Exploring the impact of CYP2D6 and UGT2B7 gene-drug interactions, and CYP-mediated DDI on oxycodone and oxymorphone pharmacokinetics using physiologically-based pharmacokinetic modeling and simulation.

Oxycodone is one of the most commonly used opioids to treat moderate to severe pain. It is metabolized mainly by CYP3A4 and CYP2D6, while only a small fraction of the dose is excreted unchanged into the urine. Oxymorphone, the metabolite primarily formed by CYP2D6, has a 40- to 60-fold higher mu-opioid receptor affinity than the parent compound. While CYP2D6-mediated gene-drug-interactions (GDIs) and drug-drug interactions (DDIs) are well-studied, they only account for a portion of the variability in oxycodone and oxymorphone exposure. The combined impact of CYP2D6-mediated GDIs and DDIs, CYP3A4-mediated DDIs, and UGT2B7 GDIs is not fully understood yet and hard to study in head-to-head clinical trials given the relatively large number of scenarios. Instead, we propose the use of a physiologically-based pharmacokinetic model that integrates available information on oxycodone's metabolism to characterize and predict the impact of DDIs and GDIs on the exposure of oxycodone and its major, pharmacologically-active metabolite oxymorphone. To this end, we first developed and verified a PBPK model for oxycodone and its metabolites using published clinical data. The verified model was then applied to determine the dose-exposure relationship of oxycodone and oxymorphone stratified by CYP2D6 and UGT2B7 phenotypes respectively, and administered perpetrators of CYP-based drug interactions. Our simulations demonstrate that the combination of CYP2D6 UM and a UGT2B7Y (268) mutation may lead to a 2.3-fold increase in oxymorphone exposure compared to individuals who are phenotyped as CYP2D6 NM / UGT2B7 NM. The extent of oxymorphone exposure increases up to 3.2-fold in individuals concurrently taking CYP3A4 inhibitors, such as ketoconazole. Inhibition of the CYP3A4 pathway results in a relative increase in the partial metabolic clearance of oxycodone to oxymorphone. Oxymorphone is impacted to a higher extent by GDIs and DDIs than oxycodone. We predict oxymorphone exposure to be highest in CYP2D6 UMs/UGT2B7 PMs in the presence of ketoconazole (strong CYP3A4 index inhibitor) and lowest in CYP2D6 PMs/UGT2B7 NMs in the presence of rifampicin (strong CYP3A4 index inducer) covering a 55-fold exposure range.

A review of the evolution of scientific literature on technology-assisted approaches using RGB-D sensors for musculoskeletal health monitoring.

The human musculoskeletal (MSK) system (also known as the locomotor system) provides strength and assistance to perform functional tasks and daily life activities. The MSK health monitoring plays a vital role in maintaining the body mobility and quality of life. Manual approaches for musculoskeletal health monitoring are subjective and require a clinician's intervention. The evolution in motion tracking technology enables us to capture the fine details of body movements. The research community has proposed various approaches to help clinicians in diagnosis and monitor treatment sessions. This paper succinctly reviews the evolution of technology-assisted approaches for musculoskeletal health monitoring, using motion capture sensors. To streamline the search through the literature database, the PICOS framework and PRISMA method have been incorporated. The present study reviews methods to transform motion capture data into kinematics variables and factors that affect the tracking performance of RGB-D sensors. Furthermore, widely utilized time-series filters for skeletal data denoising and smoothing for kinematics analysis, stochastic models for movement modeling, rule-based and template-based approaches for rehabilitation exercises assessment, and telerehabilitation sessions for remote health monitoring are explored. This article analyzes skeletal tracking methods by providing advantages and drawbacks of the state of the art rehabilitation sessions assessment, skeletal joint kinematics analysis, and MSK Telerehabilitation approaches. It also discusses the possible future research avenues to improve musculoskeletal disorder diagnosis and treatment monitoring. Our review signifies that RGB-D sensor-based approaches are inexpensive and portable for disorder diagnosis and treatment monitoring. It can also be a viable option for clinicians to provide contactless healthcare access to patients in the current scenario of the COVID-19 pandemic.

Therapeutic applications of transdermal microneedles.

Transdermal drug-delivery systems (TDDS) offer an attractive alternative to the oral route for delivery of biotherapeutics. Technological advancements in the past few decades have revolutionized the fabrication of micro-structured devices including creation of microneedles (MC). These devices are used for delivering peptides, macromolecules such as proteins and DNA, and other therapeutics through the skin. Here, we review the current use of MCs as a cost effective method for the self-administration of therapeutics. We will then review the current and common use of MCs as an effective treatment strategy for a broad range of diseases and their utility in the generation of effective vaccination delivery platforms. Finally, we will summarize the currently FDA approved MCs and their applications, along with the ongoing clinical trials that use such devices.

Kinect v2 tracked Body Joint Smoothing for Kinematic Analysis in Musculoskeletal Disorders.

Body joint monitoring is essential for disorder diagnosis and assessment of treatment effectiveness. Microsoft Kinect v2 is a low-cost and markerless human motion-tracking RGB-D sensor that provides spatial locations of tracked skeletal joints in the form of 3D coordinates. Sometimes, body tracking of kinect v2 produces erratic 3D coordinates, which affects the real-time tracking performance of the sensor. A careful study of the literature suggests that skeletal tracking of kinect v2 needs further exploration. This work proposes a filter combined with the concept of body kinematics to remove noise and enhances the quality of 3D coordinates in body frame data. Also, it generates "Motion Signature" of the tracked joint, which shows movement pattern for kinematic analysis, and helpful in joint monitoring of Musculoskeletal Disorders (MSD). The clinically relevant anatomical movement was executed, to evaluate the performance of the proposed filter. We compared Range of Motion (RoM) values obtained from the proposed filter with the gold standard goniometry. Results indicate that RoM values from the proposed filter are in high correlation with the goniometry with an Intraclass Correlation Coefficient values ranging between 0.95 to 0.98 authenticating that it improves the skeletal joint tracking of kinect v2.

Characterizing Exposure-Response Relationship for Therapeutic Monoclonal Antibodies in Immuno-Oncology and Beyond: Challenges, Perspectives, and Prospects.

Recent data from immuno-oncology clinical studies have shown the exposure-response (E-R) relationship for therapeutic monoclonal antibodies (mAbs) was often confounded by various factors due to the complex interplay of patient characteristics, disease, drug exposure, clearance, and treatment response and presented challenges in characterization and interpretation of E-R analysis. To tackle the challenges, exposure relationships for therapeutic mAbs in immuno-oncology and oncology are reviewed, and a general framework for an integrative understanding of E-R relationship is proposed. In this framework, baseline factors, drug exposure, and treatment response are envisioned to form an interconnected triangle, driving the E-R relationship and underlying three components that compose the apparent relationship: exposure-driven E-R, baseline-driven E-R, and response-driven E-R. Various strategies in data analysis and study design to decouple those components and mitigate the confounding effect are reviewed for their merits and limitations, and a potential roadmap for selection of these strategies is proposed. Specifically, exposure metrics based on a single-dose pharmacokinetic model can be used to mitigate response-driven E-R, while multivariable analysis and/or case control analysis of data obtained from multiple dose levels in a randomized study may be used to account for the baseline-driven E-R. In this context, the importance of collecting data from multiple dose levels, the role of prognostic factors and predictive factors, the potential utility of clearance at baseline and its change over time, and future directions are discussed.

Use of depth of response to predict progression-free survival in relapsed or refractory multiple myeloma: Evaluation of results from 102 clinical trials.

Progression-free survival (PFS) is the standard endpoint for demonstration of clinical effectiveness of novel therapies in relapsed or refractory multiple myeloma (RRMM). However, the long evaluation times for PFS limits its usefulness in the development of new therapies. Therefore, the objective of this analysis was to determine the relationship between response rates and median PFS in RRMM. A database was systematically developed from 268 identified RRMM trials reported from 1999 to 2016. Evaluated covariates for the relationship between response rates and PFS included age, sex, drug class(es), and number of drug classes. One-hundred two (102) trials involving 136 cohorts were included in the meta-analysis, representing 13 322 patients in total. Regression analysis using response rates and median PFS indicated that the correlation between very good partial response (VGPR) or better and median PFS was higher (R2  = 0.63) than the separately analyzed correlations between clinical benefit, overall response, or complete response rate and median PFS (R2  = 0.47 - 0.52). Subsequent covariate analysis revealed that treatment with an immunomodulatory imide drug (IMiD) further improved the relationship (R2  = 0.69), with a longer median PFS at a given VGPR or better rate when at least 1 drug treatment was an IMiD. Number of drug classes was not found to alter this relationship. In conclusion, VGPR or better rate can be used to predict the median PFS, with adjustment for the additional PFS provided by an IMiD.

Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults.

Therapeutic concentrations of voriconazole in invasive fungal infections (IFIs) are ensured using a drug monitoring approach, which relies on attainment of steady-state pharmacokinetics. For voriconazole, time to reach steady state can vary from 5-7 days, not optimal for critically ill patients. We developed a population pharmacokinetic/pharmacodynamic model-based approach to predict doses that can maximize the net benefit (probability of efficacy-probability of adverse events) and ensure therapeutic concentrations, early on during treatment. The label-recommended 200 mg voriconazole dose resulted in attainment of targeted concentrations in ≥80% patients in the case of Candida spp. infections, as compared to only 40-50% patients, with net benefit ranging from 5.8-61.8%, in the case of Aspergillus spp. infections. Voriconazole doses of 300-600 mg were found to maximize the net benefit up to 51-66.7%, depending on the clinical phenotype (due to CYP2C19 status and pantoprazole use) of the patient and type of Aspergillus infection.

Relationship between response rates and median progression-free survival in non-Hodgkin's lymphoma: A meta-analysis of published clinical trials.

Demonstration of clinical effectiveness of a non-Hodgkin's lymphoma (NHL) treatment generally involves determination of progression-free survival (PFS). However, the long evaluation time of PFS limits its utility to make timely decisions in drug development. Therefore, the objective of this analysis was to determine the relationship between response rates and median PFS in NHL. A database was systematically developed from 513 identified NHL trials reported from 1996 to 2015. Potential predictors of the relationship between response rates and PFS were evaluated, including age, sex, treatment, percentage of treatment-naïve patients, and subtype of NHL. Seventy-three trials involving 86 cohorts were included in the meta-analysis. Linear regression analysis using logit of response rates and logarithm of median PFS indicated that the correlation between overall response rate (ORR) and median PFS was higher (R2  = 0.70) when compared to that of complete response (CR) rate and median PFS (R2  = 0.57). Furthermore, the correlation was improved with the addition of percentage of treatment-naïve patients and percentage of patients with follicular lymphoma (FL) (P < .005) between ORR and median PFS (R2  = 0.78), and between CR rate and median PFS relationship (R2  = 0.74). Treatment was not found to alter this relationship. In summary, ORR is as good as CR rate in predicting median PFS. Moreover, longer median PFS is expected in the trials including treatment-naïve and/or FL patients at a given ORR/CR rate. The determined relationship can be used to project the median PFS based on ORR or CR rate.

Model Informed Dose Optimization of Dichloroacetate for the Treatment of Congenital Lactic Acidosis in Children.

Dichloroacetate (DCA) is an investigational drug used to treat congenital lactic acidosis and other mitochondrial disorders. Response to DCA therapy in young children may be suboptimal following body weight-based dosing. This is because of autoinhibition of its metabolism, age-dependent changes in pharmacokinetics, and polymorphisms in glutathione transferase zeta 1 (GSTZ1), its primary metabolizing enzyme. Our objective was to predict optimal DCA doses for the treatment of congenital lactic acidosis in children. Accordingly, a semimechanistic pharmacokinetic-enzyme turnover model was developed in a step-wise approach: (1) a population pharmacokinetic model for adults was developed; (2) the adult model was scaled to children using allometry and physiology-based scaling; and (3) the scaled model was externally qualified, updated with clinical data, and optimal doses were projected. A 2-compartment model accounting for saturable clearance and GSTZ1 enzyme turnover successfully characterized the DCA PK in adults and children. DCA-induced inactivation of GSTZ1 resulted in phenoconversion of all subjects into slow metabolizers after repeated dosing. However, rate and extent of inactivation was 2-fold higher in subjects without the wild-type EGT allelic variant of GSTZ1, resulting in further phenoconversion into ultraslow metabolizers after repeated DCA administration. Furthermore, DCA-induced GSTZ1 inactivation rate and extent was found to be 25- to 30-fold lower in children than in adults, potentially accounting for the observed age-dependent changes in PK. Finally, a 12.5 and 10.6 mg/kg twice-daily DCA dose was optimal in achieving the target steady-state trough concentrations (5-25 mg/L) for EGT carrier and EGT noncarrier children, respectively.

Response Rates as Predictors of Overall Survival: A Meta-Analysis of Acute Myeloid Leukemia Trials.

Background: Response rates such as overall response rate (ORR), complete response (CR) and complete response with incomplete blood recovery (CRi) can be evaluated in a much shorter period of time than overall survival (OS), potentially accelerating decision making during drug development. The objective of this work was to evaluate the relationship between ORR, CR, CRi or better (CRi+CR) rates and median OS to determine whether response rates could be used as predictors of median OS in acute myeloid leukemia (AML). Methods: A review of published literature was conducted to identify relevant AML clinical trials. Weighted linear regression was performed with various linearizing transformations of response rates and median OS. Covariates of interest were evaluated using a forward inclusion, backward elimination covariate model building procedure at α=0.01 and α=0.005, respectively. Results: Twenty trials involving 26 cohorts were included in the meta-analysis. Azactidine treatment was a significant predictor with longer OS compared to decitabine or low dose cytarabine for a given response rate (P < 0.005). Linear regression analysis indicated that the correlation of both CRi or better rates and CR rates with median OS was higher than that of ORR with median OS. The final model showed a strong correlation between CRi or better rates and median OS (R2=0.66). Conclusion: Significant correlation between CRi or better rates and median OS in AML highlights the potential for CRi or better rate, in addition to CR rate, to serve as surrogate markers for median OS.

Impact of the CYP2C19 genotype on voriconazole exposure in adults with invasive fungal infections.

OBJECTIVES: Voriconazole, a first-line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant proportion of patients fail to achieve therapeutic trough concentrations with standard weight-based voriconazole dosing, placing them at increased risk for treatment failure, which can be life threatening. We sought to test the association between the CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs. PATIENT AND METHODS: Adults receiving weight-based voriconazole dosing for the treatment of IFIs were genotyped for the CYP2C19*2, *3, and *17 polymorphisms, and CYP2C19 metabolizer phenotypes were inferred. Steady-state voriconazole trough plasma concentrations and the prevalence of subtherapeutic troughs (<2 mg/l) were compared between patients with the CYP2C19*17/*17 (ultrarapid metabolizer, UM) or *1/*17 (rapid metabolizer, RM) genotype versus those with other genotypes. Logistic regression, adjusting for clinical factors, was performed to estimate the odds of subtherapeutic concentrations. RESULTS: Of 70 patients included (mean age 52.5±18 years), 39% were RMs or UMs. Compared with patients with the other phenotypes, RMs/UMs had a lower steady-state trough concentration (4.26±2.2 vs. 2.86±2.3, P=0.0093) and a higher prevalence of subtherapeutic troughs (16 vs. 52%, P=0.0028), with an odds ratio of 5.6 (95% confidence interval: 1.64-19.24, P=0.0044). CONCLUSION: Our findings indicate that adults with the CYP2C19 RM or UM phenotype are more likely to have subtherapeutic concentrations with weight-based voriconazole dosing. These results corroborate previous findings in children and support the potential clinical utility of CYP2C19 genotype-guided voriconazole dosing to avoid underexposure in RMs and UMs.

Quantitative clinical pharmacology for size and age scaling in pediatric drug development: A systematic review.

The establishment of drug dosing in children is often hindered by the lack of actual pediatric efficacy and safety data. To overcome this limitation, scaling approaches are frequently employed to leverage adult clinical information for informing pediatric dosing. The objective of this review is to provide a comprehensive overview of the different scaling approaches used in pediatric pharmacotherapy as well as their proper implementation in drug development and clinical use. We will start out with a brief overview of the current regulatory requirements in pediatric drug development, followed by a review of the most commonly employed scaling approaches in increasing order of complexity ranging from simple body weight-based dosing to physiologically-based pharmacokinetic (PBPK) modeling approaches. Each of the presented approaches has advantages and limitations, which will be highlighted throughout the course of the review by the use of clinically-relevant examples. The choice of the approach employed consequently depends on the clinical question at hand and the availability of sufficient clinical data. The main effort while establishing and qualifying these scaling approaches should be directed towards the development of safe and effective dosing regimens in children rather than identifying the best model, ie models should be fit for purpose.