Development and technical validation of a smartphone-based cry detection algorithm

Introduction: The duration and frequency of crying of an infant can be indicative of its health. Manual tracking and labeling of crying is laborious, subjective, and sometimes inaccurate. The aim of this study was to develop and technically validate a smartphone-based algorithm able to automatically detect crying.Methods: For the development of the algorithm a training dataset containing 897 5-s clips of crying infants and 1,263 clips of non-crying infants and common domestic sounds was assembled from various online sources. OpenSMILE software was used to extract 1,591 audio features per audio clip. A random forest classifying algorithm was fitted to identify crying from non-crying in each audio clip. For the validation of the algorithm, an independent dataset consisting of real-life recordings of 15 infants was used. A 29-min audio clip was analyzed repeatedly and under differing circumstances to determine the intra- and inter- device repeatability and robustness of the algorithm.Results: The algorithm obtained an accuracy of 94% in the training dataset and 99% in the validation dataset. The sensitivity in the validation dataset was 83%, with a specificity of 99% and a positive- and negative predictive value of 75 and 100%, respectively. Reliability of the algorithm appeared to be robust within- and across devices, and the performance was robust to distance from the sound source and barriers between the sound source and the microphone.Conclusion: The algorithm was accurate in detecting cry duration and was robust to various changes in ambient settings.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

An exploratory first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone at a 2- and 1-week interval in patients with metastatic castration resistant prostate cancer

Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients. In this exploratory first-in-man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2-week intervals. Upon review of part A safety, patients in part B received 10 weekly doses of 18.5 mg. Primary outcomes were safety and pharmacokinetic profile, secondary outcome was antitumor efficacy. Nine mCRPC patients (5 part A, 4 part B) were enrolled. All patients experienced grade 1-2 toxicity, one (part B) patient experienced grade 3 toxicity (permanent bladder catheter-related urosepsis). No infusion-related adverse events occurred. One patient had upsloping glucose levels 50% PSA biochemical response was observed. Bi- and once weekly administrations of IV liposomal dexamethasone were well-tolerated. Weekly dosing enabled trough concentrations of liposomal- and free dexamethasone >LLOQ. The data presented support further clinical investigation in well-powered studies. Clinical trial registration: ISRCTN 10011715.Prostatic carcinom

Immunomonitoring of Tacrolimus in Healthy Volunteers: The First Step from PK- to PD-Based Therapeutic Drug Monitoring?

Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of the relationship between tacrolimus dose, tacrolimus concentration, and its effect on the target cell, we developed functional immune tests for the quantification of the tacrolimus effect. Twelve healthy volunteers received a single dose of tacrolimus, after which intracellular and whole blood tacrolimus concentrations were measured and were related to T cell functionality. A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations (r = 0.71, p = 0.009), while no correlation was found between tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) and whole blood (r = 0.35, p = 0.27). Phytohemagglutinin (PHA) induced the production of IL-2 and IFNγ, as well as the inhibition of CD71 and CD154 expression on T cells at 1.5 h post-dose, when maximum tacrolimus levels were observed. Moreover, the in vitro tacrolimus effect of the mentioned markers corresponded with the ex vivo effect after dosing. In conclusion, our results showed that intracellular tacrolimus concentrations mimic whole blood concentrations, and that PHA-induced cytokine production (IL-2 and IFNγ) and activation marker expression (CD71 and CD154) are suitable readout measures to measure the immunosuppressive effect of tacrolimus on the T cell

Clinical pharmacology of novel anticancer drug formulations

Studies outlined in this thesis describe the impact of drug formulations on pharmacology of anticancer drugs. It consists of four parts and starts with a review describing the mechanisms of low oral bioavailability of anti-cancer drugs and strategies for improvement of the bioavailability. The majority of new anti-cancer drugs are oral pharmaceutical formulations, consisting of new chemical entities, like molecular targeted agents and novel variants of existing drugs. The development of oral formulations is, however, often hampered by low and variable bioavailability. Since most anti-cancer drugs have a narrow therapeutic window and are dosed at or close to the maximum tolerated dose, a wide variability in bioavailability can have a negative impact on treatment outcome. The extent of oral bioavailability depends on many factors, including release of the drug from the pharmaceutical dosage form, a drug’s stability in the gastro-intestinal tract, factors affecting dissolution, the rate of passage through the gut wall and the pre-systemic metabolism in gut wall and liver. There are several strategies to reduce or to overcome these limitations. First, pharmaceutical adjustment of the formulation or the physicochemical characteristics of the drug can improve the dissolution rate and absorption. Second, pharmacological interventions by combining the drug with inhibitors of transporter proteins and/or pre-systemic metabolizing enzymes can overcome the physiological endogenous limitations. Third, chemical modification of a drug by synthesis of a derivative, salt form or prodrug could enhance the bioavailability by improving the absorption and bypassing physiological endogenous limitations. In the three other parts of this thesis, these strategies are applied to docetaxel, paclitaxel and gemcitabine. These existing drugs are anticancer drugs with documented significant anti-tumor activity and are already in use as first or second line treatment for several malignancies. Despite their proven anti-tumor activity, the registered drug formulations or mode of administration could be responsible for severe side effects, or lead to suboptimal dosing schedules. The results of this thesis show that drug formulations can have an impact on pharmacology of anticancer drugs. These results are used for further development of novel dosage forms of docetaxel, paclitaxel and gemcitabine, but are also relevant for the development of new drugs

Clinical pharmacology of novel anticancer drug formulations

Studies outlined in this thesis describe the impact of drug formulations on pharmacology of anticancer drugs. It consists of four parts and starts with a review describing the mechanisms of low oral bioavailability of anti-cancer drugs and strategies for improvement of the bioavailability. The majority of new anti-cancer drugs are oral pharmaceutical formulations, consisting of new chemical entities, like molecular targeted agents and novel variants of existing drugs. The development of oral formulations is, however, often hampered by low and variable bioavailability. Since most anti-cancer drugs have a narrow therapeutic window and are dosed at or close to the maximum tolerated dose, a wide variability in bioavailability can have a negative impact on treatment outcome. The extent of oral bioavailability depends on many factors, including release of the drug from the pharmaceutical dosage form, a drug’s stability in the gastro-intestinal tract, factors affecting dissolution, the rate of passage through the gut wall and the pre-systemic metabolism in gut wall and liver. There are several strategies to reduce or to overcome these limitations. First, pharmaceutical adjustment of the formulation or the physicochemical characteristics of the drug can improve the dissolution rate and absorption. Second, pharmacological interventions by combining the drug with inhibitors of transporter proteins and/or pre-systemic metabolizing enzymes can overcome the physiological endogenous limitations. Third, chemical modification of a drug by synthesis of a derivative, salt form or prodrug could enhance the bioavailability by improving the absorption and bypassing physiological endogenous limitations. In the three other parts of this thesis, these strategies are applied to docetaxel, paclitaxel and gemcitabine. These existing drugs are anticancer drugs with documented significant anti-tumor activity and are already in use as first or second line treatment for several malignancies. Despite their proven anti-tumor activity, the registered drug formulations or mode of administration could be responsible for severe side effects, or lead to suboptimal dosing schedules. The results of this thesis show that drug formulations can have an impact on pharmacology of anticancer drugs. These results are used for further development of novel dosage forms of docetaxel, paclitaxel and gemcitabine, but are also relevant for the development of new drugs

Pulsatile drug delivery to ileo-colonic segments by structured incorporation of disintegrants in pH-responsive polymer coatings

Conventional pH-responsive coatings used for oral drug delivery to the lower parts of the gastro-intestinal tract often show a poor performance. A new system for site-specific pulsatile delivery in the ileo-colonic regions is described. The system is based on the non-percolating incorporation of disintegrants in a coating which consists further of a continuous matrix of pH-responsive polymer (Eudragit S). Extensive in vitro release studies were performed in which coatings with different concentrations and disintegrants were studied and compared to non-disintegrant containing coatings. In vitro data show that the incorporation of swelling agents in an Eudragit S-coating still allows delayed release in the simulated terminal ileum. The pulse time and the robustness could be improved compared to conventional Eudragit S-coatings. The augmented pH-responsiveness of the new coating was related to the swelling index of the applied disintegrant. Based on the in vitro data comparing different swelling agents, Ac-di-sol appears to be the best performing swelling agent. A proof-of-concept study in human subjects was performed to investigate the performance of the new system in vivo. Coated capsules containing the stable isotope (13)C(6)-glucose as the test compound were administered and the occurrence of (13)CO(2) in the breath of the subjects was measured. It could be shown that the coating is able to resist the environmental conditions in the stomach and duodenum and delay release until deeper parts of the intestines are reached. Furthermore, the capsule is able to maintain a pulsatile release profile. It is concluded that the structured incorporation of swelling agents in pH-responsive polymers improves the delayed, pulsatile release kinetics of coated capsules. In a proof-of-concept in vivo study it was shown that the newly developed coating enables pulsatile delivery of the content to the lower parts of the intestines. (C) 2008 Elsevier B.V. All rights reserved

A novel dissolution method relevant to intestinal release behaviour and its application in the evaluation of modified release mesalazine products

Mesalazine (5-ASA) is a compound being used in the therapy of inflammatory bowel disease (IBD). Considering the fact that 5-ASA is locally active and that the location of inflammation in IBD may vary, it is recognized that the release profile of 5-ASA drugs is the dominant factor for adequate local bioavailability. Furthermore, it is hypothesized that systemic absorption of 5-ASA (mainly in the upper intestinal segments) increases the risk of side effects. These facts relate to the conclusion that a method determining the dissolution profile under biorelevant conditions is a valuable tool for evaluation and comparison of 5-ASA-products. We tested several commercially available products (Salofalk((R)) tablets, Salofalk((R)) granules, Asacol((R)) tablets, Pentasa((R)) tablets and granules) in a gastro-intestinal simulation system (GISS). The GISS is based on the pharmacopeial dissolution test. The release profiles of all products are in agreement with their technological concepts. The percentage of the dose released in the simulated colon is small in all products. The GISS is a robust system able to discriminate between products which apply different modified-release technologies. Colon-selectivity of modified-release 5-ASA products might further be improved. The commercially available 5-ASA containing oral dosage forms exhibit different release profiles, which suggests that the optimal product may differ per patient. (c) 2006 Elsevier B.V All rights reserved

Theoretical Performance of Nonlinear Mixed-Effect Models Incorporating Saliva as an Alternative Sampling Matrix for Therapeutic Drug Monitoring in Pediatrics: A Simulation Study

Background: Historically, pharmacokinetic (PK) studies and therapeutic drug monitoring (TDM) have relied on plasma as a sampling matrix. Noninvasive sampling matrices, such as saliva, can reduce the burden on pediatric patients. The variable plasma-saliva relationship can be quantified using population PK models (nonlinear mixed-effect models). However, criteria regarding acceptable levels of variability in such models remain unclear. In this simulation study, the authors aimed to propose a saliva TDM evaluation framework and evaluate model requirements in the context of TDM, with gentamicin and lamotrigine as model compounds. Methods: Two population pharmacokinetic models for gentamicin in neonates and lamotrigine in pediatrics were extended with a saliva compartment including a delay constant (k(SALIVA)), a saliva:plasma ratio, and between-subject variability (BSV) on both parameters. Subjects were simulated using a realistic covariate distribution. Bayesian maximum a posteriori TDM was applied to assess the performance of an increasing number of TDM saliva samples and varying levels of BSV and residual variability. Saliva TDM performance was compared with plasma TDM performance. The framework was applied to a known voriconazole saliva model as a case study. Results: TDM performed using saliva resulted in higher target attainment than no TDM, and a residual proportional error <25% on saliva observations led to saliva TDM performance comparable with plasma TDM. BSV on k(SALIVA) did not affect performance, whereas increasing BSV on saliva:plasma ratios by >25% for gentamicin and >50% for lamotrigine reduced performance. The simulated target attainment for voriconazole saliva TDM was >90%. Conclusions: Saliva as an alternative matrix for noninvasive TDM is possible using nonlinear mixed-effect models combined with Bayesian optimization. This article provides a workflow to explore TDM performance for compounds measured in saliva and can be used for evaluation during model building