Advances in Therapy

Current Practices for Outpatient Initiation of Levodopa-Carbidopa Intestinal Gel for Management of Advanced Parkinson's Disease in the United States Abstract In 2015, the US Food and Drug Administration approved levodopa-carbidopa intestinal gel (LCIG; also known as carbidopa-levodopa enteral suspension in the US) for the treatment of motor fluctuations in patients with advanced Parkinson's disease. LCIG provides a continuous infusion of levodopa and carbidopa by means of a portable pump and percutaneous endoscopic gastrojejunostomy tube. The delivery system has a two-fold pharmacokinetic advantage over orally administered carbidopa/levodopa. First, levodopa is delivered in a continuous rather than intermittent, pulsatile fashion. Second, delivery to levodopa's site of absorption in the jejunum bypasses the stomach, thereby avoiding issues with erratic gastric emptying. In blinded prospective clinical trials and observational studies, LCIG has been shown to significantly decrease "off" time, increase "on" time without troublesome dyskinesia, and reduce dyskinesia. Consistent with procedures in previous studies, LCIG initiation and titration in the pivotal US clinical trial were performed in the inpatient setting and followed a standardized protocol. In clinical practice, however, initiation and titration of LCIG have a great degree of flexibility and, in the US, almost always take place in the outpatient setting. Nonetheless, there remains a significant amount of clinician uncertainty regarding titration in outpatient clinical practice. This review aims to shed light on and provide guidance as to the current methods of titration in the outpatient setting, as informed by the medical literature and the authors' experiences. Funding AbbVie, Inc. Plain Language Summary Plain language summary available for this article.

A Randomized, Crossover Study on the Effect of Food on the Pharmacokinetic Characteristics of Morphine ARER (MorphaBond™ ER), an Abuse-Deterrent Formulation of Extended-Release Morphine Abstract Introduction Food can alter the pharmacokinetics of certain abuse-deterrent formulations. Morphine ARER is an oral abuse-deterrent formulation of ER morphine sulfate tablets formulated with physical and chemical properties that contribute to the abuse-deterrent aspects of the drug. This study compared the relative bioavailability of Morphine ARER in the presence and absence of food. Methods This was a randomized, single-dose, two-treatment, crossover study in which healthy adults received Morphine ARER 100 mg under fasting and fed conditions. Subjects were given naltrexone 50 mg to limit opioid effects. Plasma concentrations of morphine and its active metabolite morphine-6-glucuronide (M6G) were obtained up to 48 h post-dose; area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUC0–∞), maximum observed plasma concentration (Cmax) and time to Cmax (Tmax) were calculated. Safety was evaluated by observation or report of adverse events, which were monitored during the treatment periods. Results Of 28 enrolled subjects, 27 completed all treatments; 1 subject in the fasted group withdrew voluntarily. Under fed conditions, the Cmax for morphine was 33% higher (44.78 vs. 33.30 ng/ml for fed and fasted conditions, respectively) and the median Tmax was 30 min longer than under fasted conditions. The overall morphine exposure (AUC0–∞) was similar for fed (440.6 ng · h/ml) vs. fasted conditions (395.1 ng · h/ml). For M6G, the Cmaxand AUC0–∞ were similar under both conditions, and the median Tmax for M6G was 60 min longer under fed conditions. Common adverse events were somnolence and nausea. Conclusion Morphine ARER can be administered without regard to food. Plain Language Summary Plain language summary available for this article. Funding Inspirion Delivery Sciences, LLC.

Clinical Performance Comparison of Two In-Vitro Diagnostic Multivariate Index Assays (IVDMIAs) for Presurgical Assessment for Ovarian Cancer Risk Abstract Introduction Adnexal or pelvic mass is a finding that commonly raises suspicion for malignancy, especially for ovarian cancer. Proper identification prior to surgery would permit appropriate referral to a specialty center in cases likely to be ovarian cancer, as optimal outcomes in such cases are obtained when surgical staging and treatment are provided at the time of initial surgery. Methods We compared the screening capabilities of two in vitro diagnostic multivariate index assays (IVDMIAs), a new IVDMIA (second-generation multivariate index assay: MIA2G) and a currently used triage algorithm (Risk of Ovarian Malignancy Assay: ROMA). Results Among 245 subjects (24.7%) determined to have a malignancy, ROMA misclassified 51 malignancies (including 10 high-grade ovarian malignancies), whereas MIA2G misclassified 22 (including 5 high-grade ovarian malignancies). Early stage cancers were more frequently misclassified by ROMA (20 vs. 8 cases). The rate of "test-negative" malignancies was significantly higher for ROMA, while the rate of "test-positive" benign cases was significantly higher for MIA2G. Conclusion Triage algorithms play an important role in improving clinical outcomes for women presenting with an adnexal mass regardless of the eventual diagnosis. In this study, MIA2G was shown to correctly predict more cases of ovarian cancer than the ROMA algorithm. Funding Aspira Labs/Vermillion Inc.

Population Pharmacokinetic Analysis of Bintrafusp Alfa in Different Cancer Types Abstract Introduction Bintrafusp alfa, an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, has shown promising antitumor activity and manageable safety. Methods To support the dosing strategy for bintrafusp alfa, we developed a population pharmacokinetics model using a full covariate modeling approach, based on pharmacokinetic and covariate data from 644 patients with various solid tumors who received bintrafusp alfa intravenously in two clinical studies. Results A two-compartmental linear model best described bintrafusp alfa concentrations, and no time-varying clearance was identified. Using this model, the estimated clearance was 0.0158 l/h (relative standard error, 4.1%), and the central and peripheral volume of distribution were 3.21 l (relative standard error, 3.2%) and 0.483 l (relative standard error, 9.8%), respectively. The estimated mean elimination half-life of bintrafusp alfa was 6.93 days (95% CI 4.69–9.65 days). Several intrinsic factors (bodyweight, albumin, sex, and tumor type) were found to influence bintrafusp alfa pharmacokinetics, but none of these covariate effects was considered clinically meaningful and no dosage adjustments are recommended. Notably, simulations from the model suggested less variability in exposure metrics with flat dosing versus weight-based dosing. Conclusions Pharmacokinetic analysis of bintrafusp alfa supports the use of a flat dose regimen in further clinical trials (recommended phase 2 dose: 1200 mg every 2 weeks). Trial registration ClinicalTrials.gov identifiers: NCT02517398 and NCT02699515. Funding Merck Healthcare KGaA as part of an alliance between Merck Healthcare KGaA and GlaxoSmithKline.

Determining MRI Inflammation Targets When Considering a Rheumatoid Arthritis Treat-to-Target Strategy: Results of a Randomized, Placebo-Controlled Trial Abstract Introduction Magnetic resonance imaging (MRI) is increasingly used in patients with rheumatoid arthritis (RA) to determine residual inflammation after treatment and as a predictor of structural damage progression. Establishing an optimal threshold of inflammatory activity that predicts lower risk of structural damage progression may inform treatment decisions. This post hoc analysis investigated whether patients with RA at low risk of structural damage progression can be identified based on MRI inflammation thresholds. Methods Hand and wrist MRI was performed at baseline, and at months 6 and 12 in a phase 3b, randomized, active-controlled, double-blind trial of abatacept in early RA (AVERT). Pathologies were scored using the OMERACT RA MRI Score. Data were stratified into two risk subgroups (less and more severe inflammation) for structural damage progression (erosion change > 0.5) based on baseline inflammation. In this post hoc analysis, log odds ratios of probability of progression {adjusted for baseline Disease Activity Score in 28 joints [C-reactive protein; DAS28 (CRP)]} were compared between subgroups to test the performance of inflammation thresholds. Results There were 351 randomized and treated patients with baseline MRIs, of whom 276 (78.6%) and 235 (67.0%) had MRIs available at months 6 and 12, respectively. The DAS28 (CRP)-adjusted probabilities of progression from baseline to month 12 based on scores at baseline, and from months 6 to 12 based on month 6 scores, were significantly lower among patients with less inflammation (P < 0.0001–0.0459), independent of clinical disease activity. Predefined thresholds of synovitis ≤ 3 (total score 21), osteitis ≤ 3 (total score 69) and total inflammation score (osteitis double-weighted) ≤ 9 were associated with a lower likelihood of structural damage progression in unadjusted analyses. Conclusion Levels of MRI-determined inflammatory activity below defined thresholds were independently associated with a lower risk of structural damage progression in early RA, providing a potential trial endpoint for levels of inflammation not associated with progression. Trial Registration ClinicalTrials.gov identifier, NCT01142726. Funding Bristol-Myers Squibb.

Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects Abstract Introduction Hepatitis B viral capsid assembly is an attractive target for new antiviral treatments. JNJ-56136379 (JNJ-6379) is a potent capsid assembly modulator in vitro with a dual mode of action. In Part 1 of this first-in-human study in healthy adults, the pharmacokinetics (PK), safety and tolerability of JNJ-6379 were evaluated following single ascending and multiple oral doses. Methods This was a double-blind, randomized, placebo-controlled study in 30 healthy adults. Eighteen subjects were randomized to receive single doses of JNJ-6379 (25 to 600 mg) or placebo. Twelve subjects were randomized to receive 150 mg JNJ-6379 or placebo twice daily for 2 days, followed by 100 mg JNJ-6379 or placebo daily for 10 days. Results The maximum observed plasma concentration and the area under the curve increased dose proportionally from 25 to 300 mg JNJ-6379. Following multiple dosing, steady-state conditions were achieved on day 8. Steady-state clearance was similar following single and multiple dosing, suggesting time-linear PK. All adverse events (AEs) reported were mild to moderate in severity. There were no serious AEs or dose-limiting toxicities and no apparent relationship to dose for any AE. Conclusion JNJ-6379 was well tolerated in this study. Based on the safety profile and plasma exposures of JNJ-6379 in healthy subjects, a dosing regimen was selected for Part 2 of this study in patients with chronic hepatitis B. This is anticipated to achieve trough plasma exposures of JNJ-6379 at steady state of more than three times the 90% effective concentration of viral replication determined in vitro. Trial registration Clinicaltrials.gov identifier, NCT02662712. Funding Janssen Pharmaceutica.

A Randomized, Double-Blind, Double-Dummy Study of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Relative to Umeclidinium/Vilanterol Dry Powder Inhaler in COPD Abstract Introduction Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, is the only approved fixed-dose combination long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) delivered via MDI. Direct comparisons of GFF MDI versus other LAMA/LABAs have not previously been performed. We assessed the efficacy and safety of GFF MDI relative to umeclidinium/vilanterol dry powder inhaler (UV DPI) in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). Methods In this phase IIIb randomized, double-blind, double-dummy, multicenter, 24-week study, patients received GFF MDI 18/9.6 μg (equivalent to glycopyrronium/formoterol fumarate dihydrate 14.4/10 μg; two inhalations per dose, twice-daily; n = 559) or UV DPI 62.5/25 μg (one inhalation, once-daily; n = 560). Primary endpoints were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) and peak change from baseline in FEV1 within 2 h post-dose, both over 24 weeks. Additional lung function, symptom and safety endpoints were also assessed. Results For the primary endpoints, GFF MDI was non-inferior to UV DPI (using a margin of − 50 mL) for peak FEV1 (least squares mean [LSM] difference − 3.4 mL, 97.5% confidence interval [CI] − 32.8, 25.9) but not for trough FEV1 (LSM difference − 87.2 mL; − 117.0, − 57.4). GFF MDI was nominally superior to UV DPI for onset of action (p < 0.0001) and was nominally non-inferior to UV DPI for all symptom endpoints (Transition Dyspnea Index focal score, Early Morning/Night-Time Symptoms COPD instrument scores, and COPD Assessment Test score). Exacerbation and safety findings were similar between groups. Conclusions Over 24 weeks of treatment, GFF MDI was non-inferior to UV DPI for peak FEV1, but not for morning pre-dose trough FEV1. GFF MDI had a faster onset of action versus UV DPI. There were no clinically meaningful differences between treatments in symptom endpoints. Both treatments were well tolerated with similar safety profiles. Trial registration NCT03162055 (Clinicaltrials.gov) Funding AstraZeneca

Correction to: A Multicenter, Observational, Prospective Study of the Effectiveness of Switching from Budesonide/Formoterol Turbuhaler ® to Budesonide/Formoterol Easyhaler ® Unfortunately, the mean difference in change from baseline ACT was incorrectly reported in the abstract as 19.0 vs. 20.8 instead of 18.9 vs. 20.7

Some Considerations on the WHO Histological Classification of Laryngeal Neoplasms Abstract A new edition of the World Health Organization (WHO) Histological classification of tumours of the hypopharynx, larynx, trachea and parapharyngeal space was published in 2017. We have considered this classification regarding laryngeal neoplasms and discuss the grounds for said revision. Many of the laryngeal neoplasms described in the literature and in the previous WHO edition from 2005 have been omitted from this current revision. Many are described elsewhere in the book but it may give the new generation of pathologists/surgeons/oncologists the false impression that these tumour entities do not exist in the larynx.

Different Solutions for Damaged Nasotracheal Tube during Maxillofacial Surgery: A Case Series Abstract Difficult airway management and intraoperative tube damage are important problems during maxillofacial surgery. Damage occurs frequently during the surgery, and the anesthesiologist must be ready to find a quick and safe solution. Replacing the damaged endotracheal tube involves additional difficulties, and various factors must be evaluated. We present two cases of nasotracheal tube (NTT) damage suffered during maxillofacial surgery. The different intraoperative conditions led us to decide for the replacement of NTT in one case and for conservative action in the other. The purpose of this article is to highlight the difficulties that the anesthesiologist may have in deciding quickly what is the best approach in case the endotracheal tube is damaged during maxillofacial surgery and possibly try to provide a rapid and safe solution for the situation.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
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6948891480

alsfakia@gmail.com