Pharmacokinetic Bioequivalence between Generic and Originator Orally Inhaled Drug Products: Validity of Administration of Doses above the Approved Single Maximum Dose.

Pharmacokinetic bioequivalence of orally inhaled drug products is a critical component of the US FDA's "weight of evidence" approach, and it can serve as the sole indicator of safety and effectiveness of follow-on inhalation products approved in Europe and some other geographic areas. The approved labels of the orally inhaled drug products recommend the maximum number of actuations that can be administered in a single dose on one occasion. This single maximum dose may consist of one or more inhalations depending upon the product. Bioequivalence studies for the inhalation drug product registrations in the US and EU have employed single and multiple actuation doses, in some cases over and above the approved single maximum labeled doses, thus, inconsistent with the approved labeling of the reference products. Pharmacokinetics of inhaled drug products after single and multiple doses may be different, with implications for bioequivalence determined at single and multiple doses. Scientific literature indicates that the relative bioavailability of the Test and Reference products may differ between administrations of doses in one and multiple inhalations. Multiple doses not only alter the pharmacokinetics but also may reduce the sensitivity of the bioassay to actual differences between the Test and Reference product performances. Ability of the pharmacokinetic bioassay to accurately determine the extent of difference between two products may also be substantially reduced at high doses. Therefore, in our opinion, pharmacokinetic bioequivalence to support regulatory approvals of inhalation products at doses above the recommended single maximum dose should be avoided. Furthermore, the bioequivalence of products (if any) established at doses exceeding the approved single maximum doses should be revisited to determine if the products maintain bioequivalence when evaluated at the clinically relevant single maximum doses.

Designing inhaled small molecule drugs for severe respiratory diseases: an overview of the challenges and opportunities.

INTRODUCTION: Inhaled drugs offer advantages for the treatment of respiratory diseases over oral drugs by delivering the drug directly to the lung, thus improving the therapeutic index. There is an unmet medical need for novel therapies for lung diseases, exacerbated by a multitude of challenges for the design of inhaled small molecule drugs. AREAS COVERED: The authors review the challenges and opportunities for the design of inhaled drugs for respiratory diseases with a focus on new target discovery, medicinal chemistry, and pharmacokinetic, pharmacodynamic, and toxicological evaluation of drug candidates. EXPERT OPINION: Inhaled drug discovery is facing multiple unique challenges. Novel biological targets are scarce, as is the guidance for medicinal chemistry teams to design compounds with inhalation-compatible features. It is exceedingly difficult to establish a PK/PD relationship given the complexity of pulmonary PK and the impact of physical properties of the drug substance on PK. PK, PD and toxicology studies are technically challenging and require large amounts of drug substance. Despite the current challenges, the authors foresee that the design of inhaled drugs will be facilitated in the future by our increasing understanding of pathobiology, emerging medicinal chemistry guidelines, advances in drug formulation, PBPK models, and in vitro toxicology assays.

The impact of elexacaftor/tezacaftor/ivacaftor therapy on the pulmonary management of adults with cystic fibrosis: An expert-based Delphi consensus.

BACKGROUND: The advent of elexacaftor/tezacaftor/ivacaftor (ETI) resulted in unprecedented clinical benefits for eligible adults with CF. As a result, the question of whether chronic treatments can be safely stopped or adapted to this new situation has become a matter of great interest. Our objective was to derive a consensus among Italian experts on the impact of ETI on the current clinical management of CF lung disease. METHODS: From December 2021 to April 2022 a panel of Italian experts endorsed by the national CF scientific society derived and graded a set of statements on the pulmonary management of adults with cystic fibrosis through a modified Delphi methodology. RESULTS: The panel produced 13 statements exploring possible modifications in the fields of inhaled antibiotics and mucoactives; airway clearance and physical activity; chronic macrolides and bronchodilators; and lung transplant referral. The areas that the experts considered most urgent to explore were the impact of ETI on the role of inhaled antibiotics and lung transplant. CONCLUSIONS: The list of priorities that emerged from this study could be useful to guide and inform clinical research on the most urgent area of impact of ETI on CF lung disease and its clinical management.

Heterogenous Intrapulmonary Distribution of Aerosolized Model Compounds in Mice with Bleomycin-Induced Pulmonary Fibrosis.

Background: A distinctive pathological feature of idiopathic pulmonary fibrosis (IPF) is the aberrant accumulation of extracellular matrix components in the alveoli in abnormal remodeling and reconstruction following scarring of the alveolar structure. The current antifibrotic agents used for IPF therapy frequently result in systemic side effects because these agents are distributed, through the blood, to many different tissues after oral administration. In contrast to oral administration, the intrapulmonary administration of aerosolized drugs is believed to be an efficient method for their direct delivery to the focus sites in the lungs. However, how fibrotic lesions alter the distribution of aerosolized drugs following intrapulmonary administration remains largely unknown. In this study, we evaluate the intrapulmonary distribution characteristics of aerosolized model compounds in mice with bleomycin-induced pulmonary fibrosis through imaging the organs and alveoli. Methods: Aerosolized model compounds were administered to mice with bleomycin-induced pulmonary fibrosis using a Liquid MicroSprayer®. The intrapulmonary distribution characteristics of aerosolized model compounds were evaluated through several imaging techniques, including noninvasive lung imaging using X-ray computed tomography, ex vivo imaging using zoom fluorescence microscopy, frozen tissue section observation, and three-dimensional imaging with tissue-clearing treatment using confocal laser microscopy. Results: In fibrotic lungs, the aerosolized model compounds were heterogeneously distributed. In observations of frozen tissue sections, model compounds were observed only in the fibrotic foci near airless spaces called honeycombs. In three-dimensional imaging of cleared tissue from fibrotic lungs, the area of the model compound in the alveolar space was smaller than in healthy lungs. Conclusion: The intrapulmonary deposition of extracellular matrix associated with pulmonary fibrosis limits the intrapulmonary distribution of aerosolized drugs. The development of delivery systems for antifibrotic agents to improve the distribution characteristics in fibrotic foci is necessary for effective IPF therapy.

Harnessing inhaled nanoparticles to overcome the pulmonary barrier for respiratory disease therapy.

The lack of effective treatments for pulmonary diseases presents a significant global health burden, primarily due to the challenges posed by the pulmonary barrier that hinders drug delivery to the lungs. Inhaled nanomedicines, with their capacity for localized and precise drug delivery to specific pulmonary pathologies through the respiratory route, hold tremendous promise as a solution to these challenges. Nevertheless, the realization of efficient and safe pulmonary drug delivery remains fraught with multifaceted challenges. This review summarizes the delivery barriers associated with major pulmonary diseases, the physicochemical properties and drug formulations affecting these barriers, and emphasizes the design advantages and functional integration of nanomedicine in overcoming pulmonary barriers for efficient and safe local drug delivery. The review also deliberates on established nanocarriers and explores drug formulation strategies rooted in these nanocarriers, thereby furnishing essential guidance for the rational design and implementation of pulmonary nanotherapeutics. Finally, this review cast a forward-looking perspective, contemplating the clinical prospects and challenges inherent in the application of inhaled nanomedicines for respiratory diseases.

Evaluation of Different Doses in Inhaled Therapy: A Comprehensive Analysis.

BACKGROUND: Currently, there is a considerable degree of confusion over the dosage of inhaled medications. Here, we carried out a review of all the doses used for the devices used in inhalation therapy. METHODS: We first performed a systematic search of the different inhalation devices included on the July 2023 Spanish Ministry of Health Billing List. We then consulted the Spanish Agency for Medicines and Health Products to find the updated official label and to obtain the information on the exact composition. RESULTS: We identified 90 unique products, of which 22 were long-acting bronchodilators (and combinations thereof) and 68 were products containing inhaled corticosteroids (ICS). Overall, 10 products with bronchodilators and 40 with ICS were marketed with the metered dose, while 11 with bronchodilators and 28 with ICS were marketed with the delivered dose. In addition, in some bronchodilators, the drug was referred to as a type of salt, whereas in others the information referred to the drug itself. CONCLUSIONS: Our data show that for each inhaled drug there may be up to four different doses and that the marketed name may refer to any of these. Clinicians must be aware of these different dosages when prescribing inhaled medications.

Deposition and Clinical Impact of Inhaled Particles in the Lung

Particles suspended in the air we breathe are deposited in the airways as a function of the properties of the particle itself (shape, size and hydration), inspiratory air flow, airway anatomy, breathing environment, and mucociliary clearance. The scientific study of the deposition of inhaled particles in the airways has been conducted using traditional mathematical models and imaging techniques with particle markers. In recent years, the integration of statistical and computer methods, giving rise to a new discipline called digital microfluidics, has led to significant advances. In routine clinical practice, these studies are of great use for optimizing inhaler devices in line with particular characteristics of the drug to be inhaled and the pathology of the patient. (AU)

Deposition and Clinical Impact of Inhaled Particles in the Lung.

Particles suspended in the air we breathe are deposited in the airways as a function of the properties of the particle itself (shape, size and hydration), inspiratory air flow, airway anatomy, breathing environment, and mucociliary clearance. The scientific study of the deposition of inhaled particles in the airways has been conducted using traditional mathematical models and imaging techniques with particle markers. In recent years, the integration of statistical and computer methods, giving rise to a new discipline called digital microfluidics, has led to significant advances. In routine clinical practice, these studies are of great use for optimizing inhaler devices in line with particular characteristics of the drug to be inhaled and the pathology of the patient.

Therapeutic drug monitoring of corticosteroids/ß2-agonists in the hair of patients with asthma: an open-label feasibility study.

Background: Although adherence to inhaled medication is critically important for treatment efficiency, around half of patients taking these drugs are non-adherent or make critical errors when using their delivery device. Segmental hair analysis might be a valuable tool for therapeutic monitoring because hair concentrations reflect exposure from month to month. The objective of the present proof-of-concept study was to establish the feasibility of segmental hair analysis of inhaled budesonide and formoterol in asthma patients. Methods: We conducted a prospective, open-label, interventional study of adult patients being treated with budesonide/formoterol for controlled, moderate-to-severe asthma (CorticHair, NCT03691961). Asthma control, lung function, and medication adherence were recorded. Hair samples were taken 4 months after enrolment and cut into four 1 cm segments. Results: Samples were available from 21 patients (20 women; median age: 53; median budesonide dose: 600 µg/d). Budesonide and formoterol were detected in samples from 18 to 13 patients, respectively. The median hair concentrations were 6.25 pg/mg for budesonide and 0.9 pg/mg for formoterol. The intrapatient coefficient of variation between hair segments was 21% for budesonide and 40% for formoterol. Pearson's coefficients for the correlations between the hair concentration and the self-reported drug dose and the prescribed drug dose were respectively 0.42 (p = 0.08) and 0.29 (p = 0.25) for budesonide and 0.24 (p = 0.44) and 0.17 (p = 0.57) for formoterol. Conclusion: Segmental hair analysis of inhaled medications was feasible, with low intrapatient variability. This innovative, non-invasive means of assessing monthly drug exposure might help physicians to personalize drug regimens for patients with difficult-to-treat asthma.

Optimization and Scale Up of Spray Dried CPZEN-45 Aerosol Powders for Inhaled Tuberculosis Treatment.

PURPOSE: Tuberculosis (TB) remains one of the most serious diseases caused by a single organism. Multiple (MDR) and extensively (XDR) drug resistant disease poses a threat to global health and requires new drugs and/or innovative approaches to treatment. A number of drugs have been proposed as inhaled therapy for TB, frequently prepared by spray drying. CPZEN-45 is a novel anti-tubercular drug that has poor oral bioavailability but has shown promise when administered via inhalation. METHODS: Excipient-free CPZEN-45 HCl has been spray dried into a powder with physicochemical characteristics, aerodynamic particle size distribution, and delivered dose suitable for consideration as an inhaled product. RESULTS: The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the powder delivered using a RS01 inhaler were 2.62 ± 0.04 µm and 1.76 ± 0.09, respectively. Additionally, the powder was physically and chemically stable after storage at ambient conditions for >1.5 years with particle size similar to freshly manufactured product. Overages in spray dried powder were recycled the powder and resprayed into drug product likewise resulting in negligible change in quality thus allowing for further preclinical characterization as necessary. CPZEN-45 was scaled up using pilot-scale manufacturing equipment where the density of the powder was increased to facilitate larger delivered doses without affecting the aerodynamic performance properties. CONCLUSION: The spray dried powders were suitable for pharmacokinetics, efficacy and preclinical toxicology studies. The final method of manufacture may be used directly for CGMP particle manufacture to support IND and Phase I clinical trials and beyond.

iBCS: 1. Principles and Framework of an Inhalation-Based Biopharmaceutics Classification System.

For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development of immediate release oral drugs and drug products. This tool is the biopharmaceutics classification system (giBCS). Unfortunately, no such classification system exists for inhaled drugs. The perspective outlined in this manuscript provides the foundational principles and framework for a classification system for inhaled drugs. The proposed classification system, an inhalation-based biopharmaceutics classification system (iBCS), is based on fundamental biopharmaceutics principles adapted to an inhalation route of administration framework. It is envisioned that a classification system for orally inhaled drugs will facilitate an understanding of the technical challenges associated with the development of new chemical entities and their associated new drug products (device and drug formulation combinations). Similar to the giBCS, the iBCS will be based on key attributes describing the drug substance (solubility and permeability) and the drug product (dose and dissolution). This manuscript provides the foundational aspects of an iBCS, including the proposed scientific principles and framework upon which such a system can be developed.

iBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes.

This work is the second in a series of publications outlining the fundamental principles and proposed design of a biopharmaceutics classifications system for inhaled drugs and drug products (the iBCS). Here, a mechanistic computer-based model has been used to explore the sensitivity of the primary biopharmaceutics functional output parameters: (i) pulmonary fraction dose absorbed (Fabs) and (ii) drug half-life in lumen (t1/2) to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (Peff). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes. Drugs with Do < 1 and Peff > 1 × 10-6 cm/s show rapid (t1/2 < 20 min) and complete (Fabs > 85%) absorption from lung lumen into lung tissue. At Do > 1, dissolution becomes a critical drug product attribute and Fabs becomes dependent on regional lung deposition. The input attributes used here, Do and Peff, thus enabled the classification of inhaled drugs into parameter spaces with distinctly different biopharmaceutic risks. The implications of these findings with respect to the design of an inhalation-based biopharmaceutics classification system (iBCS) and to the need for experimental methodologies to classify drugs need to be further explored.

Medicinal chemistry strategies to extend duration of action of inhaled drugs for intracellular targets.

Prolonging duration of action of inhaled drugs is a challenging endeavor and guidance for medicinal chemistry teams is very limited, particularly if the site of action is intracellular. Herein, we identified recent literature reports of newly designed inhaled compounds with intracellular targets and summarized learnings from different approaches and strategies undertaken by medicinal chemistry teams. We highlight key properties that have shown to lead to longer duration of action and provide guidance on the best strategy to follow while designing a new inhaled drug with an intracellular target.

New progress of airway management in children with cystic fibrosis / 中华实用儿科临床杂志

Cystic fibrosis (CF) is a multisystem disease mainly caused by pathogenic mutation of the cystic fibrosis transmembrane conduction regulator gene.In recent years, with the deepened understanding of the disease and the popularization of gene detection technology, an increasing number of children are diagnosed with CF in China.Lung involvement is reported to affect the prognosis of the disease.Lung involvement is closely related to the airway, and good airway management can prolong the life of children.In this paper, the selection of airway clearance techniques and inhaled drugs were expounded, so as to improve the long-term airway management of children with CF in China.

Clinical trials of inhalation in pediatric population in China / 中国临床药理学与治疗学

AIM: To investigate the characteristics of clinical trials of inhalation in pediatric population in China. METHODS: The pediatric clinical trials of inhaled drugs in China registered on the www.Chinadrugtrials.org.cn and Clinical Trials in USA respectively until November 20, 2021 were reviewed. The characteristics of pediatric clinical trials of inhaled drugs including the clinical trial phases, drug indications and classificatio etc. were analyzed. RESULTS: There were 21 pediatric clinical trials of inhaled drugs registered on the www.Chinadrugtrials.org.cn, accounted for 8.9%(21/235) of inhalation clinical trials in all populations. 47.6% of them were generic drugs, mainly focusing on expectorants for Phlegm symptoms and inhaled preparations for asthma, which accounting for 71.4%(15/21). There were 34 pediatric clinical trials of inhaled drugs registered on the Clinical Trials in USA, the drug indications of which were mainly asthma and anesthesia, accounting for 76.5%(26/34). CONCLUSION: The pediatric clinical trials of inhalations in China started later, and the total number is small compared to adults, mainly focusing on generic drugs. We should pay attention to the research and development of new inhalation drugs, standardizing and promoting the clinical trials of inhaled drugs in pediatric population actively.

Aerosol delivery via invasive ventilation: a narrative review.

In comparison with spontaneously breathing non-intubated subjects, intubated, mechanically ventilated patients encounter various challenges, barriers, and opportunities in receiving medical aerosols. Since the introduction of mechanical ventilation as a part of modern critical care medicine during the middle of the last century, aerosolized drug delivery by jet nebulizers has become a common practice. However, early evidence suggested that aerosol generators differed in their efficacies, and the introduction of newer aerosol technology (metered dose inhalers, ultrasonic nebulizer, vibrating mesh nebulizers, and soft moist inhaler) into the ventilator circuit opened up the possibility of optimizing inhaled aerosol delivery during mechanical ventilation that could meet or exceed the delivery of the same aerosols in spontaneously breathing patients. This narrative review will catalogue the primary variables associated with this process and provide evidence to guide optimal aerosol delivery and dosing during mechanical ventilation. While gaps exist in relation to the appropriate aerosol drug dose, discrepancies in practice, and cost-effectiveness of the administered aerosol drugs, we also present areas for future research and practice. Clinical practice should expand to incorporate these techniques to improve the consistency of drug delivery and provide safer and more effective care for patients.

Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 µm (A-4.5), 3.8 µm (B-3.8), and 3.7 µm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 µg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0-Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0-Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).

Drug metabolism in the lungs: opportunities for optimising inhaled medicines.

INTRODUCTION: The lungs possess many xenobiotic metabolizing enzymes which influence the pharmacokinetics and safety of inhaled medicines. Anticipating metabolism in the lungs provides an opportunity to optimize new inhaled medicines and overcome challenges in their development. AREAS COVERED: This article summarizes current knowledge on xenobiotic metabolizing enzymes in the lungs. The impact of metabolism on inhaled medicines is considered with examples of how this impacts small molecules, biologics and macromolecular formulation excipients. Methods for measuring and predicting xenobiotic lung metabolism are critically reviewed and the potential for metabolism to influence inhalation toxicology is acknowledged. EXPERT OPINION: Drugs can be optimized by molecular modification to (i) reduce systemic exposure using a 'soft drug' approach, (ii) improve bioavailability by resisting metabolism, or (iii) use a prodrug approach to overcome pharmacokinetic limitations. Drugs that are very labile in the lungs may require a protective formulation. Some drug carriers being investigated for PK-modification rely on lung enzymes to trigger drug release or biodegrade. Lung enzyme activity varies with age, race, smoking status, diet, drug exposure and preexisting lung disease. New experimental technologies to study lung metabolism include tissue engineered models, improved analytical capability and in silico models.

Co-medications and Drug-Drug Interactions in People Living with HIV in Turkey in the Era of Integrase Inhibitors.

BACKGROUND: Long life expectancy in people living with human immunodeficiency virus (PLWH) caused an increase in comorbidities and co-medications. We aimed to analyse comedications and drug-drug interactions (DDIs) in antiretroviral therapy (ART)-naive PLWH in the era of integrase inhibitors. METHODS: A retrospective observational study was conducted between January 2016-August 2019. Patients' characteristics and chronic co-medications were recorded. The University of Liverpool HIV drug interaction database was used for DDIs. RESULTS: Among 745 patients, the chronic co-medication rate was 30.9%. Older age (p<0.001, OR:6.66, 95% CI: 3.86-11.49) and female gender (p=002, OR:2.25, 95%:1.14-4.44) were independently associated with co-medication. Cardiovascular system (CVS) and central nervous system (CNS) drugs were the most common co-medications. Older age patients (p<0.001, OR:12.04, 95% CI:4.63-36.71), having heterosexual (HS) contact (p=0.003, OR:3.8, 95% CI:1.57-9.22) were independently associated with CVS drugs use, while being men who have sex with men (MSM) (p=0.03, OR:2.59, 95% CI:1.11-6.03) were associated with CNS drugs use. DDIs were seen in 37.4% of patients with co-medications. Antidiabetics (23.3%), CNS (22.1%) and CVS drugs (19.8%) most commonly had DDIs. Contraindication was most commonly seen between inhaled corticosteroids and elvitegravir/cobicistat. A number of non-ART drugs, elvitegravir/cobicistat, antidiabetics, vitamins were independently associated with the presence of DDIs. CONCLUSION: Results suggested the need for attention about co-medication in PLWH regardless of whether they are young or older. CNS drugs should be questioned more detailed in MSM, as well as CVS drugs in older HS patients. Elvitegravir/cobicistat is significantly associated with DDIs and switching to an unboosted INSTI should be considered in patients with multiple comorbidities.

Estimated dermal exposure to nebulized pharmaceuticals for a simulated home healthcare worker scenario.

The duties of home healthcare workers are extensive. One important task that is frequently performed by home healthcare workers is administration of nebulized medications, which may lead to significant dermal exposure. In this simulation study conducted in an aerosol exposure chamber, we administered a surrogate of nebulizer-delivered medications (dispersed sodium chloride, NaCl) to a patient mannequin. We measured the amount of NaCl deposited on the exposed surface of the home healthcare worker mannequin, which represented the exposed skin of a home healthcare worker. Factors such as distance and position of the home healthcare worker, room airflow rate and patient's inspiratory rate were varied to determine their effects on dermal exposure. There was a 2.78% reduction in dermal deposition for every centimeter the home healthcare worker moved away from the patient. Increasing the room's air exchange rate by one air change per hour increased dermal deposition by about 2.93%, possibly due to a decrease in near field particle settling. For every 10-degrees of arc the home healthcare worker is positioned from the left side of the patient toward the right and thus moving into the ventilation airflow direction, dermal deposition increased by about 4.61%. An increase in the patient's inspiratory rate from 15-30 L/min resulted in an average of 14.06% reduction in dermal deposition for the home healthcare worker, reflecting a relative increase in the aerosol fraction inhaled by the patient. The findings of this study elucidate the interactions among factors that contribute to dermal exposure to aerosolized pharmaceuticals administered by home healthcare workers. The results presented in this paper will help develop recommendations on mitigating the health risks related to dermal exposure of home healthcare workers.