A compendium and review of pediatric pulmonary function testing assessment opportunities for asthma.

OBJECTIVE: Standard spirograms are widely used in the respiratory disease management community to help diagnosis asthma and provide longitudinal information. Surprisingly, basic information obtained on the spirogram, beyond the FEV1 and change in FEV1 after bronchodilator is underutilized. We reviewed information on pulmonary function and bronchodilator response in children since 2016. We present here a discussion of other element of the standard spirogram that can be used for pediatric asthma management.Methods: Medline search of pulmonary function, children, adolescents, bronchodilator reversibility, small airway disease, small airway function, asthma, airflow limitation, bronchodilator response. Studies since 2016 that provide information on normal or asthmatic children bronchodilator response, and/or small airway or pulmonary function values after albuterol. RESULTS: Limited data has been published on FEV1 bronchodilator response in children since 2016. Other parameters of the pulmonary function test in children have had recent documentation. CONCLUSIONS: New data on FEV1 bronchodilator response in normal children is limited since 2016. However, other details of pulmonary function interpretation in asthmatic children has had considerable attention, and are reviewed here.

Clinical and Inflammatory Features of Exacerbation-Prone Asthma: A Cross-Sectional Study Using Multidimensional Assessment.

BACKGROUND: Reducing asthma exacerbations is a major target of current clinical guidelines, but identifying features of exacerbation-prone asthma (EPA) using multidimensional assessment (MDA) is lacking. OBJECTIVE: To systemically explore the clinical and inflammatory features of adults with EPA in a Chinese population. METHODS: We designed a cross-sectional study using the Severe Asthma Web-based Database from the Australasian Severe Asthma Network (ASAN). Eligible Chinese adults with asthma (n = 546) were assessed using MDA. We stratified patients based on exacerbation frequency: none, few (1 or 2), and exacerbation prone (≥3). Univariate and multivariable negative binomial regression analyses were performed to investigate features associated with the frequency of exacerbations. RESULTS: Of 546 participants, 61.9% had no exacerbations (n = 338), 29.6% had few exacerbations (n = 162), and 8.4% were exacerbation prone (n = 46) within the preceding year. EPA patients were characterized by elevated blood and sputum eosinophils but less atopy, with more controller therapies but worse asthma control and quality of life (all p < 0.05). In multivariable models, blood and sputum eosinophils (adjusted rate ratio = 2.23, 95% confidence interval = [1.26, 3.84] and 1.67 [1.27, 2.21], respectively), FEV1 (0.90 [0.84, 0.96]), bronchodilator responsiveness (1.16 [1.05, 1.27]), COPD (2.22 [1.41, 3.51]), bronchiectasis (2.87 [1.69, 4.89]), anxiety (2.56 [1.10, 5.95]), and depression (1.94 [1.20, 3.13]) were found. Further, upper respiratory tract infection (1.83 [1.32, 2.54]) and food allergy (1.67 [1.23, 2.25]) were at high risk of asthma symptom triggers. CONCLUSION: EPA is a clinically recognizable phenotype associated with several recognizable traits that could be addressed by targeted treatment.

Tiotropium in asthma: From bench to bedside.

OBJECTIVE: Tiotropium is a long-acting muscarinic antagonist approved for maintenance treatment of asthma in children, adolescents, and adults in the United States, and recommended as add-on treatment for uncontrolled asthma despite treatment with inhaled corticosteroids and/or long-acting beta-2 agonists. This review traces the journey of tiotropium from its historical origins through early preclinical testing to human clinical trials and real-life studies. DATA SOURCES: A search was performed in PubMed using search terms 'tiotropium' and 'asthma.' Relevant references cited in those articles were reviewed. STUDY SELECTIONS: English language articles published from December 2008-December 2018 were screened. Articles evaluating the efficacy, cost-effectiveness, real-life evidence, and steroid-sparing effect of tiotropium with inadequately controlled asthma were included. RESULTS: Anticholinergics have a long history of use in the treatment of obstructive airway diseases. Evidence indicates that tiotropium's mechanism of action consists of bronchodilation and diminished mucus secretion, with preclinical evidence suggesting an anti-inflammatory effect as well. Phase 2 and 3 clinical trials have demonstrated that tiotropium is efficacious and safe, resulting in significant improvements in lung function in adults, adolescents, and children across asthma severities. Emerging evidence suggests that add-on tiotropium might potentially enable reductions in inhaled corticosteroid dose in patients with uncontrolled asthma. Further, tiotropium is a cost-effective treatment option that is also effective in the clinical practice setting. CONCLUSIONS: An increasing body of evidence indicates that tiotropium can play a significant role in the treatment of patients with uncontrolled asthma.

GOLD assessment of COPD severity in the Clinical Practice Research Datalink (CPRD).

PURPOSE: To evaluate availability of spirometry and symptom data in the Clinical Practice Research Datalink (United Kingdom) to assess COPD severity using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016 definition and comparing it with an algorithm used in other studies. METHODS: This was a descriptive, noninterventional, secondary database cohort study of patients with COPD aged 40 years or older, who initiated treatment with specific COPD medications. Patients were classified according to COPD severity (1) in GOLD 2016 "ABCD" categories based on symptoms (Medical Research Council dyspnea grade, COPD Assessment Test, breathlessness), percent predicted FEV1, and exacerbation history and (2) as mild, moderate, severe, or very severe based on treatment and exacerbation history. RESULTS: The study included 63 900 patients with COPD aged 40 years or older that were new users of 1 or more COPD medication of interest. Percent predicted FEV1 was available for 80.9% of patients; symptoms for 75.6% of patients. Classification into GOLD 2016 ABCD categories was possible for 75.6% of the patients. The GOLD 2016 ABCD definition classified more patients under the high-risk categories (22.1%, A; 18.8%, B; 21.3%, C; 37.9%, D) than did the adapted algorithm (7.9%, mild; 48.6%, moderate; 42.1%, severe; 1.4%, very severe). CONCLUSION: Using our adaptation of the GOLD 2016 COPD severity classification, the information in the Clinical Practice Research Datalink allowed us to ascertain COPD severity in approximately 75% of patients with COPD. Algorithms that include medication use tend to misclassify patients with the extreme COPD severity categories.

Novel approach to continuous adventitious respiratory sound analysis for the assessment of bronchodilator response.

BACKGROUND: A thorough analysis of continuous adventitious sounds (CAS) can provide distinct and complementary information about bronchodilator response (BDR), beyond that provided by spirometry. Nevertheless, previous approaches to CAS analysis were limited by certain methodology issues. The aim of this study is to propose a new integrated approach to CAS analysis that contributes to improving the assessment of BDR in clinical practice for asthma patients. METHODS: Respiratory sounds and flow were recorded in 25 subjects, including 7 asthma patients with positive BDR (BDR+), assessed by spirometry, 13 asthma patients with negative BDR (BDR-), and 5 controls. A total of 5149 acoustic components were characterized using the Hilbert spectrum, and used to train and validate a support vector machine classifier, which distinguished acoustic components corresponding to CAS from those corresponding to other sounds. Once the method was validated, BDR was assessed in all participants by CAS analysis, and compared to BDR assessed by spirometry. RESULTS: BDR+ patients had a homogenous high change in the number of CAS after bronchodilation, which agreed with the positive BDR by spirometry, indicating high reversibility of airway obstruction. Nevertheless, we also found an appreciable change in the number of CAS in many BDR- patients, revealing alterations in airway obstruction that were not detected by spirometry. We propose a categorization for the change in the number of CAS, which allowed us to stratify BDR- patients into three consistent groups. From the 13 BDR- patients, 6 had a high response, similar to BDR+ patients, 4 had a noteworthy medium response, and 1 had a low response. CONCLUSIONS: In this study, a new non-invasive and integrated approach to CAS analysis is proposed as a high-sensitive tool for assessing BDR in terms of acoustic parameters which, together with spirometry parameters, contribute to improving the stratification of BDR levels in patients with obstructive pulmonary diseases.

Assessment of Parasympathetic Activity in Athletes: Comparing Two Different Methods.

INTRODUCTION: A variety of methods are used to assess parasympathetic activity in athletes targeting different organs; however, the reliability of or interchangeability between measurement procedures is not clear. OBJECTIVE: The purpose of this study is to identify the repeatability of two parasympathetic activity measurement procedures, the HR variability during a 4-s exercise test (4sET), and the contractile properties of the pupil (pupillometry), and to assess their agreement. The secondary objective of this study is to assess their relationship with the bronchodilating effect of inhaled ipratropium bromide (iIB), blocking parasympathetic signals to the lungs. METHODS: Forty athletic subjects were enrolled in a cross-sectional study. After 15-min resting in semidarkness, subjects underwent pupillometry (PLR-200™, NeurOptics Inc., CA), followed by 4sET on a cycle ergometer. HR variability was assessed by Polar Electro® HR monitor (RS-800CX/G3; Oy, Kempele, Finland). Both protocols were repeated after 5 min. Statistical analysis was performed according to Bland and Altman and by using Pearson's correlation coefficient and intraclass correlation. Lung function measurements by flow volume curves were performed before and 45 min after iIB. RESULTS: The means of differences were 1.21% (limits of agreement, -3.59 to 6.02) for pupil constriction and 0.05 mm (-0.28 to 0.39) for pupil amplitude. The mean of differences for 4sET was 0.005 (-0.31 to 0.32). A very weak intraclass correlation (r = -0.01, P = 0.58) showed no agreement between the methods. No correlation was observed between pupillometry variables or 4sET with the change in lung function after iIB. CONCLUSION: Pupillometry showed better repeatability compared with the 4sET. There is poor agreement between parasympathetic activity levels measured in three different target organs of athletic subjects; the heart, the pupil, and the lung. Thus, methods assessing parasympathetic activity in different target organs cannot be used interchangeably.

Bronchodilators, receptors and cross-talk: Together is better?

The most widely used maintenance therapies in chronic obstructive pulmonary disease (COPD) are long-acting muscarinic antagonists (LAMAs), and a number of these drugs are now available in combination with long-acting ß2-agonists (LABAs). LAMAs inhibit the parasympathetic muscarinic pathway, while LABAs, as sympathomimetics, reduce airway smooth muscle (ASM) tone. As well as directly controlling the constriction and relaxation of ASM, muscarinic and adrenergic receptors are found on inflammatory cells, and drugs that target these receptors may also reduce inflammation in COPD. Evidence suggests that the muscarinic and adrenergic pathways cross-talk at the level of neuronal input to the ASM via second-messenger pathways within ASM cells. Although the cross-talk is not completely understood, pharmacologically targeting both pathways in COPD can maximize bronchodilation. Combining LAMAs and LABAs demonstrated improved efficacy compared with the individual therapies and so, for greater convenience, several fixed-dose combinations for once-daily use have been developed. These fixed-dose combinations demonstrate improvements in both lung-function and patient-reported outcomes compared with well-established monotherapies, with similar tolerability profiles to the individual agents.

[The assessment of the clinical effectiveness of fenspiride for the treatment of acute obstruction of the Eustachian tube].

The objective of the present study was to estimate the clinical effectiveness of fenspiride used to correct the obstruction of the Eustachian tube in 80 patients presenting with acute tubootitis and exudative otitis media. The algorithm of the examination included the evaluation of the severity of subjective clinical symptoms based on the relevant analog-visual scale, results of tonal audiometry, and tympanometry. The control group was comprised of 34 patients treated with antibacterial preparations, topical decongestants, and transtubal administration of glucocorticoids. The study group included 46 patients who received fenspiride at a dose of 80 mg thrice daily in addition to the above pharmacotherapy. The severity of clinical symptoms in the patients treated with fenspiride decreased faster than in the control subjects. The frequency analysis of dynamics of the air-bone gaps on the audiometric curves revealed the significantly more intensive recovery of the hearing function in the patients treated by basal pharmacotherapy in the combination with fenspiride. Type A tympanograms predominated on day 7 after the onset of the conservative treatment with the use of fenspiride whereas type C tympanograms continued to predominate in the patients of the control group. It is concluded that the introduction of fenspiride into combined therapy of acute tubootitis and exudative otitis media promotes the normalization of the ventilation and drainage functions and relieves the severity of subjective clinical symptoms.

Novel anti-cholinergics in COPD.

Anti-cholinergics have been considered the first-choice bronchodilator therapy in the routine management of stable COPD. Muscarinic cholinergic receptors are expressed on most cell types and mediate cellular signalling via the natural ligand, acetylcholine. Antagonising cholinergic receptors may not only result in bronchodilation, but also have associated localised activity. Until recently the licensed anti-cholinergics were limited to ipatropium bromide, oxitropium bromide and tiotropium bromide; the latter being the only once-daily anti-cholinergic. With the patents expired or due to expire shortly several companies have reinitiated efforts to develop safer, long-acting agents potentially improving concordance and pharmaceutical marketing opportunities. The present article reviews a number of novel anti-cholinergics that have been recently licensed and those undergoing development, some in innovative delivery devices.

The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by airflow limitation and chronic inflammation in the lungs. The mainstay of drug therapy for COPD is represented by long-acting bronchodilators, an important aspect of Novartis' development program. Novel once-daily dosing bronchodilators, such as the long-acting muscarinic antagonist (LAMA) glycopyrronium and the LAMA/long-acting ß2-agonist (LABA) fixed-dose combination QVA149, have been shown to provide significant benefits to patients with COPD in terms of improvement in lung function, exercise tolerance, health-related quality of life, symptoms and reduction in the rate of exacerbations. Despite the benefits provided by these new treatment options, prevention of disease progression and control of exacerbations in certain patient phenotypes remain key challenges in the treatment of COPD. In order to address these needs and gain new insights into the complexity of COPD, Novartis is, in addition to bronchodilator-only therapies, developing LABA/inhaled corticosteroids (ICS) combinations to target inflammation, such as QMF149, as well as non-steroid based anti-inflammatory agents against key novel targets. These commitments are central to the Novartis' final goal of improving the standard of care in respiratory medicine and offering a better quality of life to patients with COPD.

Multidetector-row computed tomography assessment of adding budesonide/formoterol to tiotropium in patients with chronic obstructive pulmonary disease.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), multidetector-row computed tomography (MDCT) showed that tiotropium dilated the inner diameters in airways from the third to the sixth generation of the bronchi. Here we aimed to evaluate the morphological effect by adding a budesonide/formoterol combination to tiotropium in COPD patients using three-dimensional MDCT. METHODS: Pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ) and MDCT imaging studies were performed at the beginning and after budesonide/formoterol combination treatment for 12 weeks in 14 patients with COPD. RESULTS: The median age was 73.5 years and the mean forced expiratory volume in 1 s (FEV1) as a percentage of the predicted value was 57.2 ± 18.3%. The luminal area in the fifth generation bronchi and the emphysema volume/CT-derived total lung volume were significantly correlated with FEV1 at baseline (r = 0.682, p < 0.02 and r = -0.868, p < 0.001, respectively). The average luminal area and wall area percentage in the third, fourth and fifth generations were correlated with the SGRQ total score. Budesonide/formoterol induced insignificant pulmonary function changes and significant symptoms improvement. CT images showed an increased inner luminal area and decreased wall area after budesonide/formoterol treatment. Average luminal area was significantly increased from 24.3 ± 9.7 to 26.0 ± 9.9 mm(2) in the third generation, 13.0 ± 6.5 to 14.7 ± 7.3 mm(2) in the fourth generation, 8.0 ± 4.8 to 9.4 ± 4.9 mm(2) in the fifth generation and 5.6 ± 2.7 to 6.7 ± 3.6 mm(2) in the sixth generation (p < 0.01). The average increase of the third generation luminal area was correlated with the FEV1 increase (r = 0.632, p < 0.03). The wall area percentage significantly decreased from 51.5 ± 9.2 to 49.1 ± 9.7 in the third generation, 56.1 ± 9.7 to 53.0 ± 11.1 in the fourth generation, and 62.3 ± 9.9 to 57.6 ± 9.8 in the fifth generation (p < 0.05). Emphysema volume/CT-derived total lung volume was unchanged with treatment. CONCLUSION: MDCT demonstrated budesonide/formoterol induced bronchodilation in the non-small airway. CT imaging can evaluate drug therapeutic effect and may provide additional insights into pharmacotherapy for COPD.

Computed tomography assessment of pharmacological lung volume reduction induced by bronchodilators in COPD.

Pharmacological lung volume reduction in COPD is an important goal in treatment with long-acting bronchodilators because in addition to airflow limitation, lung hyperinflation considerably affects COPD symptoms. Quantitative computed tomography (CT) simultaneously provides structural information about airway dimensions, emphysematous changes, and lung volumes, some of which are difficult to be evaluated by pulmonary function. Here, we evaluated changes in CT parameters and pulmonary function in 30 patients with COPD who underwent CT scans before and one year after starting tiotropium treatment and in 12 patients with COPD who were not treated with long-acting bronchodilators. Baseline pulmonary function and CT parameters did not differ between the two groups. One-year tiotropium therapy improved physiological-indices including residual volume (RV) and ratio of RV to total lung capacity (RV/TLC) (-235 mL, p = 0.005, and -2.9%, p = 0.0001, respectively), and CT-indices including wall area percent (WA%) and inner luminal area in right upper lobe apical and lower lobe basal segmental bronchi (-1.59%, p = 0.01, 2.27 mm(2), p = 0.0005; and -1.33%, p = 0.0008, 3.42 mm(2), p < 0.0001, respectively), low attenuation volume (LAV) and total lung volume (CT-TLV) (-92 mL, p = 0.0003, and -211 mL, p = 0.002, respectively). Changes in LAV, CT-TLV, RV, and RV/TLC were significantly greater in the tiotropium, than the non-bronchodilator group. The tiotropium-induced reduction in LAV correlated with the decrease in RV (ρ = 0.45, p = 0.01). Our findings not only indicate the value of the comprehensive CT measurements in assessing the effects of bronchodilators, including pharmacological lung volume reduction, but also further understanding of the structural changes underlying physiological improvements induced by bronchodilators.

Tiotropium bromide inhalation powder: a review of its use in the management of chronic obstructive pulmonary disease.

The anticholinergic agent tiotropium bromide (Spiriva®) is a long-acting bronchodilator that is indicated for the treatment of chronic obstructive pulmonary disease (COPD). This article reviews the clinical efficacy and tolerability of tiotropium bromide inhalation powder, administered using the HandiHaler® device, in patients with COPD, as well as reviewing its pharmacological properties and the results of pharmacoeconomic analyses. Shorter-term placebo-controlled trials in patients with COPD demonstrated significantly higher trough forced expiratory volume in 1 second (FEV(1)) responses with tiotropium bromide than with placebo, confirming it has a duration of action of ≥24 hours and is suitable for once-daily administration. Lung function improved to a greater extent with tiotropium bromide than with ipratropium bromide or, in most instances, salmeterol. Indacaterol was shown to be noninferior to tiotropium bromide in terms of the trough FEV(1) response. The large, 4-year UPLIFT® trial did not show a significant reduction in the annual rate of decline in FEV(1) with tiotropium bromide versus placebo in patients with COPD, although subgroup analyses demonstrated a significantly lower rate of decline with tiotropium bromide than with placebo in some patient groups (e.g. patients with moderate COPD, patients aged ≥50 years, patients not receiving maintenance therapy at baseline). Tiotropium bromide prevented exacerbations in patients with COPD, with a significantly lower exacerbation rate and a significantly longer time to first exacerbation seen with tiotropium bromide than with placebo or salmeterol. Exacerbation rates did not significantly differ between patients receiving tiotropium bromide and those receiving salmeterol/fluticasone propionate. Tiotropium bromide also had beneficial effects on health-related quality of life (HR-QOL) and other endpoints, such as dyspnoea and rescue medication use. Combination therapy with tiotropium bromide plus formoterol with or without budesonide improved lung function to a significantly greater extent than tiotropium bromide alone in patients with COPD. In addition, exacerbation rates were lower and HR-QOL was improved with tiotropium bromide plus budesonide/formoterol versus tiotropium bromide alone. Although the addition of salmeterol/fluticasone propionate to tiotropium bromide did not reduce the COPD exacerbation rate, it did improve lung function and HR-QOL. Tiotropium bromide inhalation powder is generally well tolerated in patients with COPD, with anticholinergic adverse events (e.g. dry mouth, constipation, gastrointestinal obstruction, dysuria) among the most commonly reported adverse events. The UPLIFT® trial showed no significant difference between tiotropium bromide and placebo recipients in the risk of stroke, and the risk of serious cardiac adverse events (including congestive heart failure and myocardial infarction) was significantly lower with tiotropium bromide than with placebo. The absence of a detrimental effect on cardiovascular outcomes was supported by the results of a meta-analysis and pooled analyses. In addition, on-treatment mortality was lower with tiotropium bromide than with placebo in the UPLIFT® trial. Pooled analyses showed significantly lower cardiovascular mortality with tiotropium bromide than with placebo, with a meta-analysis demonstrating no significant difference between patients receiving tiotropium bromide and controls in cardiovascular mortality. Results of modelled pharmacoeconomic analyses conducted from a healthcare payer perspective in several developed countries suggest that tiotropium bromide is a cost-effective option in patients with COPD. In conclusion, tiotropium bromide inhalation powder is a useful option for the maintenance treatment of patients with COPD.

Cost-effectiveness of combination fluticasone propionate-salmeterol 250/50 microg versus salmeterol in severe COPD patients.

OBJECTIVE: To estimate the cost-effectiveness of fluticasone propionate-salmeterol combination (FSC) compared to salmeterol for maintenance therapy in severe chronic obstructive pulmonary disease (COPD). STUDY DESIGN: Pooled economic analysis. METHODS: We performed an economic analysis of pooled data from two randomized clinical trials (combined N = 1554) that evaluated the effect of maintenance therapy with FSC (250/50 microg twice daily) or salmeterol (50 microg twice daily) on exacerbation rates in patients with severe COPD. We calculated exacerbation rates and applied standardized costs to exacerbation-related health care utilization reported in the trials (office, urgent care, and emergency department visits; hospitalizations; and oral corticosteroids and antibiotics) to determine cost differences between FSC and salmeterol treatment outcomes. RESULTS: Annual rates of any exacerbation and moderate/severe exacerbation were lower in the FSC group than the salmeterol group (4.91 vs 5.78 and 1.32 vs 2.00 respectively, both P < 0.05). Total adjusted annual COPD related exacerbation and therapeutic costs were $4,842 (95% CI; $4,731-$4,952) in the FSC group and $5,066 (95% CI; $4,937-$5,195) in the salmeterol group. CONCLUSIONS: FSC combination therapy is associated with reduced risk of any exacerbation and moderate/severe exacerbation, and incurs lower annual COPD-related health care costs compared to treatment with salmeterol. This analysis demonstrates that FSC therapy may be advantageous from both a clinical and cost-benefit standpoint for patients with severe COPD.

The role of fluticasone propionate/salmeterol combination therapy in preventing exacerbations of COPD.

Exacerbations contribute significantly to the morbidity of COPD, leading to an accelerated decline in lung function, reduced functional status, reduced health status and quality of life, poorer prognosis and increased mortality. Prevention of exacerbations is thus an important goal of COPD management. In patients with COPD, treatment with a combination of the inhaled corticosteroid fluticasone propionate (250 microg) and the long-acting beta(2)-agonist salmeterol (50 microg) in a single inhaler (250/50 microg) is an effective therapy option that has been shown to reduce the frequency of exacerbations, to improve lung function, dyspnea and health status, and to be relatively cost-effective as a COPD maintenance therapy. Importantly, results of various studies suggest that fluticasone propionate and salmeterol have synergistic effects when administered together that improve their efficacy in controlling symptoms and reducing exacerbations. The present non-systematic review summarizes the role of fluticasone propionate/salmeterol combination therapy in the prevention of exacerbations of COPD and its related effects on lung function, survival, health status, and healthcare costs.

A new definition of pharmaceutical quality: assembly of a risk simulation platform to investigate the impact of manufacturing/product variability on clinical performance.

The absence of a unanimous, industry-specific definition of quality is, to a certain degree, impeding the progress of ongoing efforts to "modernize" the pharmaceutical industry. This work was predicated on requests by Dr. Woodcock (FDA) to re-define pharmaceutical quality in terms of risk by linking production characteristics to clinical attributes. A risk simulation platform that integrates population statistics, drug delivery system characteristics, dosing guidelines, patient compliance estimates, production metrics, and pharmacokinetic, pharmacodynamic, and in vitro-in vivo correlation models to investigate the impact of manufacturing variability on clinical performance of a model extended-release theophylline solid oral dosage system was developed. Manufacturing was characterized by inter- and intra-batch content uniformity and dissolution variability metrics, while clinical performance was described by a probabilistic pharmacodynamic model that expressed the probability of inefficacy and toxicity as a function of plasma concentrations. Least-squares regression revealed that both patient compliance variables, percent of doses taken and dosing time variability, significantly impacted efficacy and toxicity. Additionally, intra-batch content uniformity variability elicited a significant change in risk scores for the two adverse events and, therefore, was identified as a critical quality attribute. The proposed methodology demonstrates that pharmaceutical quality can be recast to explicitly reflect clinical performance.