A comparison between the semisimultaneous and the stable isotope techniques for bioavailability estimation of terbutaline in humans.

A recently proposed bioavailability estimation procedure, the "semisimultaneous" method, in which the test and reference dose administrations are separated by a short time interval and total concentrations are analyzed, was compared with the stable isotope method for precision and accuracy. By administering isotope-labeled (reference) and unlabeled (test) terbutaline in a semisimultaneous fashion, the bioavailability could be determined with both methods at the same time. The extent and rate of bioavailability of oral terbutaline was determined in eight healthy volunteers by use of both model fitting, AUC methods, and deconvolution. The AUC ratio and the deconvolution methods, by use of the separate isotope data, gave bioavailability estimates of 14.5% +/- 4.1% and 12.2% +/- 3.9%, respectively. According to the semisimultaneous method, bioavailability estimates with the same data sets were 11.8% +/- 4.5% obtained from fitting a model to the data and 11.0% +/- 3.7% by use of a combined model fitting-deconvolution procedure. An excellent agreement between the semisimultaneous and the stable isotope methods was also obtained in the estimation of the rate of absorption.

Exercise increases the rate of pulmonary absorption of inhaled terbutaline.

The purpose of the study was to investigate whether a constant submaximal exercise challenge affected the plasma pharmacokinetics of an inhaled beta 2-adrenoceptor agonist, terbutaline sulfate. Eight healthy nonsmokers participated in a study comprising measurements of plasma concentrations of terbutaline on two separate study days. Plasma samples were frequently collected at rest during study day 1, and on the second study day, during and after a 30-min exercise challenge, which was performed immediately after inhalation of the drug. The rate of increase of plasma concentrations and the maximal plasma concentrations were higher during exercise than during rest (p less than 0.01 and p less than 0.05, respectively). The plasma concentration fell rapidly after cessation of the exercise and approached those obtained at rest. We suggest that increased pulmonary and/or bronchial blood flow and altered surface tension of the liquid lining of the air space may contribute to the enhancement of absorption of this hydrophilic compound during exercise. Based on the levels of the maximal plasma concentrations reached during exercise in this study, the results would be to increase the frequency of administration of the drug, rather than to increase the administered doses, if the aim is to prevent or ameliorate exercise-induced asthma and potential systemic side effects.

Relationship between plasma concentration and arousal in normal subjects after single oral and parenteral doses of melperone, a butyrophenone neuroleptic.

The relationship between plasma concentration and effect on arousal was studied in normal subjects after single oral and parenteral doses of melperone. A strong correlation between plasma concentration and effect was found when the effector compartment and central compartment were in equilibrium. The relationship was independent of the route of administration.

Sedative effects and prolactin response to single oral doses of melperone.

The pharmacokinetics of melperone and the relationship between plasma concentration and the effect on arousal and prolactin secretion after single oral doses (10, 25, 50 and 100 mg) was studied in normal subjects. Dose-dependent kinetics were indicated by the fact that higher plasma concentrations than expected were demonstrated after the 100-mg dose. Melperone decreased arousal and increased prolactin secretion in a dose-dependent manner. The level of arousal was correlated to melperone plasma concentration over the entire dose range. Prolactin secretion was also correlated to melperone plasma concentration, provided the relationship was studied separately for the individual melperone doses. Thus at higher doses, higher plasma concentrations are needed to elicit the same prolactin outflow. The possibility that reduced arousal reactions might contribute in the antipsychotic action of neuroleptic drugs was discussed.

The importance of the device in asthma therapy.

Inhalation is the preferred route for drug delivery in asthma treatment. Successful management of asthma depends on achieving adequate delivery of inhaled drug to the lungs, and to this end the role of the device used for delivery is very important. Aerosolized anti-asthma medications have been available for more than 40 years as pressurized metered dose inhalers (pMDIs), but more recently dry powder inhalers (DPIs) have been developed as an alternative. Laboratory assessment of fine particle dose has been shown to correlate to pulmonary deposition if the assessments are performed with an in vivo-like set up. The DPI Turbuhaler delivers a high proportion of the dose as fine particles suggesting high pulmonary deposition. This finding has been confirmed by lung deposition studies, which indicate superior pulmonary deposition from Turbuhaler compared with a pMDI. This superior delivery to the lungs with Turbuhaler is reflected in a better clinical effect, as measured by greater improvements in lung function. The DPIs such as Turbuhaler are easy to use, and Turbuhaler has been shown to function well in a constrained situation such as an acute asthmatic exacerbation. Furthermore, the use of Turbuhaler in acute asthma will provide rapid clinical improvement. The in vivo variability in lung deposition obtained with Turbuhaler is lower than with pMDI, indicating that the performance of Turbuhaler is less dependent on patient competence. Thus, the development of Turbuhaler represents an important step forward in the effective management of asthma.

The lack of effect of induced net fluid absorption on the in vivo permeability of terbutaline in the human jejunum.

The absorption mechanism(s) of terbutaline in the human jejunum was studied by using the intestinal perfusion instrument, Loc-I-Gut. The present study was divided into three parts. In Part I the absorption of 10 and 20 microM of both (+) and (-)-terbutaline enantiomers was studied. The influence of D-glucose (80 mM) on the net fluid transport across the intestinal wall and the effective intestinal permeability (Peff) of both (+/-)-terbutaline (10 microM) and antipyrine (0.5 mM) was investigated in Part II. The experimental design of Part III was similar to that in Part II, with the exception that the perfusion solution was hypotonic and had a D-glucose concentration of 80 mM. No statistical differences were found in the Peff between terbutaline enantiomers or their concentrations. D-glucose (80 mM) did neither affect net fluid transport nor the Peff of (+/-)-terbutaline and antipyrine in the human jejunum. In contrast, hypotonic D-glucose (80 mM) solution induced a net fluid absorption (p < 0.01). In parallel with this observation, the Peff -value of (+/-)-terbutaline was unchanged, whereas the absorption of antipyrine was found to be significantly increased (p < 0.05). The increased permeability of antipyrine during the net fluid absorption phase might be due to convective paracellular flow, but more likely is it a consequence of a higher concentration gradient of the drug close to the intestinal wall, and thereby increased transcellular absorption. Based on these findings we propose that the major route for the oral absorption of terbutaline and antipyrine might be passive transcellular diffusion.

Pulmonary deposition of inhaled terbutaline: comparison of scanning gamma camera and urinary excretion methods.

Deposition from a multidose powder inhaler (Turbuhaler, Astra) delivering 500 micrograms of terbutaline sulfate per metered dose was compared by two techniques in a group of six healthy volunteers. The deposition of the radionuclide 99mTc, which was used to label terbutaline sulfate powder, was quantified by gamma camera (G-method). Simultaneously, the gastrointestinal absorption of swallowed drug was blocked with activated charcoal, and the amount of terbutaline in a urine sample, collected over a period of 48 h and corrected by a pharmacokinetic internal standard of intravenous deuterated terbutaline, was used as a measure of lung deposition (U-method). The mean (standard deviation) depositions in lung were 26.9 (3.8%) of the dose for the G-method and 21.1 (3.2)% of the dose for the U-method. Possible reasons for the differences between the two means are discussed. Both methods are suitable for assessing deposition from medical aerosol inhalers; the U-method requires access to gas chromatography-mass spectrometric equipment, and the G-method requires access to gamma camera facilities.

Comparative pharmacokinetics of unlabeled and deuterium-labeled terbutaline: demonstration of a small isotope effect.

An equimolar mixture of terbutaline and [2H6]terbutaline was given as an oral solution to six healthy volunteers (three men and three women). Frequent blood samples were collected during a 24-h period and the plasma concentrations of unlabeled and deuterium-labeled terbutaline were measured by GC-MS. The overall geometric mean plasma concentration ratio of terbutaline to [2H6]terbutaline (isotope ratio) was 1.04 and differed significantly from unity. The difference can be explained by a difference in lipophilicity between the analogues, affecting their absorption. No trend in isotope ratio over the experimental time was observed. For unknown reasons, the isotope ratio was higher for women (1.07) than for men (1.00). Deuterium-labeled terbutaline can be used, intravenously or orally, as an absolute reference in bioavailability studies on terbutaline. If deuterium-labeled terbutaline is given orally in a single-day relative bioavailability study, a correlation should be made for the observed isotope effect.

Variability in lung deposition of inhaled drug, within and between asthmatic patients, with a pMDI and a dry powder inhaler, Turbuhaler.

In vitro analysis of inhaled formulations measures, among other parameters, the variability in delivered dose, while a corresponding in vivo analysis also includes the variability caused by patient performance and distribution of drug between the oropharynx and the lungs. In vitro, the dose variability is higher for Turbuhaler(R) than for the corresponding pMDI, whereas in vivo, the converse is true: the variability in lung deposition is significantly higher, both between and within subjects, for pMDI than for Turbuhaler. The observation can be due to several factors such as the non-continuous working principle of inhalation via pMDI as opposed to the continuous working principle of inhalation via Turbuhaler.

On the use of dry powder inhalers in situations perceived as constrained.

Dose delivery from dry powder inhalers (DPIs) are dependent on the inhalation effort of the patient. Some patient groups, including asthmatic children, patients with acute asthma, and patients with advanced chronic obstructive pulmonary disease (COPD) are perceived as having problems in readily inhaling from a DPI in an efficient way; this opinion is based on alleged low inhalation flows. A review of the literature however shows that these groups can use a DPI in an efficient way and gain good clinical effect from its use. Particularly, it has been shown that children can generate a good peak inhalation flow through a DPI, albeit a lower inhaled volume. Similarly, patients with acute asthma can use a DPI in an efficient way, even reaching a better clinical effect with the DPI than with a pressurized metered dose inhaler with a spacer. Finally, it was shown that patients with severe COPD can generate the inhalation flows needed to generate an efficient drug aerosol from a DPI. Collectively, the discussed patient groups seem to perform as well as other subjects when it comes to their ability to generate an adequate inhalation flow through a DPI.

Deposition patterns with Turbuhaler.

The degree of lung deposition is an important factor in the evaluation of different inhalation flow driven dry powder inhalers. A number of studies using radioactive and non-radioactive methods have been performed with Turbuhaler to assess lung deposition under different conditions. Mean total lung deposition of terbutaline sulfate or budesonide via Turbuhaler in healthy volunteers ranged from 21-32% of the dose when a normal inhalation flow (60L/min) was used. At a low flow (30L/min) a mean 15% of the dose was deposited in the lungs, a similar value as for a well-performed inhalation via a pressurized metered dose inhaler. Regional deposition of inhaled drug can be expressed as the ratio between the amount of drug deposited in the more peripheral parts of the lung relative to the more central parts. In a comparative study, budesonide and terbutaline sulfate were given by inhalation via Turbuhaler to healthy volunteers. The ratio of peripheral to central deposition was 2.03 for terbutaline and 1.72 for budesonide. Thus, both the water-soluble terbutaline sulfate and the non-water soluble budesonide seemed to behave in the same way when inhaled via Turbuhaler. In conclusion, Turbuhaler delivers over 20% of a metered dose to the lungs when inhaled at a normal inhalation flow rate. The regional deposition pattern in the lungs was the same for terbutaline sulfate and budesonide, in spite of differences in water solubility.

Local versus total systemic bioavailability as a means to compare different inhaled formulations of the same substance.

For inhaled formulations of a drug substance, the balance between desired local activity and undesired systemic activity can be expressed with an L:T ratio, where L stands for the local bioavailability and T stands for the total systemic bioavailability. The L:T ratio depends not only on the ability of the different devices to divide the delivered dose between the lungs and the oropharynx but also on the inherent difference in gastrointestinal (GI) first-pass metabolism between different substances. The L:T ratio should therefore not be used to make comparisons across different drug substances but only to compare the same drug formulated in different inhalation systems. A high L:T ratio expresses a good targeting ability of the combination of substance and device or a low contribution from the GI tract. A high L:T ratio also reflects a more beneficial balance between wanted and unwanted effects. The L:T ratio was calculated from literature data for a number of salbutamol (albuterol) formulations and for two budesonide and two terbutaline formulations. For salbutamol, values ranged from 0.15 to 0.55 with different devices. For budesonide, the values ranged from 0.66 to 0.85, and for terbutaline, the values ranged from 0.59 to 0.79. The L:T ratio can thus be used to aid in the choice of inhaler.

Pulmonary clearance rate of two chemically different forms of inhaled pertechnetate.

Attempts to image the pulmonary deposition site of radiolabeled aerosols delivered by dry powder inhalers (DPIs) and pressurized metered-dose inhalers (pMDIs) using single photon emission computed tomography (SPECT) have been limited by the rapid pulmonary clearance of radiolabel. To determine whether aqueous solubility of the radiolabel is a significant factor, the pulmonary clearance rates of two chemically different forms of 99mTc were calculated. A dry powder formulation of terbutaline sulphate was radiolabeled for inhalation by Turbuhaler (AstraZeneca) using the water-soluble salt sodium pertechnetate and the water-insoluble salt tetraphenylarsonium pertechnetate. A pilot study was conducted during which two control subjects each inhaled the two radiolabeled aerosols on separate days. Intrasubject clearance rates for the two species were very similar. It was therefore concluded that water insolubility of the pertechnetate salt alone was not enough to extend the lung residency time of the radiolabel.

Developing and advancing dry powder inhalation towards enhanced therapeutics.

Enhanced therapeutics are drug products derived from existing generic drugs that provide additional benefits to the patients and the healthcare system. Enhanced therapeutics are considered to be an important and relatively low risk source of innovation. Pulmonary drug delivery is the major delivery route to treat chronic respiratory diseases and has been proven as a potential delivery route for complex drugs that cannot be delivered orally. Development of dry powder inhalation systems targets the delivery of fine drug particles to the deep lung surface by a combination of drug formulation, primary packaging and a device, whereby each contributes to the overall performance. Various methodologies for the non-clinical and clinical performance testing of orally inhaled products have been proposed and applied with variable success. Regulatory pathways have been developed and applied since. Considerable efforts have been made during the past decade to understand and optimize pulmonary drug delivery including their efficient commercial manufacturing. Pulmonary drug delivery remains an area of future innovation in the effective treatment of pulmonary diseases as well as the systemic delivery of systemically active complex drugs.

Idealhalers or realhalers? A comparison of Diskus and Turbuhaler.

Medication for the treatment of asthma and chronic obstructive pulmonary disease should be given locally by inhalation. There is, however, no such thing as an ideal inhaler, or 'Idealhaler', which has all desired properties with no drawbacks. In this short review, we have compared the relative merits of the two most commonly used dry powder inhalers -- Turbuhaler and Diskus. Clinical effect is related to the amount of inhaled drug that reaches the lungs, and this in turn depends on the amount of fine particles generated at inhalation. Turbuhaler is more than twice as effective as Diskus at generating fine particles, and the higher lung deposition with Turbuhaler is accompanied by a lower variability in lung deposition. Compared with Diskus, the lung deposition with Turbuhaler is affected less by factors such as humidity.

The pharmacokinetics of inhaled hydrofluoroalkane formulations.

To obtain the full picture of a formulation, the in vitro and the in vivo information can be looked upon as components of a "prediction bridge" where the in vitro information can be used to predict lung deposition, which in turn can be used to predict clinical outcome. This bridging concept can be used as a template to evaluate new information on emerging inhaled formulations. The concept was used to evaluate literature data on new hydroflouroalkane formulations of salbutamol and beclomethasone dipropionate (BDP). The new salbutamol hydroflouroalkane formulations seem to have properties similar to those of the old chlorofluorocarbon formulations even if the presented information on effect comparisons is limited. The first BDP hydroflouroalkane formulation is a solution formulation with in vitro properties that are quite different from those of the old chlorofluorocarbon suspension formulation. The BDP hydroflouroalkane formulation has a much greater fine particle mass, which eventually results in greater lung deposition and better clinical effect.

In vitro, ex vivo, in vivo veritas.

In vitro assessments of inhaler performance are important in product development and quality control, but are not, as such, good predictors of performance in vivo. It is, however, possible to modify in vitro techniques so that they more closely resemble the in vivo situation. Measurements of fine-particle dose (defined as the amount of drug with an aerodynamic diameter less than 5 microm) by cascade impactor have shown that the measured fine-particle dose in vitro is highly dependent on the geometry of the inlet to the impactor, the fine-particle dose being considerably lower when the cast of a human throat (an "anatomical throat") is used than when a standard glass inlet is used. This difference is, however, less with a dry-powder inhaler such as Turbuhaler than with a pressurized metered-dose inhaler (pMDI). Furthermore, there is a good correlation between fine-particle dose measured in vitro and in vivo lung deposition, provided that an anatomically correct inlet is used for the in vitro determination. Studies in children have shown that the degree of lung deposition of budesonide, delivered via Turbuhaler, is of the same order of size as the in vitro fine-particle dose. No comparable data are available for pMDIs; however, since children are smaller than adults, it is likely that differences in lung deposition between Turbuhaler and pMDIs are probably greater in children than in adults.