Evidence about the role of acute kidney injury (AKI) in idiosyncratic drug-induced liver injury (DILI) is still scarce. We aimed to ascertain the incidence, clinical profile, culprit drugs, and prognosis associated with concomitant DILI and AKI. We include patients from two long-term prospective DILI registries, the Spanish DILI registry and the Latin American DILI (LATINDILI) Network. Demographics, clinical characteristics, and outcome of patients with DILI-AKI were compared to those patients with DILI and without AKI. Overall, 54 out of 978 patients had AKI at the time of DILI diagnosis (5.5%). The most frequent culprit drug implicated in DILI-AKI was amoxicillin-clavulanate (11%) followed by anabolic androgenic steroids, antituberculosis drugs, ebrotidine, and ticlopidine (5.5% each). DILI-AKI cases were older than patients without AKI (60 ± 18 vs. 52 ± 18; P = 0.001), and mostly men (63%; P = 0.022). Furthermore, DILI-AKI cases showed higher comorbidity burden, and cholestatic damage and lymphopenia were more prevalent. Notably, DILI-AKI cases had higher incidence of liver-related death and all-cause mortality than those patients with no renal dysfunction (P = 0.029 and P = 0.015, respectively). In both a multivariable logistic regression (odds ratio [OR] = 3.46; 95% confidence interval [CI] 1.39-8.59; P = 0.008), and a rigorous propensity score-matched analysis (OR = 5.20; 95% CI 1.06-25.52; P = 0.042), renal damage was found as a risk factor of poor outcome. In conclusion, AKI in DILI mostly occurs in older male patients with cholestatic injury, lymphopenia, and greater burden of comorbidities, but mortality is restricted to DILI-AKI patients with hepatocellular damage. Overall, AKI is a risk factor of poor outcome in idiosyncratic DILI.

Host metabolic changes in response to drug treatment may shape individual pharmacological outcomes. This study aims to identify serum metabolomics signatures potentially associated with individual responses to enzalutamide treatment in metastatic castrate-resistant prostate cancer (mCRPC) patients. Targeted metabolomic profiles in serum collected from 18 mCRPC patients treated with 160 mg/day of enzalutamide were measured at baseline, after 3 months of treatment, and until disease progression by a validated liquid chromatography tandem mass spectrometry analytical platform. The difference in the serum metabolomic profiles during enzalutamide treatment between good and poor responders was investigated by both multivariate and univariate statistical analysis. Primary mouse hepatocytes and Caco-2 cell models were employed to gain mechanistic insights into the most relevant changes detected. Enzalutamide induced a significant and sustained increase in several amino acids, with taurine displaying the most significant change. The in vitro data suggest that enzalutamide-induced elevation of systemic taurine results from both increased intestinal absorption and decreased hepatic extraction. Finally, serum metabolomic changes observed after 3 months of treatment were found to be significantly associated with the pharmacological response. This hypothesis-generating study reveals that enzalutamide significantly alters the host serum metabolome, inducing changes that correlate with therapeutic response over time. These results highlight the importance of host-drug metabolic interactions during androgen receptor inhibitor treatment and, although further validation is required, they support the hypothesis that metabolic profiling could eventually aid in the personalized management of enzalutamide therapy.

Tramadol is frequently co-prescribed with oxycodone or hydrocodone after surgery under the assumption that its dual mechanism of action provides an opioid-sparing benefit. However, evidence supporting this practice is limited and inconsistent. We conducted a secondary analysis of the multicenter IGNITE ADOPT-PGx pragmatic trial of patients undergoing elective surgery who were prescribed oxycodone alone (n = 317) versus tramadol + oxycodone (n = 96), or hydrocodone alone (n = 563) versus tramadol + hydrocodone (n = 42). Co-primary outcomes of this study were cumulative morphine milligram equivalents (MME) consumed during the 10 days following surgery and composite pain scores at day 10 defined as the sum of current pain and average and worst pain in the past 7 days (score ranges from 3 to 15). Inverse probability of treatment weighting (IPTW) was used to adjust for demographic characteristics, comorbidities, and concomitant analgesics. Sensitivity analyses restricted to CYP2D6 normal metabolizers and sites prescribing both monotherapy and combination therapy and subgroup analysis including total knee arthroplasty patients were conducted. Compared to oxycodone alone, the combination of oxycodone and tramadol was associated with higher MME (adjusted mean 205.2 vs 122.5; P < 0.0001) and lower mobility, without meaningful differences in pain scores (adjusted mean 9.6 vs 9.4; P = 0.41). Similar findings were observed for hydrocodone-only vs hydrocodone + tramadol groups. Results were consistent in sensitivity and subgroup analyses. Co-administration of tramadol with oxycodone or hydrocodone was associated with substantially higher total MME and reduced mobility without any demonstrable improvement in pain control.

The comprehensive understanding of triplet repeat expansion (TRE) disorders as monogenic neurodegenerative diseases presents a fundamental challenge for developing treatments capable of modifying the disease course, as neurogenetic research indicates. The past 30 years reveal that preclinical results demonstrating strong effectiveness have not translated into success in human clinical trials, with multiple phase II and III studies for polyglutamine and non-coding, loss-of-function repeat disorders yielding unfavorable outcomes. This review emphasizes that clinical systems, which measure target engagement do not generate effective outcomes for these TRE neurodegenerative conditions. We highlight that these failures arise not from a fundamental misunderstanding of the underlying genetic mutations, but from recurring methodological and pharmacological limitations across the translational pipeline. The main reasons for these unsuccessful clinical trials include two factors: the necessity for clinicians to monitor pharmacodynamic biomarkers indicating central nervous system target engagement, and the reliance on traditional clinical rating scales that linearly assess disease progression in patients with complex medical conditions. The use of non-selective gene silencing methods can lead to unexpected toxic effects, especially when treatments begin after patients reach an advanced disease stage, causing irreversible brain cell damage. The field of precision neurogenetics must advocate for future trials to employ objective fluid and digital biomarkers, utilize allele-specific treatments, and prioritize patients who have not yet experienced severe brain cell loss. We further propose evidence-based design principles to improve the probability of clinical success in future TRE disease trials.

Low-dose aspirin is no longer routinely recommended for the primary prevention of cardiovascular disease in older adults due to a lack of net benefit over bleeding risk. We hypothesized that genetic subgroups may experience differential harm or benefit from aspirin therapy. To investigate this, we screened 572 polygenic scores (PGSs) for modification of aspirin's effect on major bleeding and major adverse cardiovascular events (MACE) in the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, placebo-controlled trial of daily 100 mg aspirin. Participants were aged ≥70 years (≥65 years for US minorities) and free of cardiovascular disease, dementia, or physical disability at enrolment. Among participants with high-quality genotyping data (n = 13,571), PGS-aspirin interactions were tested using Cox proportional hazards models with Bonferroni correction for multiple testing. During a median follow-up of 4.6 years, 414 major bleeding events and 464 MACE occurred. A triglyceride-related PGS (PGS003144) significantly modified aspirin-associated bleeding (interaction P = 5.9 × 10[-5]; Bonferroni-adjusted P = 0.034). In the lowest quintile of the PGS distribution, aspirin increased major bleeding risk (HR 2.28; 95% CI: 1.45-3.58; P = 0.00036), including separate bleeding subgroups gastrointestinal (HR 3.17; 95% CI: 1.48-6.80; P = 0.0029), and intracranial bleeding (HR 4.10; 95% CI: 1.54-11.0; P = 0.0049). In contrast, in the highest quintile, aspirin was associated with lower risk of bleeding (HR 0.62; 95% CI 0.38-0.97) and reduced MACE (HR 0.66; 95% CI 0.44-0.99). Baseline serum triglycerides showed similar effect modification. These hypothesis-generating findings suggest triglyceride-related genetic variation may identify individuals with differential responses to aspirin.

Rifampicin is a prototypical clinical inducer used in drug-drug interaction (DDI) studies. However, the clinical relevance and predictability of rifampicin-mediated hepatic transporter induction remain poorly defined. Conventional hepatocyte culture models fail to capture clinically relevant regulation of transporters and drug-metabolizing enzymes (DMEs), particularly at the protein level. In this study, we characterized a liver tissue chip (LTC) as a new approach methodology (NAM) for long-term transporter- and DME-mediated induction risk assessment. Transporter-certified® cryopreserved primary human hepatocytes from three donors were cultured in the LTC under recirculating flow with or without 10 μM rifampicin for 7 days. The LTC facilitated simultaneous mRNA-protein quantification for transporters and mRNA-protein-activity profiling for cytochrome P450s (CYPs) within individual chips across treatment and control conditions. In addition, extracellular bile acid profiling and intracellular rifampicin concentrations were measured by LC-MS/MS. Rifampicin induced multiple transporters and enzymes at the protein level, including organic anion transporting polypeptide (OATP)2B1, P-glycoprotein, CYP3A4, CYP2C19, and uridine 5'-diphospho-glucuronosyltransferase (UGT)1A4. Induction patterns differed between transporter mRNA and protein in many cases, suggesting regulatory mechanisms beyond PXR-mediated activation. Matched mRNA-protein-activity measurements of five CYP enzymes also revealed discrepancies in rifampicin-mediated induction magnitude. Rifampicin altered bile acid composition, increasing taurine-conjugated bile acids and inducing bile acid-related genes. Measured intracellular rifampicin concentrations differed substantially from experimentally employed media concentrations. Overall, these findings demonstrate that the LTC enables integrated assessment of mRNA, protein, and activity measurements in addition to bile acid profiles and intracellular drug exposure, which may improve mechanistic understanding of induction processes.

Cofetuzumab pelidotin (Cofe-P) is an anti-protein tyrosine kinase 7 (PTK7) antibody-drug conjugate (ADC) being investigated for the treatment of adults with PTK7-expressing, recurrent non-small cell lung cancer (NSCLC). The first-in-human (FIH) trial demonstrated tolerability of dosages ≤ 2.8 mg/kg once every 3 weeks (Q3W) and ≤ 3.2 mg/kg Q2W. Population pharmacokinetics (popPK) and exposure-response analyses were conducted to characterize Cofe-P and unconjugated auristatin (Aur0101) payload pharmacokinetics and exposure-efficacy (objective response rate (ORR)) and exposure-safety (Grade ≥ 3 neutropenia, Grade ≥ 2 peripheral neuropathy or rash) endpoints to inform the selection of dosages for optimization. Data from the FIH (0.2-3.7 mg/kg Q3W, 2.1-3.2 mg/kg Q2W) and Phase 1b (2.8 mg/kg Q3W) studies were used for popPK and exposure-response analyses. PopPK models adequately described pharmacokinetic data. Exposure-response analyses showed that higher Cofe-P (ADC) exposures increased the probability of achieving an objective response but also the occurrence of examined adverse events, particularly Grade ≥ 3 neutropenia. In non-squamous epidermal growth factor receptor wild-type NSCLC patients (≥ 90% with PTK7 2+ staining), analyses predicted that 3.2 mg/kg vs. 2.8 mg/kg Q3W dosing led to a higher ORR (35% vs. 21%) while maintaining a manageable safety profile (Grade ≥ 3 neutropenia: ≤ 39%). Predicted ORR and Grade ≥ 3 neutropenia are improvements over the standard-of-care, docetaxel. Dosing regimens < 2.4 mg/kg were not predicted to improve efficacy. Mean relative dose intensity was ≥ 86% across all Cofe-P doses and schedules tested. Together, popPK and exposure-response analyses support optimal dosing regimens of 2.4, 2.8, and 3.2 mg/kg Cofe-P Q3W in patients with NSCLC.

Regulatory bodies play a central role in providing guidance that enables safe and effective use of artificial intelligence tools in medicine development and evaluation. Regulators can also act as catalysts for regulatory science research. To inform these efforts, a European-wide survey was conducted to solicit stakeholder perspectives on the priority areas for regulatory science research related to the use of artificial intelligence in the medicine lifecycle. Twenty-eight regulatory science research questions were developed covering seven thematic domains: (1) research integrity and intellectual property; (2) accuracy and reliability of AI tools; (3) data governance, confidentiality, and consent; (4) regulation and oversight; (5) ethics, fairness, and bias prevention; (6) resources and support for AI use; and (7) impact on jobs and skills. Within each domain, stakeholders ranked four research challenges. A total of 273 responses were collected from regulators, pharmaceutical industry professionals, patients and consumers, academics, and healthcare professionals. Rankings of research challenges frequently converged across stakeholder groups and levels of AI experience. The top-ranked research questions within each domain were weighted according to the overall importance ranking of each domain to identify a list of 10 priority areas of research. The majority of the 10 priority areas fell within the domains of "Accuracy and reliability of AI tools," "Data governance, confidentiality, and consent," and "Ethics, fairness, and bias prevention." This list aims to support researchers and research funding bodies in addressing knowledge gaps on artificial intelligence in the medicines lifecycle.