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Introduction: An unsafe injection practice is one of the major contributors to new hepatitis C virus (HCV) infections; thus, people who inject drugs are a key population to prioritize to achieve HCV elimination. The introduction of highly effective and well-tolerated pangenotypic direct-acting antivirals, including glecaprevir/pibrentasvir (GLE/PIB), has revolutionized the HCV treatment landscape. Glecaprevir is a weak cytochrome P450 3A4 (CYP3A4) inhibitor, so there is the potential for drug–drug interactions (DDIs) with some opioids metabolized by CYP3A4, such as fentanyl. This study estimated the impact of GLE/PIB on the pharmacokinetics of intravenous fentanyl by building a physiologically based pharmacokinetic (PBPK) model. Methods: A PBPK model was developed for intravenous fentanyl by incorporating published information on fentanyl metabolism, distribution, and elimination in healthy individuals. Three clinical DDI studies were used to verify DDIs within the fentanyl PBPK model. This model was integrated with a previously developed GLE/PIB PBPK model. After model validation, DDI simulations were conducted by coadministering GLE 300 mg + PIB 120 mg with a single dose of intravenous fentanyl (0.5 µg/kg). Results: The predicted maximum plasma concentration ratio between GLE/PIB + fentanyl and fentanyl alone was 1.00, and the predicted area under the curve ratio was 1.04, suggesting an increase of only 4% in fentanyl exposure. Conclusion: The administration of a therapeutic dose of GLE/PIB has very little effect on the pharmacokinetics of intravenous fentanyl. This negligible increase would not be expected to increase the risk of fentanyl overdose beyond the inherent risks related to the amount and purity of the fentanyl received during recreational use. [ABSTRACT FROM AUTHOR]

In lieu of large bioequivalence studies and exposing healthy postmenopausal women to additional drug exposure for elagolix coadministered with hormonal add-back therapy, physiologically based pharmacokinetic (PBPK) modeling was used with in vitro dissolution data to test for virtual bioequivalence. For endometriosis, elagolix is approved at doses of 150 mg once daily and 200 mg twice daily as a tablet. As a combination therapy, two individual tablets, consisting of an elagolix tablet and an estradiol/norethindrone acetate 1/0.5 mg (E2/NETA) tablet, were utilized in Phase 3 endometriosis trials. However, the commercial combination drug products consist of a morning capsule (containing an elagolix tablet and E2/NETA tablet as a fixed-dose combination capsule, AM capsule) and an evening capsule (consisting of an elagolix tablet, PM capsule). In vitro dissolution profiles were dissimilar for the tablet and capsule formulations; thus, in vivo bioequivalence studies or a bioequivalence waiver would have been required. To simulate virtual cross-over, bioequivalence trials, in vitro dissolution data was incorporated into a previously verified PBPK model. The updated PBPK model was externally validated using relevant bioequivalence study data. Based on results of the virtual bioequivalence simulations, the commercial drug product capsules met the bioequivalence criteria of 0.80–1.25 when compared to the reference tablets. This was a novel example where PBPK modeling was utilized along with in vitro dissolution data to demonstrate virtual bioequivalence in support of a regulatory bioequivalence waiver. [ABSTRACT FROM AUTHOR]

This paper considers a pursuit-evasion scenario among three agents– an evader, a pursuer, and a defender. We design cooperative guidance laws for the evader and the defender team to safeguard the evader from an attacking pursuer. Unlike differential games, optimal control formulations, and other heuristic methods, we propose a novel perspective on designing effective nonlinear feedback control laws for the evader-defender team using a time-constrained guidance approach. The evader lures the pursuer on the collision course by offering itself as bait. At the same time, the defender protects the evader from the pursuer by exercising control over the engagement duration. Depending on the nature of the mission, the defender may choose to take an aggressive or defensive stance. Such consideration widens the applicability of the proposed methods in various three-agent motion planning scenarios such as aircraft defense, asset guarding, search and rescue, surveillance, and secure transportation. We use a fixed-time sliding mode control strategy to design the control laws for the evader-defender team and a nonlinear finite-time disturbance observer to estimate the pursuer's maneuver. Finally, we present simulations to demonstrate favorable performance under various engagement geometries, thus vindicating the efficacy of the proposed designs. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is one of the most common types of allergy worldwide. It has significant negative impact on the quality of life (QOL). One of the available causal treatments of AR is allergen specific immunotherapy which remains effective even after the end of treatment course, unlike symptomatic drugs. AR patients aged above five years, allergic to unavoidable allergen like house dust, mite etc., and refractory to maximal pharmacotherapy were included in present study. Patients allergic to avoidable allergen, taking beta-blocker medication, having other immunological disease, and who were pregnant, breast-feeding or lost to follow up, were excluded from the study. All patients included in the study underwent sublingual immunotherapy (SLIT). The impact of treatment is measured by calculating the difference between SNOT-20 score before and after treatment (which is 6 months interval). Total 30 patients were studied. Paired-t test calculated value of cumulative score and nasal symptom score are 7.853 and 6.85 respectively. Both are greater than table value of 2.46. So paired-t test shows that SLIT is very much effective in treatment of AR. The present study re-establish the fact that SLIT not only reduces AR symptoms, it also improves the QOL. It has very good patient compliance with minimal side effects. [ABSTRACT FROM AUTHOR]

This paper employs a nonlinear cooperative deviated pursuit guidance strategy, for multiple interceptors, to ensure salvo interception. The problem of ensuring salvo is transformed into one of achieving consensus in time-to-go within a finite time, over a directed cycle. By using a deviated pursuit-based guidance approach, the computation of exact time-to-go is facilitated based on interceptors' present states, thereby avoiding the need for estimation of time-to-go and small-angle approximations. Greater flexibility in controlling consensus value and time can be achieved by the choice of heterogeneous gains in the consensus algorithm. The stability and performance of the proposed nonlinear guidance are analysed using Lyapunov-based methods. A sensitivity analysis of time-to-go with respect to various engagement parameters is also carried out. Effectiveness of the proposed salvo guidance strategy is demonstrated through numerical simulations on constant speed, and also realistic, time-varying speed interceptor models. [ABSTRACT FROM AUTHOR]

Purpose: Venetoclax, a targeted anticancer agent approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, is a substrate of cytochrome P450 (CYP) 3A enzyme (CYP3A4). Posaconazole, commonly used to prevent invasive fungal infections in neutropenic patients with hematological malignancies, potently inhibits CYP3A4. The purpose of this evaluation was to predict venetoclax exposures following co-administration of posaconazole at doses not previously studied clinically. Methods: Two physiologically based pharmacokinetic (PBPK) models were developed for posaconazole based on published parameters, one for an oral suspension and another for delayed released tablets. Parameter optimization, guided by sensitivity analyses, was conducted such that the models could replicate clinical exposures of posaconazole and drug–drug interactions with sensitive CYP3A substrates including venetoclax. The clinically verified posaconazole PBPK models were then utilized to predict DDI with a previously published venetoclax PBPK model at clinically relevant dosing scenarios. Results: The posaconazole PBPK models predicted posaconazole exposure and DDI related fold changes with acceptable prediction errors for both posaconazole formulations. The model predicted exposures of venetoclax, when co-administered with a 300 mg QD dose of delayed release tablets of posaconazole, were in concordance with observed data. Increasing the posaconazole dose to 500 mg QD increased venetoclax exposures by about 12% relative to 300 mg QD, which were still within the venetoclax safe exposure range. Conclusions: The posaconazole PBPK models were developed and clinically verified. Predictions using the robust PBPK model confirmed the venetoclax label recommendation of 70 mg in the presence of posaconazole at doses up to 500 mg QD. [ABSTRACT FROM AUTHOR]

Amlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug-drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously. A novel physiologically-based pharmacokinetic (PBPK) model was developed for amlodipine, and the model was verified using published clinical PK and DDI data. The verified amlodipine PBPK model was linked to a pharmacodynamics model that describes changes in systolic blood pressure (SBP) during and after co-administration with RTV. The magnitude and time course of RTV effects on amlodipine plasma exposures and SBP were evaluated, to provide guidance on dose adjustment of amlodipine during and after co-administration with RTV-containing regimens. Model simulations suggested that the increase in amlodipine’s plasma exposure by RTV diminishes by approximately 80% within 5 days after the last dose of RTV. PBPK simulations suggested that resuming a full dose of amlodipine [5 mg once daily (QD)] immediately after RTV’s last dose would decrease daily average SBP by a maximum of 3.3 mmHg, while continuing with the reduced dose (2.5 mg QD) for 5 days after the last dose of RTV would increase daily average SBP by a maximum of 5.8 mmHg. Based on these results, either approach of resuming amlodipine’s full dose could be appropriate when combined with appropriate clinical monitoring. [ABSTRACT FROM AUTHOR]

Odontogenic tumours are a group of heterogeneous diseases that range from hamartomatous or non-neoplastic tissue proliferations to benign neoplasms to malignant tumours with metastatic potential. They are rare, comprising about <2-3% of all oral and maxillofacial biopsy specimens. The aim of the present study was to determine the clinico-pathological presentation of this heterogeneous group of lesions and review of literature. The present study was conducted in the ENT department of a Government Medical College and Hospital, West Bengal, India, over the period of 5 years from January 2011 to December 2015. It included a total of 15 patients who were clinico-radiologically diagnosed as odontogenic tumours, and were given appropriate treatment. Their diagnostic and management approaches are discussed. Among 15 odontogenic tumours, 13 were benign and two were malignant. Male to female ratio was 2:3. Mandible to maxilla ratio was 1.8:1. The patients were in between 4 and 56 years of age with highest incidence in 3rd decade of life. All patients are doing well till date with a minimum follow-up of 1 year. Incisional biopsy is considered as gold standard for preoperative diagnosis but FNAC can offer clinicians a less invasive alternative. CT is the choice of investigation for study of lesion, analysis of its extension and surgical planning. The challenge to proper management lies in balancing between conservative and radical approach to reduce morbidity and recurrence both. Final diagnosis is made by post-operative histopathological examination. [ABSTRACT FROM AUTHOR]

Brain abscess is the ultimate otogenic complication, both in severity and difficulty of management. In developing countries with high incidence of cholesteatoma, brain abscess is not a rare complication. In India, brain abscesses constitute about 8 % of all intracranial lesions. The surgical treatment of brain abscess is very controversial. This prospective study was done in ENT department of a tertiary care hospital in Kolkata, during the period from May 2009 to April 2014. 22 such cases of otogenic brain abscess managed by single-stage trans-mastoid drainage along with meticulous mastoid clearance. On the basis of clinical, radiological and operative findings, data of all patients with otogenic brain abscess were analyzed. There was male predominance and 9 (40.91 %) of them were younger than 20 years. 15 (68.18 %) cases were of cerebellar abscess and in 7 (31.82 %) cases were of the temporal abscess. Lateral sinus thrombosis was the most common associated complication found (22.73 %) in our study. All the patients peri-operatively revealed cholesteatoma. All the patients recovered well and there was no recurrence of symptoms on a minimum 15 months follow-up. This approach suits the otologists in clearing the cause and effect of pathology, at the same sitting. This single-stage approach decreases the peri-operative morbidity and mortality of the two-stage procedure. It also decreases the hospital stay and financial burden. [ABSTRACT FROM AUTHOR]

Engineered nanomaterials (ENMs) possess unique characteristics affecting their interactions in biological media and biological tissues. Systematic investigation of the effects of particle properties on biological toxicity requires a comprehensive modeling framework which can be used to predict ENM particokinetics in a variety of media. The Agglomeration-diffusion-sedimentation-reaction model (ADSRM) described here is stochastic, using a direct simulation Monte Carlo method to study the evolution of nanoparticles in biological media, as they interact with each other and with the media over time. Nanoparticle diffusion, gravitational settling, agglomeration, and dissolution are treated in a mechanistic manner with focus on silver ENMs (AgNPs). The ADSRM model utilizes particle properties such as size, density, zeta potential, and coating material, along with medium properties like density, viscosity, ionic strength, and pH, to model evolving patterns in a population of ENMs along with their interaction with associated ions and molecules. The model predictions for agglomeration and dissolution are compared with in vitro measurements for various types of ENMs, coating materials, and incubation media, and are found to be overall consistent with measurements. The model has been implemented for an in vitro case in cell culture systems to inform in vitro dosimetry for toxicology studies, and can be directly extended to other biological systems, including in vivo tissue sub-systems by suitably modifying system geometry. [ABSTRACT FROM AUTHOR]

In early drug development, the selection of a formulation platform and decisions on formulation strategies have to be made within a short timeframe and often with minimal use of the active pharmaceutical ingredient (API). The current work evaluated the various physicochemical parameters required to improve the prediction accuracy of simulation software for immediate release tablets in early drug development. DDDPlus™ was used in simulating dissolution test profiles of immediate release tablets of ritonavir and all simulations were compared with experimental results. The minimum data requirements to make useful predictions were assessed using the ADMET predictor (part of DDDPlus) and Chemicalize (an online resource). A surfactant model was developed to estimate the solubility enhancement in media containing surfactant and the software's transfer model based on the USP two-tiered dissolution test was assessed. One measured data point was shown to be sufficient to make predictive simulations in DDDPlus. At pH 2.0, the software overestimated drug release while at pH 1.0 and 6.8, simulations were close to the measured values. A surfactant solubility model established with measured data gave good dissolution predictions. The transfer model uses a single-vessel model and was unable to predict the two in vivo environments separately. For weak bases like ritonavir, a minimum of three solubility data points is recommended for in silico predictions in buffered media. A surfactant solubility model is useful when predicting dissolution behavior in surfactant media and in silico predictions need measured solubility data to be predictive. [ABSTRACT FROM AUTHOR]