First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours.

BACKGROUND: Interleukin-1 (IL-1) signalling is involved in various protumoural processes including proliferation, immune evasion, metastasis and chemoresistance. CAN04 is a first-in-class monoclonal antibody that binds IL-1 receptor accessory protein (IL1RAP), required for IL-1 signalling. In this first-in-human phase 1 study, we assessed safety, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of CAN04 monotherapy. METHODS: Patients with advanced solid tumours known to express IL1RAP and refractory to standard treatments were enrolled in a dose-escalation study with 5 dose levels (1.0-10.0 mg/kg) of weekly CAN04. RESULTS: Twenty-two patients were enrolled. Most common adverse events were infusion-related reactions (41%), fatigue (32%), constipation (27%), diarrhoea (27%), decreased appetite (23%), nausea (23%) and vomiting (23%). One dose limiting toxicity was reported. No maximum tolerated dose was identified. Pharmacokinetics analyses indicate higher exposures and slower elimination with increasing doses. Decreases in serum IL-6 and CRP were observed in most patients. Twenty-one patients were evaluable for response, 43% had stable disease per immune-related response criteria with no partial/complete responses. CONCLUSIONS: The IL1RAP targeting antibody CAN04 can be safely administered to patients up to 10.0 mg/kg weekly, which was defined as the RP2D. Serum biomarkers supported target engagement and IL-1 pathway inhibition. CLINICAL TRIAL REGISTRATION: NCT03267316.

Relative systemic availability of budesonide in patients with asthma after inhalation from two dry powder inhalers.

BACKGROUND: To improve dosing consistency and product features, budesonide inhalation powder delivered via a dry powder inhaler (DPI) (DPI-A 200 microg) was redesigned to include lactose, a newly shaped mouthpiece, and a new dose indicator (DPI-B). Budesonide DPI-B is available in two strengths (90 microg, 180 microg). OBJECTIVE: To compare the relative rate and extent of the systemic availability of budesonide inhaled via DPI-A and DPI-B and test for systemic absorption bioequivalence. METHODS: Adults (n = 37) with asthma as defined by the American Thoracic Society were randomized in an open-label, crossover, single-center, single-dose study to budesonide DPI-A 200 microg x 4 inhalations, budesonide DPI-B 180 microg x 4 inhalations, or budesonide DPI-B 90 microg x 8 inhalations, on 3 days, each separated by a washout period of >or= 5 days. Plasma samples were collected immediately before and up to 12 h after dosing. Primary pharmacokinetic variables were area under the drug plasma concentration-time curve from 0 to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)); plasma concentration at 12 h (C(12h)) and time to maximum plasma concentration (T(max)) were secondary variables. Treatments were considered bioequivalent if the 90% confidence intervals (CIs) for their AUC(0-infinity) and C(max) ratios fell between 80 and 125%. Adverse events were collected. RESULTS: The 90% CIs for the ratios of AUC(0-infinity) and C(max) for budesonide DPI-A 200 microg and DPI-B 180 microg and for both budesonide DPI-B strengths fell between 80% and 125% (AUC(0-infinity): budesonide DPI-B 180 microg x 4/DPI-A 200 microg x 4: 96.3% [90% CI: 90.9, 102.1]; budesonide DPI-B 180 microg x 4/DPI-B 90 microg x 8: 92.2% [90% CI: 87.0, 97.7]; C(max): (budesonide DPI-B 180 microg x 4/DPI-A 200 microg x 4: 100.4% [95% CI: 92.1, 109.4]; budesonide DPI-B 180 microg x 4/DPI-B 90 microg x 8: 94.4% [90% CI: 86.6, 102.9]). No differences in C(12h) and T(max) were found between treatments. All treatments were well tolerated. CONCLUSIONS: Budesonide DPI-A 200 mug and DPI-B 180 mug have systemic absorption bioequivalence, and DPI-B 90 microg and 180 microg are dose-strength equivalent when administered at the same dose. These results may not be generalized to all patients with asthma, as this analysis included only patients with mild-to-moderate asthma aged >or= 19 years.

Evidence of the in vivo esterification of budesonide in human airways.

AIMS: Budesonide, unlike fluticasone propionate, undergoes fatty acid esterification in the lungs, and there is a need to characterize fully the distribution and fate of the two drugs after inhalation in humans. METHODS: This open-label, randomized study was performed in adults undergoing whole lung or lobar resection resulting from lung cancer. Patients were given single 1000-mug doses of both budesonide and fluticasone propionate via dry powder inhalers before surgery. Tissue samples from peripheral and central lung, an ex vivo bronchial brush sample and intercostal muscle, together with plasma samples, were taken during surgery and analysed by liquid chromatography plus tandem mass spectrometry. RESULTS: Lung tissue samples were obtained from 22 patients at surgery, 1-43 h after drug dosing. Budesonide was detectable from earliest sampling in central and peripheral lung tissue up to 10 h (in six of 22 samples), fluticasone propionate up to 22 h after inhalation (in 16 of 22 samples), and budesonide oleate up to 43 h after inhalation (in 21 of 22 samples). Budesonide, but not fluticasone propionate, was detected in intercostal muscle for up to 10 h after inhalation. Bronchial brush samples showed the presence of fluticasone propionate for up to 18 h, suggesting the presence of undissolved drug powder particles in the airway lumen. CONCLUSION: Sustained retention of esterified budesonide in the lungs supports the prolonged duration of action of budesonide and suitability for once-daily administration.

Exposure of infants to budesonide through breast milk of asthmatic mothers.

BACKGROUND: Maintenance treatment with inhaled corticosteroids is often required for asthmatic nursing women. Data on the transfer of inhaled corticosteroids from plasma to breast milk and the subsequent exposure of the breast-feeding infant has been unavailable. OBJECTIVE: We sought to assess budesonide concentrations in milk and plasma of asthmatic nursing women receiving maintenance treatment with the Pulmicort Turbuhaler and estimate the exposure of their breast-fed infants. METHODS: Milk and plasma samples were collected up to 8 hours after dosing from 8 mothers receiving budesonide maintenance treatment (200 or 400 microg twice daily). Pharmacokinetic parameters were calculated from budesonide milk and plasma concentrations. Infant exposure was estimated based on average milk budesonide concentrations. A single blood sample was obtained from 5 infants close to expected infant maximum concentration. RESULTS: Budesonide concentrations in milk reflected those in maternal plasma, supporting passive diffusion of budesonide between plasma and milk, and was always lower than that in plasma. The mean milk/plasma ratio was 0.46. The estimated daily infant dose was 0.3% of the daily maternal dose for both dose levels, and the average plasma concentration in infants was estimated to be 1/600th of the concentrations observed in maternal plasma, assuming complete infant oral bioavailability. Budesonide concentrations in infant plasma samples were all less than the limit of quantification. CONCLUSION: Maintenance treatment with inhaled budesonide (200 or 400 microg twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants. CLINICAL IMPLICATIONS: These data support continued use of inhaled budesonide during breast-feeding.

Effects of topical formoterol alone and in combination with budesonide in a pollen season model of allergic rhinitis.

BACKGROUND: beta(2)-Agonists may exert mast cell stabilizing and anti-plasma exudation effects. While available data suggest no or only marginal effects of beta(2)-agonists on symptoms of allergic rhinitis, little is known about whether these drugs may add to the efficacy of anti-rhinitis drugs. OBJECTIVE: To examine effects of a beta(2)-agonist, alone and in combination with an intranasal glucocorticosteroid, on symptoms and signs of allergic rhinitis. METHODS: Patients were examined in a pollen season model. Budesonide 64 microg, alone and in combination with formoterol 9 microg, as well as formoterol 9 microg alone was given in a placebo-controlled and crossover design. After 7 days of treatment, the patients received allergen challenges for 7 days. Symptoms and nasal peak inspiratory flow (PIF) were recorded. Nasal lavages with and without histamine were carried out at the end of each challenge series. These lavages were analysed for tryptase, eosinophil cationic protein (ECP), and alpha(2)-macroglobulin as indices of mast cell activity, eosinophil activity, and plasma exudation, respectively. RESULTS: Budesonide reduced symptoms of allergic rhinitis and improved nasal PIF in the morning, in the evening as well as post allergen challenge. Formoterol alone did not affect symptoms or nasal PIF and did not affect the efficacy of budesonide. Tryptase, ECP, and alpha(2)-macroglobulin were significantly reduced by budesonide. Formoterol alone did not affect these indices and did not affect the anti-inflammatory effect of budesonide. CONCLUSION: The present dose of formoterol does not affect symptoms and inflammatory signs of allergic rhinitis and does not add to the efficacy of topical budesonide.

Degree of throat deposition can explain the variability in lung deposition of inhaled drugs.

Inhalation is a mainstay for treatment of asthma, and lung deposition can be seen as a surrogate marker for the ensuing clinical effects. Not only absolute lung deposition, but also its variability is of interest, as it indicates the range of expected lung deposition in an individual patient when prescribing the drug and the expected day-to-day variability when using it. A literature survey found 71 studies with relevant information on lung deposition and its variability. Further characteristics of the studies, such as if the subjects were healthy or asthmatics, adults or children, and what device that was used, were noted. In all, 187 data points were included. Variability in lung deposition was depicted as a function of mean lung deposition; for the entire data set and for subsets thereof. Independent of device type or subject category high lung deposition was associated with low relative variability and vice versa. Using a published throat deposition model, the observed correlation of lung deposition variability to mean lung deposition could be explained as being determined largely by the extent of and variability in throat deposition. We hypothesize that throat deposition is the major determinant for lung deposition of an inhaled aerosol, and its absolute variability will largely be determined by the absolute variability in throat deposition. The relative variability in lung deposition will therefore tend to be high for low lung deposition and low for high lung deposition. Consequently, low relative variability in lung deposition can only be attained if high lung deposition is achieved.

Factors guiding the choice of delivery device for inhaled corticosteroids in the long-term management of stable asthma and COPD: focus on budesonide.

Inhaled corticosteroids (ICSs) have become the mainstay of chronic controller therapy to treat airways inflammation in asthma and to reduce exacerbations in chronic obstructive pulmonary disease. An array of ICSs are now available that are aerosolized by a range of delivery systems. Such devices include pressurized (or propellant) metered-dose inhalers (pMDIs), pMDIs plus valved holding chambers or spacers, breath-actuated inhalers, and nebulizers. More recently, dry-powder inhalers (DPIs) were developed to help overcome problems of hand-breath coordination associated with pMDIs. The clinical benefit of ICSs therapy is determined by a complex interplay between the nature and severity of the disease, the type of drug and its formulation, and characteristics of the delivery device together with the patient's ability to use the device correctly. The ICSs budesonide is available by pMDI, DPI, and nebulizer-allowing the physician to select the best device for each individual patient. Indeed, the availability of budesonide in three different delivery systems allows versatility for the prescribing physician and provides continuity of drug therapy for younger patients who may remain on the same ICSs as they mature.

Drug disposition analysis: a comparison between budesonide and fluticasone.

The characterisation of distribution and elimination properties of a drug is usually done using parameters like clearance and distributional volumes. To refine this characterisation, in this paper, we use drug disposition analysis to compare the distribution and elimination of the two glucocorticosteroids budesonide and fluticasone propionate, known to differ in this respect. This gives a more detailed description of the well known differences in distributional volumes using concepts like mean residence time and fraction of dose outside the central compartment. It clearly shows that fluticasone, although having lower plasma concentrations, still resides in the body in appreciable quantities.

Systemic availability and lung deposition of budesonide via three different nebulizers in adults.

BACKGROUND: Budesonide is an inhaled corticosteroid widely used in the treatment of asthma. The local and systemic availability of budesonide has been determined in adults via pressurized metered-dose inhaler and dry-powder inhaler. OBJECTIVE: To estimate lung deposition and systemic availability of budesonide inhalation suspension in healthy adults. METHODS: Twelve adult volunteers entered an open, randomized, five-way crossover study and received the following treatments, with 1-week washout between treatments: separate 2-mg (nominal dose) budesonide doses via the Pari Inhalierboy (Inhalierboy; Pari GmbH, Starnberg, Germany), Pari LC Jet Plus (Jet Plus, Pari GmbH), and Maxin MA-2 (MA-2; Clinova Medical AB, Malmö, Sweden) jet nebulizers, 4 mg budesonide orally, and 0.5 mg budesonide intravenously. The plasma concentration of budesonide was measured up to 8 hours postadministration. Lung deposition and systemic availability of nebulized budesonide were estimated using pharmacokinetic evaluation. RESULTS: In this first study of the bioavailability of budesonide inhalation suspension in adults, there were no differences between nebulizers in lung deposition (14 to 16%) or systemic availability (15 to 17%) relative to the nominal budesonide dose. Relative to the actual dose inhaled (dose-to-subject), lung deposition and systemic availability were statistically significantly higher for the Jet Plus (58 and 63%, respectively) and MA-2 (59 and 64%, respectively) nebulizers than the Inhalierboy (36 and 44%, respectively). The Inhalierboy produced larger aerosol droplets than Jet Plus or MA-2 nebulizers (7-, 5-, and 3-microm mass median diameters, respectively) and delivered a higher dose-to-subject than the other two nebulizers. CONCLUSION: Relative to the nominal dose, lung deposition and systemic availability of budesonide were similar via the three nebulizers tested.