iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products.

In this article, we specify for the first time a quantitative biopharmaceutics classification system for orally inhaled drugs. To date, orally inhaled drug product developers have lacked a biopharmaceutics classification system like the one developed to navigate the development of immediate release of oral medicines. Guideposts for respiratory drug discovery chemists and inhalation product formulators have been elusive and difficult to identify due to the complexity of pulmonary physiology, the intricacies of drug deposition and disposition in the lungs, and the influence of the inhalation delivery device used to deliver the drug as a respirable aerosol. The development of an inhalation biopharmaceutics classification system (iBCS) was an initiative supported by the Product Quality Research Institute (PQRI). The goal of the PQRI iBCS working group was to generate a qualitative biopharmaceutics classification system that can be utilized by inhalation scientists as a "rule of thumb" to identify desirable molecular properties and recognize and manage CMC product development risks based on physicochemical properties of the drug and the deposited lung dose. Herein, we define the iBCS classes quantitatively according to the dose number and permeability. The proposed iBCS was evaluated for its ability to categorize marketed inhaled drugs using data from the literature. The appropriateness of the classification of each drug was assessed based on published development, clinical and nonclinical data, and mechanistic physiologically based biopharmaceutics modeling. The inhaled drug product development challenges for each iBCS classification are discussed and illustrated for different classes of marketed inhaled drugs. Finally, it is recognized that discriminatory laboratory methods to characterize regional lung deposition, dissolution, and permeability will be key to fully realizing the benefits of an iBCS to streamline and derisk inhaled drug development.

Opioid Dependence and Overdose After Surgery: Rate, Risk Factors, and Reasons.

OBJECTIVE: To determine: (1) incidence of " opioid never events " ( ONEs ), defined as the development of opioid dependence or overdose in an opioid-naive surgical patient who is prescribed opioids postoperatively and (2) risk factors predicting ONEs. BACKGROUND: Patients receiving opioids after surgery are at risk of experiencing life-threatening opioid-related adverse events. METHODS: An electronic medical record review identified surgical patients at an academic medical center between January 1, 2015, and December 31, 2018, followed through March 31, 2020. ONEs were determined by International Classification of Diseases, Ninth/10th Revision (ICD-9/10) codes, and electronic medical record review. RESULTS: A total of 35,335 opioid-naive surgical patients received a perioperative opioid prescription. The median follow-up was 3.47 years (range: 1.25-5.25 years). ONEs occurred in 0.19% (67/35,335) of patients. The ONE rate was 5.6 per 10,000 person-years of follow-up. Ten of 67 ONE patients overdosed on opioids. The median time to ONE was 1.6 years; the highest ONE rate was observed 1 to 2 years after surgery. In multivariate analysis, patients receiving opioid prescriptions 90 to 180 or 90 to 360 days after surgery had the highest risk of developing ONEs [hazard ratio (HR)=6.39, confidence interval (CI): 3.72-10.973; HR=6.87, CI: 4.24-11.12, respectively]. Surgical specialty (HR=5.21, 2.65-0.23) and patient age (HR=4.17, CI: 2.50-6.96) were also risk factors for ONEs. Persistent opioid use 90 to 360 days after surgery was present in 45% of patients developing ONEs. CONCLUSIONS: Postoperative opioid dependence or overdose is a significant health problem, affecting roughly 2 per 1000 opioid-naive surgical patients prescribed an opioid and followed for 5 years. Risk factors for the development of ONEs include opioid use 3 to 12 months after surgery, patient age, and surgical procedure.

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.

Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation.

BACKGROUND: Allograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure. METHODS: This multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis. FINDINGS: avddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%-9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6-19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable. INTERPRETATION: Lung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure. FUND: National Institutes of Health.

Inhaled formulation and device selection: bridging the gap between preclinical species and first-in-human studies.

The factors that influence inhaled first-in-human (FIH) device and formulation selection often differ significantly from the factors that have influenced the preceding preclinical experiments and inhalation toxicology work. In order to minimize the risk of delivery issues negatively impacting a respiratory pipeline program, the preclinical and FIH delivery systems must be considered holistically. This topic will be covered in more detail in this paper. Several examples will be presented that highlight how appropriate scientific strategy can help bridge the gap between delivering to preclinical species and human. Considerations for the FIH device selection (metered dose inhaler, dry powder inhaler and nebulizer) and formulation optimization for small molecules will be discussed in context with the preclinical delivery systems.

Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis.

BACKGROUND: Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation. METHODS: We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs. RESULTS: Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels. CONCLUSION: Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.

Mixed Reality Meets Pharmaceutical Development.

As science evolves, the need for more efficient and innovative knowledge transfer capabilities becomes evident. Advances in drug discovery and delivery sciences have directly impacted the pharmaceutical industry, though the added complexities have not shortened the development process. These added complexities also make it difficult for scientists to rapidly and effectively transfer knowledge to offset the lengthened drug development timelines. While webcams, camera phones, and iPads have been explored as potential new methods of real-time information sharing, the non-"hands-free" nature and lack of viewer and observer point-of-view render them unsuitable for the R&D laboratory or manufacturing setting. As an alternative solution, the Microsoft HoloLens mixed-reality headset was evaluated as a more efficient, hands-free method of knowledge transfer and information sharing. After completing a traditional method transfer between 3 R&D sites (Rahway, NJ; West Point, PA and Schnachen, Switzerland), a retrospective analysis of efficiency gain was performed through the comparison of a mock method transfer between NJ and PA sites using the HoloLens. The results demonstrated a minimum 10-fold gain in efficiency, weighing in from a savings in time, cost, and the ability to have real-time data analysis and discussion. In addition, other use cases were evaluated involving vendor and contract research/manufacturing organizations.

Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation.

BACKGROUND: Use of new genomic techniques in clinical settings requires that such methods are rigorous and reproducible. Previous studies have shown that quantitation of donor-derived cell-free DNA (%ddcfDNA) by unbiased shotgun sequencing is a sensitive, non-invasive marker of acute rejection after heart transplantation. The primary goal of this study was to assess the reproducibility of %ddcfDNA measurements across technical replicates, manual vs automated platforms, and rejection phenotypes in distinct patient cohorts. METHODS: After developing and validating the %ddcfDNA assay, we subjected the method to a rigorous test of its reproducibility. We measured %ddcfDNA in technical replicates performed by 2 independent laboratories and verified the reproducibility of %ddcfDNA patterns of 2 rejection phenotypes: acute cellular rejection and antibody-mediated rejection in distinct patient cohorts. RESULTS: We observed strong concordance of technical-replicate %ddcfDNA measurements across 2 independent laboratories (slope = 1.02, R2 > 0.99, p < 10-6), as well as across manual and automated platforms (slope = 0.80, R2 = 0.92, p < 0.001). The %ddcfDNA measurements in distinct heart transplant cohorts had similar baselines and error rates. The %ddcfDNA temporal patterns associated with rejection phenotypes were similar in both patient cohorts; however, the quantity of ddcfDNA was significantly higher in samples with severe vs mild histologic rejection grade (2.73% vs 0.14%, respectively; p < 0.001). CONCLUSIONS: The %ddcfDNA assay is precise and reproducible across laboratories and in samples from 2 distinct types of heart transplant rejection. These findings pave the way for larger studies to assess the clinical utility of %ddcfDNA as a marker of acute rejection after heart transplantation.

The in vitro and in vivo investigation of a novel small chamber dry powder inhalation delivery system for preclinical dosing to rats.

PURPOSE: This research describes a novel "minitower" dry powder delivery system for nose-only delivery of dry powder aerosols to spontaneously breathing rats. METHODS: The minitower system forces pressurized air through pre-filled capsules to deliver aerosolized drug to four nose ports; three of which house spontaneously breathing rats, with the fourth used as a control. Within each port are vent filters which capture drug that was not inhaled for further quantitation. These vent filters along with a novel control system referred to as the "artificial rat lung", allow for the theoretical amount of drug delivered and subsequently inhaled by each rat to be calculated. RESULTS: In vitro and in vivo studies have demonstrated this system's ability to deliver aerosolized drug to rats. The in vitro study showed that ∼30% of the starting dose reached the 4 ports and was available for inhalation. During in-vivo studies, rats inhaled ∼34% of the delivered dose. Of the estimated inhaled dose, 12-18% was detectable in the various tissue samples, with over 30% of the recovered dose found in the rat's lungs. CONCLUSION: Results show that this system is capable of reproducibly delivering drug to the lungs of spontaneously breathing rats. Advantages over current delivery methods include being amenable to the administration of multiple doses and using less (milligram) amount of starting material. In addition, this technique avoids anesthesia which is typically required for instillation or insufflation, and thus has the potential as an efficient and noninvasive aerosol delivery method for preclinical drug development.

The in vitro and in vivo investigation of inhaled migraine therapies using a novel aerosol delivery system consisting of an air pressurized capsule device (APCD) in combination with a pMDI spacer for endotracheal dosing into beagle dogs.

CONTEXT: Aerosol delivery to animals in preclinical settings has historically been very challenging, requiring the use of techniques, such as intratracheal instillation and dry powder insufflation, that are somewhat invasive, inefficient and not representative of clinical inhalation. OBJECTIVE: The objective of this work is to develop a system to deliver dry powder to dogs in an efficient and effective manner for the study of new anti-migraine compounds in development. MATERIALS AND METHODS: The new device uses a metered aliquot of a dry gas to force dry powder drug from a pre-filled HPMC capsule into an AeroChamber® spacer for subsequent inhalation by the animal. RESULTS: The delivery of two invesigational migraine drugs via the new device was assessed in vitro using abbreviated Andersen cascade impaction and showed the device is capable of generating a reproducible delivered dose of up to ∼68% with more than 50% of the dose in the respirable range. In vivo studies have also been performed showing that this device effectively delivered the migraine drugs to spontaneously breathing dogs using a proprietary validated dog inhalation model. DISCUSSION: Results confirmed that the air pressurized capsule device (APCD) was effective in delivering the APIs to lungs of the animals. The in vivo data verified the advantages of inhaled delivery over oral delivery for this class of drugs and were used to establish the cardiopulmonary and respiratory side effect liability profile for these compounds. CONCLUSIONS: This work has demonstrated the utility of this device for quick and accurate screening of prospective drug candidates, representing a significant improvement in ease of use and reprodicibility over current delivery methods.

An Unusual Extranodal Presentation of Mycobacterium Tuberculosis in the Upper Lip.

Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide, with a peak incidence in South-East Asia and Sub- Saharan Africa. A significant number of patients in the UK are affected. Extra-pulmonary TB presentation varies, and includes head and neck manifestations that can present on routine examination in the dental practice setting. We report an unusual case of extra-nodal TB in the upper lip, and provide some guidance to general dental practitioners on the presenting features of such lesions, and what to refer for further investigation where TB is included in the differential diagnosis. CPD/CLINICAL RELEVANCE: This case report highlights important factors in TB diagnosis, with particular emphasis on presenting features relevant to general dental practitioners, and informs on the accepted and current treatment regimen.

Orally inhaled fixed-dose combination products for the treatment of asthma and chronic obstructive pulmonary disease: not simple math.

Over the past decade, orally inhaled fixed-dose combination products (FDCs) have emerged as an important therapeutic class for the treatment of asthma and chronic obstructive pulmonary disease. However, the conceptual simplicity of inhaled FDCs belies both the complexity of their development, and the profound advantages they offer patients. The benefits of combining agents are not merely additive, and range from increased compliance via simple convenience to complex receptor-level synergies. Similarly, though, the development challenges often exceed the sum of their parts. FDC formulation and analytical method development is generally more complex than for two monotherapy products. Likewise, FDC clinical programs can easily eclipse those of their monotherapy peers and their inherent complexity is often furthered by the diverse regulatory requirements for worldwide approval. As such, the proposition of developing an orally inhaled FDC for global registration often represents a significant increase in both the potential rewards and assumed risks of drug development.

Peroneal perforator flap for intraoral reconstruction.

Thin and pliable flaps with long, high calibre pedicles are ideally suited to lining the inside of the mouth. The radial forearm free flap has been our flap of choice until now, but we are unhappy with its potential for complications at the donor site. As an alternative, 30 patients have been treated in our unit with peroneal perforator flaps. Magnetic resonance (MR) angiography is necessary preoperatively to identify major perforating vessels. Flaps were raised using a lateral approach after the position of the most suitable perforator had been marked on the skin. The skin flaps were outlined in the proximal half of the lower leg with a maximum width of 5 cm to allow for direct closure of the wound. Five patients (of the original 35) were excluded after the results of MR angiography were known. All perforators identified on MR angiography could be exposed in the proximal half of the lower leg and most had a septocutaneous course. Reconstructions were in the floor of the mouth (n=16), tongue (n=11), and buccal mucosa (n=3). All but one flap survived with satisfactory functional results. The donor site morbidity was low. With the aid of MR angiography the peroneal perforator flap is a safe option for intraoral reconstruction. For small and medium sized defects we think that this flap is a good alternative to others, particularly if direct closure at an inconspicuous donor site is desired.

Atypical fibroxanthoma: Case series of 16 patients.

Atypical fibroxanthoma is an unusual tumour of skin seen mainly in the head and neck region of elderly patients. Clinically it appears as red, ulcerated nodules, which can be difficult to differentiate from other tumours without histopathological examination. Immunohistochemical analysis also aids diagnosis. The mainstay of treatment is operation. We present a case series of 16 patients with 17 atypical fibroxanthomas over a 5-year period in a district general hospital.

Role of CT angiography and embolisation in the management of life-threatening haemorrhage following microvascular head and neck reconstruction.

Post-operative haemorrhage in the head and neck cancer patient can have a catastrophic outcome either for the patient or the free flap if microvascular reconstruction has been performed. The life of the patient always takes priority over the flap; however the pedicle can be at risk when the patient is returned to theatre for arrest of the haemorrhage. CT angiography is a good non-invasive method of determining the source of bleeding and facilitating superselective embolisation, minimizing risk to the flap pedicle. We present a case which this treatment was successfully used with a good result and would recommend its use when similar situations occur.