, has been the focus of many other groups7.

The BSPCI was developed to provide potentially a highly efficient and reproducible delivery system that would allow a patient to self- administer and titrate drugs with narrow therapeutic windows. While pursuing several drug candidates for the treatment of pain, research and development focused on migraine treatment and DHE in particular. Before embarking on full scale clinical studies with the BSPCI, it was desirable to confirm that aerosol delivery of ergots by the BSPCI device would overcome some of the inconsistency and low delivery efficiency typical of pMDIs,12,13,20,21.

Conventional ‘press-and-breathe’ pMDIs often provide highly variable lung deposition for two reasons: first because many patients cannot use them correctly, and second because the mean lung deposition is generally only a small percentage of the dose. In a study in patients with poor inhaler technique22, lung deposition from a press-and-breathe pMDI was shown to range between < 1% and 28% of the dose (mean 7.2%, CV 134%). But when the same patients used an Autohaler breath-actuated inhaler, average lung deposition was higher and less variable (mean 20.8%, CV 24%). Most pMDIs have mean lung deposition averaging less than 20% of the metered dose, but higher mean lung deposition occasionally exceeding 50% of the metered dose is possible using devices that reduce the spray velocity23, with spacer devices added to the pMDI24,25, or with some HFA formulations delivered via narrow actuator nozzles2627. A review of over 70 deposition studies has shown that there is an inverse correlation between mean lung deposition from inhaler devices and the variability of lung deposition28. The interaction between the spray and the human upper airways varies according to individual airway anatomies. When oropharyngeal deposition is high, it is also variable, leading to low and highly variable lung deposition. Conversely, when oropharyngeal deposition is low, it is less variable, leading to higher but less variable lung deposition. Examination of the data summarized by Borgstrom et al.2s indicates that an inhaler such as the BSPCI with mean lung deposition exceeding 30% of the dose is likely to have a %CV of lung deposition < 30%, whereas an inhaler with a mean lung deposition of only 10% of the dose may have a CV >50%. The manufacturer chose to perform this preliminary work with ET because of the availability of a commercial preparation of inhaled ET and the presence of a sublingual formulation. These provided two existing ET products to compare with BSPCI for the systemic pharmacokinetics of ET. A gamma scintigraphy study was chosen to quantify delivery of ET to the lungs from the BSPCI delivery system and to assess the extent of aerosol deposition in the peripheral lung.

As is appropriate for pharmacokinetic studies, where the objective endpoint of plasma levels is less subject to observer or subject bias, the studies reported here were open-label. In addition, the results are from two separate studies rather than a single study comparing the three formulations of ET. In both studies, crossover methodology was employed to ensure the use of within-subject comparisons; six and 12 subjects, respectively, are usually considered a sufficient sample size, and gamma scintigraphy from 12 volunteers is also generally adequate to describe aerosol deposition in the lung. No serious or significant adverse events and no episodes of bronchoconstriction were reported.

The BSPCI provided efficient delivery of ET compared to the traditional press and breathe pMDI with rapid absorption resulting in peak ET concentrations a few minutes after dosing. The BSPCI required only 5-10% of the ET dose required by the pMDI or the sublingual tablet to achieve therapeutic blood levels of ET, which are reported to be at least 200 pg/mL11. The C^sub max^ for ET delivered by inhalation with BSPCI ET or ME was eight times higher than with the sublingual formulation. High peripheral lung deposition and low oropharyngeal deposition were seen with the BSPCI. These results are consistent with other inhaled drugs, where small particles achieve lower oropharyngeal (<40%) and higher lung deposition than larger particles26.

The slightly earlier occurrence of C^sub max^ and the different plasma level profile observed with the BSPCI versus the traditional press-and-breathe pMDI device suggest a slight delay of systemic absorption from the ME formulation. This could be the result of much higher oropharyngeal deposition from the ME formulation delivered by a traditional press-and-breathe pMDI leading to greater oral deposition (and direct absorption) and subsequent gastrointestinal absorption after swallowing. This would be consistent with the lower bioavailable fraction seen with ME since the oral bioavailability following tablet dosing is reported to be low16. Absorption from oral dosing is also prolonged with a reported peak plasma ET concentration at 69 min16. Thus, the observed plasma concentration profile seen after ME could represent a combination of the elements of rapid absorption from a relatively poor lung delivery plus some slower absorption from oropharyngeal or gastrointestinal sites. The estimated F-value of 30% for the BSPCI formulation is similar to the percent dose delivered to the lung (Table 3) and this suggests that ET is efficiently absorbed from the lung.

The BSPCI also reduced oropharyngeal deposition of ET; the mean percentage of ET delivered to the oropharynx was 40.4%, a much lower rate than the typical 70% oropharyngeal deposition expected from a CFC pMDI17. The BSPCI also delivered greater amounts of drug to the lung periphery as intended. The P: C ratio of 1.5 indicates a high deposition of drug in the peripheral lung. The P: C ratio is consistent with approximately two-thirds of the drug reaching the alveoli, a finding that has positive implications for the BSPCI – specifically for its ability to efficiently administer drugs for systemic delivery via the lung29.

Conclusion

The BSPCI allows rapid systemic delivery of antimigraine ergots at approximately 5-10% of the delivered dose of traditional press- and-breathe pMDIs, providing peak systemic levels within minutes. Improved lung deposition and reduced dose variability may allow targeting of more potent and narrow therapeutic range drugs that require accurate targeting to biological sites of action. The BSPCI containing ET was never intended for full-scale clinical development but purely to test out the BSPCI against a commercial formulation. The manufacturer’s migraine program has subsequently focused on the development of a novel formulation of dihydroergotamine (DHE) in HFA propellant, and clinical trials with a BSPCI containing DHE are underway to further confirm these findings.

Acknowledgment

Declaration of interest: This study was sponsored by MAP Pharmaceuticals, Mountain View, CA, USA. TAA and SBS are employees of MAP Pharmaceuticals. SPN and GP were responsible for performing the study, which was conducted at Pharmaceutical Profiles, Ltd, Nottingham, UK under a contract with Sheffield Pharmaceuticals Inc, whose assets were acquired by MAP Pharmaceuticals. NR is a consultant to MAP Pharmaceuticals. The manuscript was prepared by the authors, and all authors reviewed and approved the manuscript. The bioanalytical and pharmacokinetic work was performed by Simbec Research Ltd and Dr Glyn Taylor, Cardiff, UK, respectively. The authors would like to acknowledge the assistance of Richard S. Perry, PharmD, in the preparation of this manuscript.

* Tempo ET is a registered trademark of MAP Pharmaceuticals, Mountain View, CA, USA

[dagger] Lingraine is a registered trademark of Sanofi Winthrop, provided by Pharmaceutical Profiles, Nottingham, UK

[double dagger] Medihaler is a registered trademark of 3M and sourced from Pharmaceutical Profiles, Nottingham, UK

* Tempo ET is a registered trademark of MAP Pharmaceuticals, Mountain View, CA, USA

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-4029_2, Accepted for publication: 16 October 2007

Published Online: 07 November 2007

doi:10.1185/030079907X242881

T. A. Armer(a), S. B. Shrewsbury(a), S. P. Newman(b), G. Pitcairn(b) and N. Ramadan(c)

a MAP Pharmaceuticals, Mountain View, CA, USA

b Pharmaceutical Profiles Ltd, Nottingham, UK

c Rosalind Franklin University of Medicine and Science, Chicago, IL, USA

Address for correspondence: Stephen B. Shrewsbury, MD, MAP Pharmaceuticals Inc., 2400 Bayshore Parkway, Suite 200, Mountain View, CA 94043, USA. Tel.: +1 650 386 3113; Fax: +1 650 386 3101; sshrewsbury@mappharma.com

Copyright Librapharm Dec 2007

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