Clinical Pharmacology & Therapeutics最新文献

The KEYNOTE-042^1,2 trial showed the benefit of treating patients with non-oncogene addicted advanced NSCLC with PD-L1 tumor proportion score over 50% with pembrolizumab as monotherapy over platinum-doublet chemotherapy. To contextualize these results, we undertake a detailed emulation of the inclusion criteria in KEYNOTE-042 using Norwegian health registry data and discuss both the clinical contexts, as well as the general utility of such registry data for pharmacoepidemiologic research in oncology. Within the population of patients with PD-L1 tumor proportion score over 50%, an observational analog of an intention-to-treat analysis showed similar results to those of the KEYNOTE-042 study.

Platelet reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT) is heterogeneous and influenced by various patient- and transplantation-related factors, associated with poor prognoses for poor graft function (PGF) and isolated thrombocytopenia. Tailored interventions could improve the outcome of patients with PGF and post-HCT thrombocytopenia. To provide individual predictions of 180-day platelet counts from early phase data, we developed a model of long-term platelet reconstitution after allo-HCT. A large cohort (n = 1949) of adult patients undergoing their first allo-HCT was included. Real-world data from 1,048 retrospective patients were used for non-linear mixed-effects model development. Bayesian forecasting was used to predict platelet-time profiles for 518 retrospective and 383 prospective patients during internal and external model validation, respectively. Thrombocytopenia was defined as mean platelet count < 75 × 10⁹/L, derived from the last 12 platelet measurements within the first 180 days post-HCT. Thrombocytopenia affected 37% of all patients and was associated with significantly reduced overall survival (P-value < 0.0001). On days +7, +14, +21, and +28, the developed model achieved areas under the receiver-operating characteristic of ≥ 0.68, ≥ 0.75, ≥ 0.78, and 0.81 for the prediction of post-HCT thrombocytopenia, respectively, with anti-thymocyte globulin, donor relation, and total protein measurements representing prognostic markers for post-HCT platelet kinetics. A publicly accessible web-based demonstrator of the model was established (https://hsct.precisiondosing.de). In summary, the developed model predicts individual platelet counts from day +28 post-HCT adequately, utilizing internal and external datasets. The web-based demonstrator provides a basis to implement model-based predictions in clinical practice and to confirm these findings in future clinical studies.

Aurora kinases are a family of serine/threonine kinases that includes Aurora kinase A, Aurora kinase B, and Aurora kinase C. These kinases play crucial roles in mitotic spindle formation and cell proliferation. Over the past several decades, extensive research has elucidated the multifaceted roles of Aurora kinases in cancer development and progression. Recent studies have also highlighted the significant involvement of Aurora kinases in various kidney diseases, such as renal cell carcinoma, diabetic nephropathy, chronic kidney disease, and polycystic kidney disease. The mechanisms by which Aurora kinases contribute to renal diseases are complex and influenced by both specific pathological conditions and environmental factors. In this review, we comprehensively summarize the role and mechanisms through which Aurora kinases operate in kidney diseases and discuss the efficacy and application of existing inhibitors targeting these kinases in managing renal disorders in animal models.

Pivotal clinical trials (PCTs) are often conducted across multiple nations and regions to achieve geographic, racial, or ethnic diversity. However, the diversity of PCT participants remains inadequate. PCTs for new drugs approved by the US Food and Drug Administration in 2012-2021 and their primary publications (PPub) were identified from the label and review documents. The country information about the PCT investigators and PPub authors were extracted from the PPubs or clinicaltrials.gov. The racial/ethnic diversity of PCT participants as reported in PPubs was assessed using the Diversity Index (DI). For 429 new drugs, 734 PCTs and 718 PPubs were identified. North America and Western Europe (NAWE) contributed the largest proportion of PCT investigators, PPub authors, and lead authors (62.9%, 81.7%, and 90.9%, respectively). Of 521 PPubs that reported the racial/ethnic distribution of PCT participants, the median DI was low at 0.33 (interquartile range 0.18-0.46) and only 16.3% PPubs had a DI >0.5. The number of PPub authors in non-NAWE and the number of countries of PPub authors in non-NAWE was significantly associated with the racial/ethnic diversity of PCT participants (OR 1.17 [95% CI 1.08-1.26] and OR 1.25 [1.08-1.46], respectively). Evidence generation for the regulatory approval of new drugs has been predominantly centered in NAWE. The dominance is even more pronounced in the authorship of PPubs. To improve the racial/ethnic diversity of PCT participants, investigators from non-NAWE countries should be encouraged to play more leadership roles, thereby increasing their likelihood of serving as authors in PPub.

Patients with rare diseases worldwide face substantial unmet therapeutic needs. In Japan, drug lag-delays in drug approval compared to other countries-has resurfaced as a pressing public health issue. This study analyzes orphan drugs (ODs) approved in the United States (US) from 2005 to 2021, examining OD lag trends, and research and development (R&D) models to streamline OD development in Japan. Despite increased OD approval in the United States since 2018, the number of unapproved ODs in Japan has substantially increased. Although OD lag decreased, it has resurged since 2017. This is largely due to changes in the R&D strategies of pharmaceutical companies, which are driven by the growing presence of US- and Europe-based small- to mid-sized enterprises (SMEs) and the evolving industry landscape. Large foreign pharmaceutical companies have shifted toward a global development strategy for Japan, aiming for more efficient development and competitive advantage. This has been propelled by a move toward in-licensing earlier-stage drug candidates with global exclusivity from SMEs. Japanese pharmaceutical companies have focused on in-licensing late-stage drug candidates for the Japanese market from SMEs without a business presence in Japan, which have not been developed locally, thereby employing a bridging strategy for Japan. With the increase in ODs developed in the United States by these SMEs, this practice has substantially exacerbated the OD lag. As these SMEs are unlikely to enter the Japanese market, it is crucial for Japanese pharmaceutical companies to proactively pursue earlier, more proactive global partnerships with SMEs.

Emergency department visits due to cannabinoid-induced toxicity, including acute cannabinoid intoxication (ACI) have increased worldwide as more states have liberalized cannabis policy. ACI symptoms include anxiety, panic attacks, tachycardia, and psychosis, primarily mediated through cannabinoid type 1 receptor (CB₁) agonism by Δ⁹-tetrahydrocannabinol (THC). This phase II randomized, double-blind, placebo-controlled study assessed the potential of CB₁ receptor antagonist selonabant (ANEB-001) to block THC-induced effects in healthy adults. In Part A of the study, 10.5 mg of THC was coadministered with 50 mg (N = 20) or 100 mg (N = 20) selonabant, or matching placebo (N = 20). In Part B, 21-mg THC was coadministered with 30 mg (N = 9) or 10 mg (N = 7) selonabant, or matching placebo (N = 9). THC-related effects were assessed using visual analogue scales (VAS) for feeling high and alertness, objective measures of postural stability, and heart rate and analyzed using a mixed effects model. Selonabant significantly reduced VAS "Feeling High" (up to -82.8% (95% CI: -91.0%, -67.2%, P < 0.0001) at 30-mg selonabant) and increased VAS "Alertness" (up to 10.8 mm (95% CI: 4.7, 16.8 mm, P = 0.001) at 30-mg selonabant) vs. placebo. Selonabant 10 and 30 mg significantly reduced body sway (up to -30.6% (95% CI: -44.1%, -13.9%, P = 0.002) at 30 mg selonabant) vs. placebo. Effects on heart rate were not significant. Selonabant was generally safe and no clinically meaningful changes in mood occurred. Nausea and vomiting occurred more frequently at high selonabant doses; 10-mg selonabant was both well tolerated and efficacious. Present results support further development of selonabant for emergency treatment of ACI.

With the advancements in algorithms and increased accessibility of multi-source data, machine learning in pharmacokinetics is gaining interest. This review summarizes studies on machine learning-based pharmacokinetics analysis up to September 2024, identified from the PubMed and IEEE Xplore databases. The main focus of this review is on the use of machine learning in predicting drug concentration. This review provides a comprehensive summary of the advances in the machine learning algorithms for pharmacokinetics analysis. Specifically, we describe the common practices in data preprocessing, the application scenarios of various algorithms, and the critical challenges that require attention. Most machine learning models show comparable performance to those of population pharmacokinetics models. Tree-based algorithms and neural networks have the most applications. Furthermore, the use of ensemble modeling techniques can improve the accuracy of these models' predictions of drug concentrations, especially the ensembles of machine learning and pharmacometrics.

The safety of systemic fluoropyrimidines (e.g., 5-fluorouracil, capecitabine) is impacted by germline genetic variants in DPYD, which encodes the dihydropyrimidine dehydrogenase (DPD) enzyme that functions as the rate-limiting step in the catabolism of this drug class. Genetic testing to identify those with DPD deficiency can help mitigate the risk of severe and life-threatening fluoropyrimidine-induced toxicities. Globally, the integration of DPYD genetic testing into patient care has varied greatly, ranging from being required as the standard of care in some countries to limited clinical use in others. Thus, implementation strategies have evolved differently across health systems and countries. The primary objective of this tutorial is to provide practical considerations and best practice recommendations for the implementation of DPYD-guided systemic fluoropyrimidine dosing. We adapted the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework to cover topics including the clinical evidence supporting DPYD genotyping to guide fluoropyrimidine therapy, regulatory guidance for DPYD genotyping, key stakeholder engagement, logistics for DPYD genotyping, development of point-of-care clinical decision support tools, and considerations for the creation of sustainable and scalable DPYD genotype-integrated workflows. This guide also describes approaches to counseling patients about DPYD testing and result disclosure, along with examples of patient and provider educational resources. Together, DPYD testing and clinical practice integration aim to promote safe prescribing of fluoropyrimidine therapy and decrease the risk of severe and life-threatening fluoropyrimidine toxicities.

Ritonavir-boosted atazanavir is a victim of drug-drug interaction with rifampicin, a key component of antitubercular treatment. In a recent dose escalation clinical trial, we showed that increasing atazanavir/ritonavir to 300/100 mg b.i.d. compensates for reduced drug exposure in plasma due to rifampicin, but the intracellular effects remained unexplored. This sub-study investigated the intracellular penetration of atazanavir/ritonavir and dolutegravir into peripheral blood mononuclear cells (PBMC). Twenty-six healthy volunteers living with HIV, virologically suppressed, and taking atazanavir/ritonavir containing regimens were enrolled. The trial consisted of four sequential periods: PK1, participants were on atazanavir/ritonavir 300/100 mg q.d.; at PK2, rifampicin 600 mg q.d. and dolutegravir 50 mg b.i.d. were added (2 weeks); at PK3, atazanavir/ritonavir dose was increased to 300/100 mg b.i.d. (1 week); at PK4, rifampicin dose was doubled (1 week). Atazanavir, ritonavir, and dolutegravir were quantified in plasma and PBMC using LC-MS/MS methods to evaluate steady-state concentrations at the end of each period. Atazanavir/ritonavir dose escalation successfully restored intracellular concentrations comparable to those observed without rifampicin, with a geometric mean ratio of 0.99 (CI₉₀ 0.72-1.41) for atazanavir at PK3 compared with PK1. The intracellular concentration of dolutegravir increased significantly with atazanavir/ritonavir dose escalation, similar to plasma. Finally, further, increasing the rifampicin dose did not show an additional impact on atazanavir/ritonavir concentrations in PBMC. The study confirms that increasing the ATV/r dose can be an effective strategy for compensating rifampicin effects even at the intracellular level, supporting its use in clinical settings.

Obeldesivir is an oral nucleoside analog prodrug inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase and other viral polymerases. Here, two Phase I studies evaluated potential drug-drug interactions between obeldesivir and substrates or inhibitors of cytochrome P450 and drug transporters in healthy participants. When obeldesivir was tested as a precipitant, pharmacokinetic parameter point estimates for midazolam (CYP3A4 inhibition/induction), caffeine (CYP1A2 inhibition), and metformin (organic cation transporter 1 inhibition) exposures were within 80-125% no-effect bounds representing the interval within which a systemic exposure change does not warrant clinical action based on EMA/FDA guidance. Dabigatran (P-glycoprotein substrate) and pitavastatin (organic anion transporting polypeptide 1B1/1B3 substrate) exposures decreased by approximately 25% and 30%, respectively, with obeldesivir coadministration; these were considered not clinically relevant, as these exposure changes are not associated with dose changes or precautions in the US prescribing information for these drugs. When obeldesivir was evaluated as an object, exposures of GS-441524, the parent nucleoside monophosphate metabolite of obeldesivir, were within the 80-125% no-effect bounds for ritonavir (P-glycoprotein inhibition) and cyclosporin A (breast cancer resistance protein inhibition) coadministration. Famotidine (gastric acid suppression) coadministration decreased GS-441524 exposure by approximately 26%; this was within the range of exposures observed in previous Phase III studies and was considered not clinically relevant. Obeldesivir was well tolerated, and adverse events were mild to moderate. These findings indicate that obeldesivir has low potential for drug-drug interactions. Obeldesivir remains a promising treatment against a broad spectrum of viruses given its antiviral activity and favorable safety profile.