Real-world data on herb-drug interactions in oncology: A scoping review of pharmacoepidemiological studies.

BACKGROUND: The concurrent use of conventional drugs and herbal medicines is becoming popular among patients with cancer. However, the potential risk of herb-drug interactions (HDI) remains under-addressed in the literature. Previous reviews have mainly focused on the prevalence of interactions, with less attention paid to the methods used by pharmacoepidemiological studies on evaluating HDI. This scoping review aims to summarize the existing pharmacoepidemiological studies that evaluate HDI using real-world data and to identify gaps to be addressed in future research. METHODS: A comprehensive search was performed in nine English- and Chinese-language databases from their inception to May 2021. Gray literature and manual searches were conducted to identify additional studies. The recommended components of the pharmacoepidemiological studies and key findings related to HDI were summarized. The proportion (%) of patients with cancer at risk of HDI was estimated by combining data from eligible studies. RESULTS: Twenty-eight studies were included in the review. More than half of these studies were cross-sectional studies (n = 18, 64.3%), followed by retrospective cohort studies (n = 5, 17.9%) and prospective cohort studies (n = 2, 7.1%). The three cancer drugs most commonly studied for their interaction potential with herbs were tamoxifen (n = 11, 39.3%), cyclophosphamide (n = 6, 21.4%), and paclitaxel (n = 6, 21.4%). Most cross-sectional studies identified potential HDI using tertiary databases and primary literature searches. Conversely, prospective and retrospective studies mainly investigated actual clinical outcomes, such as adverse events and secondary cancer occurrences. Most interaction outcomes identified using real-world data did not lead to negative clinical consequences. Collectively, 45.4% of herbal medicine users of the included studies were found to be at risk of HDI. We infer from this review that the common limitations of these studies were limited sample size, lack of data on herbal medicine use and details of HDI, and lack of evidence of HDI. Based on the study limitations, several recommendations to enrich the data sources and optimize the study designs were proposed. CONCLUSIONS: There is a high demand for pharmacoepidemiological research on HDI, considering the increasing popularity of herbal medicine among patients with cancer. It is anticipated that emerging real-world data in this field can guide the development of safe and effective approaches to integrative oncology.

Application of exposure bracketing to streamline the development of contraceptive products.

Developing new long-acting products of well-characterized contraceptive drugs is one way to address some of the reasons for unmet need for modern methods of family planning among women in low- and middle-income countries. Development and approval of such products traditionally follow a conventional paradigm that includes large Phase 3 clinical trials to evaluate efficacy (pregnancy prevention) and safety of the investigational product. Exposure-bracketing is a concept that applies known pharmacokinetics and pharmacodynamics of a drug substance to inform its safe and efficacious use in humans. Several therapeutic areas have applied this concept by leveraging established drug concentration-response relationships for approved products to expedite development and shorten the timeline for the approval of an investigational product containing the same drug substance. Based on discussions at a workshop hosted by the Bill & Melinda Gates Foundation in December 2020, it appears feasible to apply exposure-bracketing to develop novel contraceptive products using well-characterized drugs.

Development and validation of a paper spray mass spectrometry method for the rapid quantitation of remdesivir and its active metabolite, GS-441524, in human plasma.

Introduction: Remdesivir (GS-5734) is a nucleoside analog prodrug with antiviral activity against several single-stranded RNA viruses, including the novel severe respiratory distress syndrome virus 2 (SARS-CoV-2). It is currently the only FDA-approved antiviral agent for the treatment of individuals with COVID-19 caused by SARS-CoV-2. However, remdesivir pharmacokinetics/pharmacodynamics (PK/PD) and toxicity data in humans are extremely limited. It is imperative that precise analytical methods for the quantification of remdesivir and its active metabolite, GS-441524, are developed for use in further studies. We report, herein, the first validated anti-viral paper spray-mass spectrometry (PS-MS/MS) assay for the quantification of remdesivir and GS-441524 in human plasma. We seek to highlight the utility of PS-MS/MS technology and automation advancements for its potential future use in clinical research and the clinical laboratory setting. Methods: Calibration curves for remdesivir and GS-441524 were created utilizing seven plasma-based calibrants of varying concentrations and two isotopic internal standards of set concentrations. Four plasma-based quality controls were prepared in a similar fashion to the calibrants and utilized for validation. No sample preparation was needed. Briefly, plasma samples were spotted on a paper substrate contained within pre-manufactured plastic cassette plates, and the spots were dried for 1 h. The samples were then analyzed directly for 1.2 min utilizing PS-MS/MS. All experiments were performed on a Thermo Scientific Altis triple quadrupole mass spectrometer utilizing automated technology. Results: The calibration ranges were 20 - 5000 and 100 - 25000 ng/mL for remdesivir and GS-441524, respectively. The calibration curves for the two antiviral agents showed excellent linearity (average R2 = 0.99-1.00). The inter- and intra-day precision (%CV) across validation runs at four QC levels for both analytes was less than 11.2% and accuracy (%bias) was within ± 15%. Plasma calibrant stability was assessed and degradation for the 4 °C and room temperature samples were seen beginning at Day 7. The plasma calibrants were stable at -20 °C. No interference, matrix effects, or carryover was discovered during the validation process. Conclusions: PS-MS/MS represents a useful methodology for rapidly quantifying remdesivir and GS-441524, which may be useful for clinical PK/PD, therapeutic drug monitoring (TDM), and toxicity assessment, particularly during the current COVID-19 pandemic and future viral outbreaks.

Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders.

Urea cycle disorders (UCDs), inborn errors of hepatocyte metabolism, cause hyperammonemia and lead to neurocognitive deficits, coma, and even death. Sodium 4-phenylbutyrate (NaPB), a standard adjunctive therapy for UCDs, generates an alternative pathway of nitrogen deposition through glutamine consumption. Administration during or immediately after a meal is the approved usage of NaPB. However, we previously found that preprandial oral administration enhanced its potency in healthy adults and pediatric patients with intrahepatic cholestasis. The present study evaluated the effect of food on the pharmacokinetics and pharmacodynamics of NaPB in five patients with UCDs. Following an overnight fast, NaPB was administered orally at 75 mg/kg/dose (high dose, HD) or 25 mg/kg/dose (low dose, LD) either 15 min before or immediately after breakfast. Each patient was treated with these four treatment regimens with NaPB. With either dose, pre-breakfast administration rather than post-breakfast administration significantly increased plasma PB levels and decreased plasma glutamine availability. Pre-breakfast LD administration resulted in a greater attenuation in plasma glutamine availability than post-breakfast HD administration. Plasma levels of branched-chain amino acids decreased to the same extent in all tested regimens. No severe adverse events occurred during this study. In conclusion, preprandial oral administration of NaPB maximized systemic exposure of PB and thereby its efficacy on glutamine consumption in patients with UCDs.

Deimmunization of protein therapeutics - Recent advances in experimental and computational epitope prediction and deletion.

Biotherapeutics, and antimicrobial proteins in particular, are of increasing interest for human medicine. An important challenge in the development of such therapeutics is their potential immunogenicity, which can induce production of anti-drug-antibodies, resulting in altered pharmacokinetics, reduced efficacy, and potentially severe anaphylactic or hypersensitivity reactions. For this reason, the development and application of effective deimmunization methods for protein drugs is of utmost importance. Deimmunization may be achieved by unspecific shielding approaches, which include PEGylation, fusion to polypeptides (e.g., XTEN or PAS), reductive methylation, glycosylation, and polysialylation. Alternatively, the identification of epitopes for T cells or B cells and their subsequent deletion through site-directed mutagenesis represent promising deimmunization strategies and can be accomplished through either experimental or computational approaches. This review highlights the most recent advances and current challenges in the deimmunization of protein therapeutics, with a special focus on computational epitope prediction and deletion tools.

Efficacy predictors of omalizumab in Chinese patients with moderate-to-severe allergic asthma: Findings from a post-hoc analysis of a randomised phase III study.

BACKGROUND: Omalizumab has demonstrated efficacy as an add-on therapy in Chinese patients with moderate-to-severe allergic asthma. This post-hoc analysis assessed the potential predictors for the efficacy of omalizumab in these patients. METHODS: A post-hoc analysis was performed on a Phase III, randomised, controlled study conducted in Chinese patients with moderate-to-severe persistent allergic asthma (NCT01202903). We evaluated if levels of pre-treatment serum total immunoglobulin-E (IgE) and blood eosinophil (EOS), asthma severity, allergen profile, history of perennial allergic rhinitis (PAR), and free IgE level during omalizumab treatment were predictive of omalizumab's efficacy. RESULTS: This analysis included 608 patients (omalizumab, N = 306; placebo, N = 302). Improvements in forced expiratory volume in 1 s (FEV1), standardized Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Questionnaire (ACQ), and Global Evaluation of Treatment Effectiveness (GETE) scores with omalizumab treatment compared with placebo were observed in patients with baseline IgE levels ≥76 IU/mL (irrespective of the EOS count). Relatively greater improvements with omalizumab treatment was also noted in patients with both moderate or severe allergic asthma (regardless of asthma severity), and patients sensitised to >3 allergens and with a history of PAR. All patients who were treated with omalizumab achieved free IgE levels below 50 ng/mL by Week 1. Similar clinical outcomes were observed in the subset of patients who achieved free IgE levels of <25 and ≥ 25 ng/mL. CONCLUSIONS: In Chinese patients with moderate-to-severe allergic asthma, baseline IgE and allergen profile (number/PAR history) are potential predictors of treatment response to omalizumab. TRIAL REGISTRATION: NCT01202903 (www.clinicaltrials.gov).

Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy.

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure-activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRß simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.

A sensitive method for the simultaneous UHPLC-MS/MS analysis of milrinone and dobutamine in blood plasma using NH4F as the eluent additive and ascorbic acid as a stabilizer.

The purpose of this work was to develop and validate an HPLC-MS/MS method suitable for quantifying two important cardiovascular drugs, milrinone and dobutamine, in neonatal and paediatric patients' blood plasma samples. Sufficiently low LLOQ levels were required to obtain adequate pharmacokinetic data for the evaluation of optimal dosing. Since the specifics of the patient group set some restrictions on the available sample volume, the method was designed to use only 20 µL of plasma for the analysis. Analytes were separated chromatographically in a biphenyl column using a conventional water-methanol-formic acid eluent with the addition of ammonium fluoride. The latter provided a significant signal enhancement in positive ion mode detection for both analytes allowing the LLOQ to reach below 1 ng/mL. Matrix matched calibration was linear in the range of 1-300 ng/mL, between-run accuracy remained within 107-115%, and precision within 4.8-7.4% for both analytes over the calibration range (including LLOQ level). Dobutamine degradation in plasma samples was prevented by the usage of ascorbic acid. The method was applied to plasma samples of neonates from two pharmacokinetic/pharmacodynamics studies (n = 38).

Microfluidic Organ-on-a-Chip Models of Human Intestine.

Microfluidic organ-on-a-chip models of human intestine have been developed and used to study intestinal physiology and pathophysiology. In this article, we review this field and describe how microfluidic Intestine Chips offer new capabilities not possible with conventional culture systems or organoid cultures, including the ability to analyze contributions of individual cellular, chemical, and physical control parameters one-at-a-time; to coculture human intestinal cells with commensal microbiome for extended times; and to create human-relevant disease models. We also discuss potential future applications of human Intestine Chips, including how they might be used for drug development and personalized medicine.

Recent developments in topoisomerase-targeted cancer chemotherapy.

The DNA topoisomerase enzymes are essential to cell function and are found ubiquitously in all domains of life. The various topoisomerase enzymes perform a wide range of functions related to the maintenance of DNA topology during DNA replication, and transcription are the targets of a wide range of antimicrobial and cancer chemotherapeutic agents. Natural product-derived agents, such as the camptothecin, anthracycline, and podophyllotoxin drugs, have seen broad use in the treatment of many types of cancer. Selective targeting of the topoisomerase enzymes for cancer treatment continues to be a highly active area of basic and clinical research. The focus of this review will be to summarize the current state of the art with respect to clinically used topoisomerase inhibitors for targeted cancer treatment and to discuss the pharmacology and chemistry of promising new topoisomerase inhibitors in clinical and pre-clinical development.

A feasibility study prior to an international multicentre paediatric study to assess pharmacokinetic/pharmacodynamic sampling and sample preparation procedures, logistics and bioanalysis.

BACKGROUND: Variability in pre-analytical procedures such as blood sampling, sample preparation and transport can substantially influence bioanalytical results and subsequently impair reliability of data gathered during clinical trials. Especially in vulnerable populations, all efforts should be made to facilitate high-quality data extraction excluding unnecessary or repeated intervention. METHODS: The EU-funded LENA project (Labeling of Enalapril from Neonates up to Adolescents) included a feasibility study in its preparatory procedures prior to first-in-child studies. Derived from a regular study visit, it encompassed all procedures, from sampling of two study-specific drugs and four sensitive humoral parameters to bioanalysis, to evaluate the quality of obtained samples and applicability of logistical and bioanalytical procedures. Drug administration to healthy adults was circumvented by pre-spiking the blood collection tubes with a drug solution. Five clinical sites were evaluated. RESULTS: Clinical teams' preparedness and applicability of required sampling procedures was investigated in 18 volunteers, on-site. 97% of collected pharmacokinetic (PK) samples and 93% of samples for humoral parameters were obtained eligibly. Results met expectations, though one team had to be re-trained and performed a re-run. Planned procedures for sampling, sample preparation, transport and analysis were found to be suitable for being applied within paediatric trials. CONCLUSION: The concept of the presented feasibility study that simultaneously assesses PK/PD sampling, sample preparation, logistics and bioanalysis proved to be a promising tool for trial preparation. It revealed improperly installed processes and bottlenecks that required adjustments prior to start of recruitment. It facilitated high-quality conduct from the first moment of paediatric pivotal studies.

Pharmacogenomics-guided policy in opioid use disorder (OUD) management: An ethnically-diverse case-based approach.

INTRODUCTION: Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes. METHODS: We analyzed a patient who reported discomfort at daily buprenorphine dose of 24 mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management. RESULTS: At the 24 mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32 mg) for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing. CONCLUSION: Pharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management.

Bioanalytical strategy used in development of pharmacokinetic (PK) methods that support biosimilar programs.

The development of biosimilar products is expected to grow rapidly over the next five years as a large number of approved biologics reach patent expiry. The pathway to regulatory approval requires that similarity of the biosimilar to the reference product be demonstrated through physiochemical and structural characterization, as well as within in vivo studies that compare the safety and efficacy profiles of the products. To support nonclinical and clinical studies pharmacokinetic (PK) assays are required to measure the biosimilar and reference products with comparable precision and accuracy. The most optimal approach is to develop a single PK assay, using a single analytical standard, for quantitative measurement of the biosimilar and reference products in serum matrix. Use of a single PK assay for quantification of multiple products requires a scientifically sound testing strategy to evaluate bioanalytical comparability of the test products within the method, and provide a solid data package to support the conclusions. To meet these objectives, a comprehensive approach with scientific rigor was applied to the development and characterization of PK assays that are used in support of biosimilar programs. Herein we describe the bioanalytical strategy and testing paradigm that has been used across several programs to determine bioanalytical comparability of the biosimilar and reference products. Data from one program is presented, with statistical results demonstrating the biosimilar and reference products were bioanalytically equivalent within the method. The cumulative work has established a framework for future biosimilar PK assay development.

Critical role of bioanalytical strategies in investigation of clinical PK observations, a Phase I case study.

RG7652 is a human immunoglobulin 1 (IgG1) monoclonal antibody (mAb) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and is designed for the treatment of hypercholesterolemia. A target-binding enzyme-linked immunosorbent assay (ELISA) was developed to measure RG7652 levels in human serum in a Phase I study. Although target-binding assay formats are generally used to quantify free therapeutic, the actual therapeutic species being measured are affected by assay conditions, such as sample dilution and incubation time, and levels of soluble target in the samples. Therefore, in the presence of high concentrations of circulating target, the choice of reagents and assay conditions can have a significant effect on the observed pharmacokinetic (PK) profiles. Phase I RG7652 PK analysis using the ELISA data resulted in a nonlinear dose normalized exposure. An investigation was conducted to characterize the ELISA to determine whether the assay format and reagents may have contributed to the PK observation. In addition, to confirm the ELISA results, a second orthogonal method, liquid chromatography tandem mass spectrometry (LC-MS/MS) using a signature peptide as surrogate, was developed and implemented. A subset of PK samples, randomly selected from half of the subjects in the 6 single ascending dose (SAD) cohorts in the Phase I clinical study, was analyzed with the LC-MS/MS assay, and the data were found to be comparable to the ELISA data. This paper illustrates the importance of reagent characterization, as well as the benefits of using an orthogonal approach to eliminate bioanalytical contributions when encountering unexpected observations.