Leveraging Physiologically Based Modelling to Provide Insights on the Absorption of Paliperidone Extended-Release Formulation under Fed and Fasting Conditions.

Paliperidone was approved by the US FDA in 2006 as an extended-release (ER) tablet (Invega®) for the once-daily treatment of schizophrenia. This osmotic-controlled release oral delivery system (OROS) offers advantages, such as the prevention of plasma concentration fluctuation and reduced dosing frequency. The administration of the ER after a high-fat/high-calorie meal leads to increased maximum plasma concentration and area under the curve values by 60% and 54%, respectively. Food has various effects on gastrointestinal (GI) physiology, including changed transit times, changed volumes, altered pH in different GI compartments, secretion of bile salts, and increased hepatic blood flow. This may affect solubility, the dissolution rate, absorption, and the pharmacokinetics. The aim of this study was to apply physiologically based absorption modeling (PBAM) to provide insights on paliperidone ER absorption under fed and fasting conditions. The PBAM adequately predicted absorption from the OROS formulation under both conditions. Absorption primarily occurs in the ascending colon and caecum. After a high-fat/high-calorie meal, absorption is increased through the jejunum, ileum, and colon due to either increased solubilization or the better efficiency of the OROS technology. PBAM-guided approaches can improve the understanding of branded drugs and thereby aid in guiding the development of generic formulations or formulation alternatives.

Application of physiologically based absorption and pharmacokinetic modeling in the development process of oral modified release generic products.

Physiologically based pharmacokinetic (PBPK) modeling for biopharmaceutics applications holds great promise as modelling and simulation tool in the field of modern oral modified release (MR) products. Understanding of gastro-intestinal absorption related processes is crucial to ensure the successful development of complex oral drug generic products. In the recent years, PBPK approach has been gradually influencing decision making ability of pharmaceutical industry as well as regulatory agencies. However, there is a gap in understanding its contribution in the field of oral modified release products. In this review, we have collected different recent research articles illustrating the significant contribution of PBPK to the research and development process of oral MR products, with special emphasis on generic drug products. Concretely, literature examples on the utility of PBPK formulation development, for in vitro- in vivo correlations (IVIVC) and prediction of oral bioavailability, and for in-silico food effect predictions were included in the review.

Clinical Anti-aging Efficacy of Propolis Polymeric Nanoparticles Prepared by a Temperature-induced Phase Transition Method.

BACKGROUND: Collagen forms a dermal matrix in the skin. Biosynthesis and decomposition of collagen are the major processes in skin aging. Propolis is rich in flavonoids and phenolic compounds, which are known to be effective in preventing skin aging, including the enhancement of fibroblast proliferation, activation, and growth capacity. OBJECTIVES: The aim of this study was to develop a poorly soluble propolis extract as an active ingredient in cosmetic products for anti-aging efficacy. METHODS & RESULTS: Polymeric nanoparticles containing propolis extract, polyethylene glycol 400, and poloxamer 407 were prepared via a temperature-induced phase transition method. The particle size of the polymeric nanoparticles was approximately 20.75 nm. The results of an in vitro procollagen type I carboxy-terminal peptide assay and a matrix metalloproteinase-1 inhibition assay showed that the polymeric nanoparticles increased collagen production by 19.81%-24.59% compared to blank (p < 0.05), and significantly reduced intracellular collagenase activity by 7.46%-31.52% compared to blank (p < 0.05). In a clinical trial, polymeric nanoparticles in a cosmetic formulation were applied around the eyes of 24 female subjects for 8 weeks. Five skin parameters were significantly improved after the application of the test ampoule. Visual evaluation using the Global Photo Damage Score showed a significant reduction in wrinkles after the application of the test ampoules (p < 0.001). CONCLUSIONS: This study outlines the development of stable polymeric nanoparticles containing poorly soluble propolis in a cosmetic formulation, and its efficacy in wrinkle improvement. The developed polymeric nanoparticles were effective for alleviating wrinkles and can be used for pharmaceutical applications that utilize propolis as antiseptic, anti-inflammatory, antimycotic, antifungal, antibacterial, antiulcer, anticancer, and immunomodulatory agents.

Application of a dual mechanistic approach to support bilastine dose selection for older adults.

The objective of this study was to evaluate bilastine dosing recommendations in older adults and overcome the limitation of insufficient data from phase I studies in this underrepresented population. This was achieved by integrating bilastine physicochemical, in vitro and in vivo data in young adults and the effect of aging in the pharmacology by means of two alternative approaches: a physiologically-based pharmacokinetic (PBPK) model and a semi-mechanistic population pharmacokinetic (Senescence) model. Intestinal apical efflux and basolateral influx transporters were needed in the PBPK model to capture the observations from young adults after single i.v. (10 mg) and p.o. (20 mg) doses, supporting the hypothesis of involvement of gut transporters on secretion. The model was then used to extrapolate the pharmacokinetics (PKs) to elderly subjects considering their specific physiology. Additionally, the Senescence model was develop starting from a published population PK) model, previously applied for pediatrics, and incorporating declining functions on different physiological systems and changes in body composition with aging. Both models were qualified using observed data in a small group of young elderlies (N = 16, mean age = 68.69 years). The PBPK model was further used to evaluate the dose in older subjects (mean age = 80 years) via simulation. The PBPK model supported the hypothesis that basolateral influx and apical efflux transporters are involved in bilastine PK. Both, PBPK and Senescence models indicated that a 20 mg q.d. dose is safe and effective for geriatrics of any age. This approach provides an alternative to generate supplementary data to inform dosing recommendations in under-represented groups in clinical trials.

Retrospective study evaluating the safety of administering pegfilgrastim on the final day of 5-fluorouracil continuous intravenous infusion.

BACKGROUND: Pegfilgrastim, a long-acting granulocyte-colony-stimulating factor used to prevent neutropenia, is not indicated for administration within 24 h of completion of chemotherapy. The safety of administering pegfilgrastim in gastrointestinal cancer chemotherapy regimens containing continuous intravenous infusion of 5-fluorouracil (5-FUCI) on the day of completion of 5-fluorouracil has not been adequately studied. METHODS: An institutional review board-approved retrospective analysis of patients with a gastrointestinal malignancy receiving pegfilgrastim on the final day of 5-FUCI was conducted. The primary end point was to determine the incidence of grade 3 and grade 4 neutropenia and febrile neutropenia when pegfilgrastim was administered on the final day of 5-FUCI. The secondary endpoint was to determine rate of dose reductions and treatment delays. RESULTS: A total of 300 patients were reviewed from January 2010 to May 2017. The most common cancers were colorectal (25%) and pancreatic (60%), with 77% of patients having late stage disease. The risk of a patient developing grade 3 neutropenia was 0.010 (95% CI 0.002-0.029) and grade 4 neutropenia was 0.007 (95% CI 0.001-0.024). The risk of febrile neutropenia was 0.007 (95% CI 0.001-0.024). The risks of treatment delay and treatment reduction were 0.013 (95% CI 0.004-0.034) and 0.010 (95% CI 0.002-0.029), respectively. CONCLUSION: The low risk of grade 3 and grade 4 neutropenia, febrile neutropenia, as well as dose delays and/or reduction suggests that pegfilgrastim can be administered on the final day of 5-FUCI. Limitations of this study were that it was retrospective in nature and was conducted at a single institution.

Association Between Motor Subtype and Visuospatial and Executive Function in Mild-Moderate Parkinson Disease.

OBJECTIVE: To compare participants with Parkinson disease (PD) motor subtypes, postural instability and gait difficulty (PIGD) (n=46) and tremor dominant (TD) (n=28), in cognitive and motor-cognitive assessments with the purpose of identifying associations between subtype and visuospatial, whole-body spatial, inhibition and/or switching, and planning and/or organizational aspects of cognitive and motor-cognitive function. DESIGN: Retrospective cohort study. Fisher exact test was used for categorical variables, while 2-sample independent t tests were used to analyze continuous variables. SETTING: Assessments took place at Emory University. PARTICIPANTS: Participants (N=72) were 40 years and older, had a clinical diagnosis of PD, exhibited 3 of the 4 cardinal signs of PD, had shown benefit from antiparkinsonian medications, and were in Hoehn and Yahr stages I-IV. Participants could walk 3 m or more with or without assistance. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Balance and mobility tests included Fullerton Advanced Balance Scale and the time needed to turn 360 degrees. Cognitive assessments included Montreal Cognitive Assessment, Brooks Spatial Memory Task, Color-Word Interference Test, Tower of London, Trail Making Test, Corsi Blocks, Serial 3s Subtraction, and Body Position Spatial Task. Motor-cognitive function measures included Four Square Step Test and Timed Up and Go. RESULTS: Participants with PIGD performed lower than those with TD symptoms on mental status (P=.005), spatial memory (P=.027), executive function (P=.0001-.034), and visuospatial ability (P=.048). CONCLUSIONS: Findings suggest that PIGD subtype is linked to greater deficits in spatial cognition, attentional flexibility and organizational planning, and whole-body spatial memory domains. These findings support the need for more personalized approaches to clinically managing PD.

Differentiating Parkinson Disease Subtypes Using Clinical Balance Measures.

BACKGROUND AND PURPOSE: People with Parkinson disease (PD) present phenotypes that are characterized as tremor-dominant (TD) or postural instability/gait difficulty (PIGD) subtypes. Differentiation of subtypes allows clinicians to predict disease course and adjust treatment. We examined whether brief mobility and balance measures can discriminate PIGD from TD phenotypes. METHODS: We performed a cross-sectional study with individuals with PD (n = 104). Blinded raters assessed participants with the Unified Parkinson's Disease Rating Scale (UPDRS) or Movement Disorders Society revision (MDS-UPDRS), and balance assessments: 360° turn test, one-leg stance, a reactive postural control test, and tandem walk. Participants were classified as PIGD or TD based on the UPDRS or MDS-UPDRS assessment results. Differences in balance variables between subtypes were assessed with univariate analyses. Receiver operating characteristic (ROC) curve analyses were performed to investigate the ability of balance variables to differentiate PD subtypes. RESULTS: No differences between subtypes were observed for tandem walk or reactive postural control. Participants with PIGD performed worse on number of steps and time to complete the 360° turn test and on one-leg stance time. ROC curves showed only the 360° turn test discriminated PIGD from TD with high specificity (0.84). Post hoc analyses revealed that the 360° turn test is the most discriminatory for classifying PD subtypes in early stages of the disease. ROC analyses based on combined models including both the 360° test and tandem walk test performance increased the specificity to 0.97. DISCUSSION AND CONCLUSIONS: The 360° turn test requires minimal time to administer and may be useful in mild-moderate PD for distinguishing PIGD from TD subtypes.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A295).

Are Lymph Node Characteristics on Axillary Ultrasound Associated with ≥3 Positive Lymph Nodes in Patients Managed by the American College of Surgeons Oncology Group Z0011 Trial Criteria?

Patients often receive axillary ultrasound-biopsy (AUS-B) before clinical evaluation. One positive biopsy in the absence of palpable disease rarely indicates additional nodal involvement, but it eliminates patients from being managed by the American College of Surgeons Oncology Group Z0011 trial criteria. To determine which patients may benefit from AUS-B, we analyzed whether characteristics on AUS were associated with large-volume axillary disease and, thus, the need for axillary lymph node (LN) dissection. A retrospective review identified patients who met Z0011 criteria and underwent AUS. Clinicopathologic and ultrasound characteristics were compared between patients with ≤2 versus ≥3 positive LNs. Two hundred and seven patients with cT1-2N0 tumors underwent preoperative AUS and breast-conserving surgery. On multivariate analysis, three AUS combinations were associated with ≥3 positive LNs: cortical thickness (CT) > 4 mm + loss of fatty hilum + round shape (P = 0.0218), CT > 4 mm + loss of fatty hilum (P = 0.0211), and CT > 4 mm + round shape (P = 0.0155). Preoperative axillary LN biopsy in patients with a single abnormal LN characteristic on AUS may be unnecessary because a positive finding will eliminate management according to Z0011 criteria. Cortical thickness >4 mm combined with any other abnormal characteristic was associated with ≥3 positive LNs, supporting the performance of AUS-B in this population.

Analysis of Opioid Use Following Curative Cancer Treatment at a Large Urban Safety-net Hospital.

OBJECTIVES: This study examined the pattern of use and factors predicting prolonged prescription opioid medications among cancer patients following treatment with curative intent. MATERIALS AND METHODS: Patients diagnosed with cancer over a 3-year period at a large urban safety-net hospital were included. Univariate and multivariate analyses was used to identify factors associated with continued opioid use. RESULTS: Of the 199 patients included in the study, 38% continued to receive an opioid prescription well beyond the acute diagnosis and treatment phase. Mean age was 60.3 years, with a female preponderance (63%). Surgical resection only (31.6%) and the combination of surgery, chemotherapy, and radiation (19.7%) were the commonest treatment modalities. Pain-related comorbidities predating cancer diagnosis were reported in 53.3% of the patients, and about 33% were also on pain-modifying medications (odds ratio [OR], 3.58; 95% confidence interval [CI], 1.92-6.77; Fisher exact test P<0.001). Average number of prescriptions received per patient was 4.8 (range, 1 to 31), over an average of 9.5 months (range, 1.2 to 28.1 mo). Mean morphine milligram equivalents prescribed per prescription was 319 mg (range, 48 to 2475 mg). According to multivariate model, patients who received chemotherapy (OR, 7.25; 95% CI, 2.09-25.17; P=0.0018), or pain-modifying medications (OR, 4.61; 95% CI, 2.25-9.44; P<0.0001) were significantly more likely to continue to receive prescriptions for opioids. DISCUSSION: Treatment with chemotherapy, pain-modifying medications, cancer stage, and interval between diagnosis and treatment are the best predictors for continuous opioid use. The current epidemic of opioid misuse and abuse makes examination current practices and identifification of areas of improvement imperative.