Clinical Pharmacology & Therapeutics最新文献

Despite being approved by the US FDA and the EU European Medicines Agency, the performance of esketamine nasal spray as an adjunctive therapy with an antidepressant in major depressive disorder is still controversial. Comprehensive retrieval in Embase, Pubmed, and Web of Science was conducted to identify randomized controlled trials comparing esketamine nasal spray versus control in major depressive disorder or treatment-resistant depression. The primary efficacy outcome was a reduction of the Montgomery-Asberg Depression Rating Scale, from baseline to Day 2 or Day 28 for patients with or without suicidal ideation, respectively. The long-term efficacy outcome was the relapse rate of patients who achieved stable remission. The certainty of evidence was assessed according to the Cochrane recommendation. Esketamine nasal spray was superior to placebo in reduction of Montgomery-Asberg Depression Rating Scale from baseline to Day 28 in patients without suicidal ideation (standardized mean difference: -0.24, 95% confidence interval: -0.38, -0.09, P = 0.001, I² = 24%), and on Day 2 in patients with suicidal ideation (standardized mean difference: -0.30, 95% confidence interval: -0.47, -0.12, P = 0.0008, I² = 0%). The long-term relapse rate was significantly lower in the esketamine nasal spray group than in the placebo/quetiapine group (risk ratio: RR: 0.60, 95% confidence interval: 0.45-0.80, I² = 0%). The rate of suicidal ideation was similar between the two groups. The certainty of evidence was graded as "moderate" or "high" in the abovementioned results. Esketamine nasal spray in conjunction with an antidepressant effectively controls short-term and long-term depressive symptoms in major depressive disorder and treatment-resistant depression, with a manageable trade-off between efficacy and safety.

OATP1B, P-gp, BCRP, and CYP3A are the most contributing drug-metabolizing enzymes or transporters (DMETs) for commonly prescribed medication. Their activities may change in end-stage renal disease (ESRD) patients with large inter-individual variabilities (IIVs), leading to altered substrate drug exposure and ultimately elevated safety risk. However, the changing extent and indictive influencing factors are not quantified so far. Here, a microdose cocktail regimen containing five sensitive substrate drugs (pitavastatin, dabigatran etexilate, rosuvastatin, midazolam, and atorvastatin) for these DMETs was administrated to Chinese healthy volunteers and ESRD patients. Drug pharmacokinetics profiles were determined, together with physiological, pharmacogenetic, and gut microbiome signature. Population pharmacokinetic and machine learning model were established to identify key influencing factors and quantify their contribution to drug exposure change. The exposure of pitavastatin, dabigatran, rosuvastatin, and atorvastatin increased to 1.8-, 3.1-, 1.1-, and 1.3-fold, respectively, whereas midazolam exposure decreased by 72% in ESRD patients. Notably, in addition to disease state, the relative abundance of genus Veillonella and Clostridium_XIVb were firstly identified as significant influencing factors for PTV and RSV apparent clearance, respectively, suggesting their indicative role for OATP and BCRP activity evaluation. Moreover, several genera were found to strongly associate with drug clearance and reduce unexplained IIVs. Accordingly, it was estimated that OATP1B and intestine P-gp activity decreased by 35-75% and 29-44%, respectively, whereas BCRP and CYP3A4 activity may upregulate to some extent. Our study provides a quantitative and mechanistic understanding of individual DMET activity and could support precision medicine of substrate drugs in ESRD patients.

The value of a medicine is defined by its impact on patients, caregivers, health system, and society. A pharmaceutical company will generate evidence to demonstrate this value in various studies, including randomized clinical trials, non-interventional and observational studies, real-world data analyses, modeling, and simulation. The quality and strength of the evidence supporting a medicine's effectiveness, safety and product quality will drive decisions by healthcare system stakeholders for marketing authorization (regulatory authorities). Additional evidence of comparative clinical, humanistic, economic, and societal value of the medicine will be critical for reimbursement coverage by HTA (health technology assessment) bodies and payers, guideline inclusion by clinical societies, and ultimately the treatment decision between a patient and their healthcare provider (HCP). The purpose of this article is to provide practical guidance for an effective approach to evidence planning for pharmaceutical companies. In the first section, we give a brief overview of the requirements for evidence generation from the perspectives of healthcare system decision makers, key functions involved in evidence generation within a pharmaceutical company, and different archetypes of products. We then discuss how a company can implement effective integrated evidence planning across the lifecycle of a product. We also review how requirements are likely to evolve given recent changes in major healthcare system regulations, such as Centers for Medicare & Medicaid Services (CMS) drug price negotiations in the US and EU HTA Regulation (HTAR) in Europe, and finally provide some practical recommendations of how to start implementing a new integrated evidence approach.

Pharmacogenetic testing can prevent severe toxicities from several oncology drug therapies; it also has the potential to improve the outcomes from supportive care drugs. Paired tumor and germline sequencing is increasingly common in oncology practice; these include sequencing of pharmacogenes, but the germline pharmacogenetic variants are rarely included in the clinical reports, despite many being clinically actionable. We established an informatics workflow to evaluate the clinical sequencing results for pharmacogenetic variants. We used the Aldy computational tool, which we have previously shown to determine the variant alleles in 14 pharmacogenes in clinical sequencing data with >99% accuracy, to identify pharmacogenetic variants in the clinical whole exome sequencing from our molecular tumor board. Patients with genetic variants that are clinically actionable for their individual therapy programs, including both treatment and supportive care, are referred to a clinical pharmacogenetics testing laboratory for confirmation. Through an evaluation of our weekly informatics workflow, we determined it took approximately 3.25 hours to complete the analysis of the sequencing data from approximately 20 patients. Using a United States pharmacist's median salary, we estimated the incremental added cost of the process to be only ~$15 per patient. This adds only a minor increase to the patient's cost of testing and has the potential to improve the safety and efficacy of their treatment.

Studies with negative results are less likely to be published than others, potentially leading to publication bias. Introduced in 2000, trial registration could have participated in decreasing the proportion of unpublished studies. We assessed the proportion of negative randomized controlled trials (RCT) over the last 20 years. We searched Medline for RCT published in 2000, 2005, 2010, 2015, and 2020 in the British Medical Journal, the Journal of the American Medical Association, the Lancet, and the New England Journal of Medicine. The primary endpoint was the proportion of negative (final comparison on the primary study-endpoint without statistical significance or favoring the control arm) studies published in 2000 and 2020. Factors independently associated with the publication of negative studies were identified using multivariable analysis. A total of 1,542 studies were included. The proportion of negative RCT significantly increased between 2000 and 2020 (from 27.6% to 37.4%; P = 0.01), however, the trend over time was not significant (P = 0.203). In multivariable analysis, the following factors were associated with a higher proportion of published negative studies: superiority (P < 0.001), two-group trials (P < 0.001), number of patients ≥510 (P < 0.001), cardiology trials (P = 0.003), emergency/critical care trials (P < 0.001), obstetrics trials (P = 0.032), surgery trials (P = 0.006), pneumology trials (P = 0.029). Exclusive industry funding was associated with a lower proportion of published negative studies (P < 0.001). The proportion of published negative studies in 2020 was higher only when compared to 2000. During the two decades, no trend was noticeable. There is no clear relationship between trial registration and the publication of negative results over time.

Two observational studies were conducted to support an initiative to qualify translational kidney safety biomarkers as clinical drug development tools that identify tubular injury prior to changes in estimated glomerular filtration rate (eGFR). Normal healthy volunteers provided three morning spot urine collections over 4 weeks. Patients undergoing surgical resection and intrathoracic cisplatin for malignant pleural mesothelioma provided urine samples pre- and postoperatively at 4, 8, and 12 hours and daily for 6 days. Using receiver-operating characteristics curves, "statistically significant thresholds" established peak longitudinal changes for 8 biomarkers to differentiate mesothelioma patients who developed acute kidney injury (AKI) from normal healthy volunteers. We also assessed "medically significant thresholds" to differentiate mesothelioma patients who did vs. did not develop AKI. Statistically and medically significant thresholds for a fold-change from baseline of urine creatinine (UCr)-normalized values were established for 6 biomarkers: clusterin (2.2, 5.1); osteopontin (3.1, 7.1); N-acetyl-ß-D-glucosaminidase (2.7, 8.1); kidney injury molecule-1 (4.3, 7.5); cystatin C (1.8, 4.5); neutrophil gelatinase-associated lipocalin (2.9, 7.8). For urine albumin and total protein, thresholds were established based on UCr-normalized absolute values: (> upper limit normal, > 10× upper limit normal). Statistically significant thresholds for all biomarkers outperformed eGFR at discriminating mesothelioma subjects exposed to cisplatin from healthy volunteers, demonstrating their utility for enhancing safe drug development. Medically significant thresholds provide perspective on when patients begin to exhibit AKI. These studies have established guideposts for confirmatory studies with additional cohorts and nephrotoxicants to formally qualify the selected biomarkers with worldwide regulatory authorities.

Recent discussions about the utilization of real-world data (RWD) and real-world evidence (RWE) have been more focused on drug development for regulatory approval rather than during the post-marketing stage. In Japan, RWD/RWE have been practically utilized as an external control for drug approval. Most cases were related to orphan diseases where the feasibility of conducting randomized controlled clinical trials was generally low. The utilization of RWD/RWE as an external control provides additional information that can support regulatory review for drug approval. However, many points should be taken into consideration through all stages of a study that is based on RWD/RWE, including planning, analysis, and interpretation. In this article, we present our recent review experience focusing on efficacy evaluations with an external control based on RWD/RWE that were submitted as a part of new drug applications in Japan, and we describe our regulatory consideration of the utilization of RWD/RWE for drug evaluation and approval. Points described in this article promote appropriate drug development based on RWD/RWE and facilitate a proper discussion about RWD/RWE utilization with PMDA. Further accumulation of regulatory experience in PMDA with RWD/RWE utilization will enhance our knowledge and contribute to better regulatory decision making for drug approvals based on RWD/RWE.

Physiologically Based Pharmacokinetic (PBPK) Models are routinely used in drug development and therefore appear frequently in marketing authorization applications (MAAs) to the European Medicines Agency (EMA). For a model to be a key source of evidence for a regulatory decision, it must be considered qualified for the intended use. Advice on the data expected to allow qualification of a PBPK model or platform is provided in the EMA Guideline on the reporting of PBPK modeling and simulation. The present study is an EMA review of the use of PBPK models in submitted MAAs in 2022 and 2023 focussing on the concept of qualification and the reasons why models were not considered qualified. A review of the 95 MAAs with a “full” legal basis approved during these years showed that 25 of them contained PBPK modeling. There were 65 proposed general areas of intended use for PBPK modeling identified across the applications, with the most common being a prediction of drug–drug interactions with enzymes or transporters (69%). Finally, this review showed that most of the models submitted in applications to EMA were not considered qualified for the intended use(s). The reasons identified for this are reported and the need for further EMA guidance, particularly around requirements for qualification of PBPK models, are discussed.

Green tea (Camellia sinensis) is a commonly consumed beverage or dietary supplement. As a natural product with a myriad of proposed health benefits, patients are likely to consume green tea while taking their medications unaware of its potential to interact with drugs and influence drug efficacy and safety. Catechins are the abundant polyphenolic compounds in green tea (e.g., (-)-epigallocatechin-3-gallate), which are reported to influence determinants of drug pharmacokinetics, such as drug solubility and the activity of drug transporters and drug metabolizing enzymes. This review summarized the results of clinical studies investigating the influence of green tea catechins on the pharmacokinetics of clinically used medications. The majority of analyses (72%) reported significant decreases (by 18-99%) in systemic drug exposure with green tea consumption (atorvastatin, celiprolol, digoxin, fexofenadine, folic acid, lisinopril, nadolol, nintedanib, raloxifene, and rosuvastatin). One analysis (6%) reported a 50% increase in drug systemic exposure (sildenafil) and for 22% of analyses drug pharmacokinetics were not affected by green tea consumption (fluvastatin, pseudoephedrine, simvastatin, and tamoxifen). For most drugs reporting an interaction, green tea catechins were proposed to decrease intestinal drug absorption by inhibiting OATP uptake (particularly OATP1A2), enhancing P-gp efflux activity or reducing drug solubility. Case reports have associated changes in drug pharmacokinetics with green tea consumption to changes in drug efficacy or safety (e.g., nadolol and erlotinib). These findings prompt the need for further research in relating evidence from existing literature to predict additional clinically important green tea-drug interactions and to provide appropriate recommendations for patients and clinicians.

The complexity of the currently registered dosing schedules for bedaquiline and delamanid is a barrier to uptake in drug-resistant tuberculosis treatment across all ages. A simpler once-daily dosing schedule is critical to ensure patient-friendly regimens with good adherence. We assessed expected drug exposures with proposed once-daily doses for adults and compared novel model-informed once-daily dosing strategies for children with current World Health Organization (WHO) recommended dosing. A reference individual and virtual pediatric population were generated to simulate exposures in adults and children, respectively. Published population models characterizing the exposures of bedaquiline and its metabolite M2, delamanid, and its metabolite DM-6705 were utilized. During simulation, child growth during treatment along with several CYP3A4 ontogeny profiles was accounted for. Exposures in children were compared with simulated adult targets to assess the expected treatment efficacy and safety. In adults, the proposed bedaquiline once-daily dosing (400 mg daily for 2 weeks followed by 100 mg daily for 22 weeks) yielded 14% higher exposures of bedaquiline and M2 compared to the labeled dosing scheme at 24 weeks; for delamanid and DM-6705, the suggested 300 mg daily dose provided 13% lower exposures at steady state. For children, the cumulative proportions of exposures of both drugs showed < 5% difference between WHO-recommended and proposed once-daily dosing. This study demonstrated the use of model-informed approaches to propose rational and simpler regimens for bedaquiline and delamanid in adults and children. The new once-daily dosing strategies will be tested in the PARADIGM4TB and IMPAACT 2020 trials in adults and children, respectively.