Clinical Pharmacology & Therapeutics最新文献

Cisplatin is a chemotherapy drug that causes permanent hearing loss by damaging a critical tissue lining the inner ear, called the stria vascularis (SV). Currently, the molecular mechanisms of SV damage are largely unknown and the incidence of ototoxicity in patients cannot be reliably predicted. Growing evidence suggests certain genetic variants expressed in the SV are significant risk factors for ototoxicity, which may be leveraged to better understand cisplatin-induced hearing loss. Also highlighted are innovative developments in integrating genomic and transcriptomic data through multi-omic approaches that may be translated to improve future genetic testing and otoprotectant development.

The impact of CYP2C19 genotype in relation to clinical risk is unclear during clopidogrel treatment following drug-eluting stent (DES) implantation. This study aimed to evaluate the prognostic significance of CYP2C19 genotypes based on clinical risk stratification in DES-treated patients. From the nationwide multicenter PTRG-DES (Platelet function and genoType-Related long-term progGosis in DES-treated patients) consortium, patients were classified according to the presence of CYP2C19 loss-of-function (LoF) allele: rapid or normal metabolizers (RMs/NMs) vs. intermediate or poor metabolizers (IMs/PMs), and clinical risk was stratified using the CHADS-P₂A₂RC and TRS 2°P scores. The primary endpoint (1°EP) was a composite of cardiac death, myocardial infarction, and stent thrombosis during a 3-year follow-up. Among clopidogrel-treated patients with CYP2C19 genotyping (n = 8,163), IMs/PMs (62.1%) demonstrated an increased risk of 1°EP compared with RMs/NMs (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.05-2.07; Log-rank P < 0.001), Most notable in those with high CHADS-P2A2RC (≥ 4) and TRS 2°P (≥ 3) scores (HR_adj: 1.68; 95% CI: 1.01-2.80; P = 0.047 and HR_adj: 1.63; 95% CI: 1.05-2.54; P = 0.029, respectively). In patients with low scores, there was no difference in 1°EP between IMs/PMs vs. RMs/NMs; however, an interaction was observed between acute and chronic coronary syndromes for both low CHADS-P₂A₂RC (HR_adj: 2.12; 95% CI: 1.11-4.03 and HR_adj: 0.68; 95% CI: 0.34-1.36; P_interaction = 0.017) and TRS 2°P scores (HR_adj: 2.34; 95% CI: 1.07-5.12 and HR_adj: 0.52; 95% CI: 0.22-1.17; P_interaction = 0.008). Among clopidogrel-treated patients, the carriage of the CYP2C19 LoF allele was associated with higher ischemic risk, particularly in those with high clinical risk or an acute coronary syndrome presentation.

Grapefruit juice is a well-established inhibitor of cytochrome P450 (CYP) 3A4, but its effects on other CYP enzymes or organic anion transporting polypeptides (OATPs) are not fully characterized in humans. Recently, lingonberry powder was shown to induce murine CYP enzymes. We investigated the effects of lingonberry powder and grapefruit juice on seven CYP enzymes and two OATPs. Eleven healthy volunteers received three pretreatments three times per day: water for 1 day (control), lingonberry powder for 9 days, and grapefruit juice for 3 days. CYP index drugs (caffeine/CYP1A2, bupropion/CYP2B6, repaglinide/CYP2C8, flurbiprofen/CYP2C9, omeprazole/CYP2C19, dextromethorphan/CYP2D6, midazolam/CYP3A4, and simvastatin/CYP3A4) were administered orally on the study day of each pretreatment (day 1, 10, and 3, respectively). Venous blood samples were collected until 23 hours postdose. The concentrations of index drugs, their metabolites and endogenous OATP1B1 and OATP1B3 biomarkers glycochenodeoxycholate 3-O-glucuronide (GCDCA-3G) and glycochenodeoxycholate 3-sulfate (GCDCA-3S), respectively, were quantified. Grapefruit juice expectedly increased the AUC_0-23h values of the CYP3A4 index drugs midazolam and simvastatin (P < 0.01). Additionally, grapefruit juice decreased the hydroxybupropion/bupropion (CYP2B6), 4'-hydroxyflurbiprofen/flurbiprofen (CYP2C9), 5'-hydroxyomeprazole/omeprazole (CYP2C19), and 1'-hydroxymidazolam/midazolam AUC_0-23h ratios to 0.57-fold (90% confidence interval: 0.45-0.74), 0.78-fold (0.69-0.87), 0.43-fold (0.36-0.52), and 0.72-fold (0.63-0.84) of control, respectively (P < 0.01). Lingonberry pretreatment did not change any CYP indices. GCDCA-3G and GCDCA-3S concentrations were unaffected by grapefruit juice or lingonberry pretreatment. Collectively, our findings indicate that in addition to inhibiting CYP3A4, repeated grapefruit juice intake causes clinically relevant inhibition of CYP2B6, CYP2C9, and CYP2C19, revealing previously underappreciated interaction risks. Conversely, lingonberry powder is unlikely to induce CYP enzymes in humans.

Cannabidiol (CBD) is one of the most abundant bioactive cannabinoids. Research has demonstrated CBD's ability to inhibit metabolic enzymes like cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), potentially leading to drug interactions. However, clinical knowledge gaps remain, particularly with regard to drugs that are more commonly taken by consumers of unregulated CBD products. This study aimed to characterize the effects of daily CBD consumption, at doses typical of unregulated CBD products, on the pharmacokinetics of citalopram and morphine. These two commonly prescribed medications are metabolized by CYPs and UGTs, respectively. This open-label, sequential study involved two cohorts of 20 healthy participants. Cohort one received a single dose of citalopram (20 mg) on days 1 and 13, with CBD (2.5 mg/kg twice daily) administered for 12 days. Cohort two received a single dose of morphine (15 mg) on days 1, 4, and 11, with CBD (2.5 mg/kg twice daily) given for 9 days. The geometric mean ratio (GMR, [90% confidence interval]) for citalopram with and without CBD for 12 days was 1.43 (1.34-1.52) for the area under the plasma concentration-time curve (AUC_0-inf) and 1.12 (1.06-1.17) for the maximum observed plasma concentration (C_max). The GMR for AUC_0-inf and C_max for morphine coadministered with CBD compared to morphine alone was 1.06 (0.96-1.16) and 1.19 (1.05-1.35), respectively. For morphine with CBD for 9 days compared to morphine alone, the GMR for AUC_0-inf and C_max was 1.12 (1.00-1.26) and 1.11 (0.94-1.30), respectively. While a significant pharmacokinetic interaction between CBD and citalopram was observed, interactions between CBD and morphine, as well as its metabolites, were limited.

Fezolinetant is a first-in-class, selective, non-hormonal, neurokinin 3 receptor antagonist that is approved for the treatment of moderate to severe vasomotor symptoms due to menopause. In a phase 2b clinical study (n = 352), nine study participants experienced elevations in serum transaminases exceeding three times the upper limit of normal. DILIsym, a quantitative systems toxicology model of drug-induced liver injury, was used to assess the potential hepatotoxicity of fezolinetant prior to initiating phase 3 trials. In vitro toxicity assays and physiologically-based pharmacokinetic estimates of fezolinetant and primary metabolite exposure were leveraged to simulate the incidence of hepatotoxicity for various fezolinetant treatment regimens and virtual simulated populations. DILIsym simulations indicated a dose-dependent relationship between fezolinetant exposure and hepatotoxicity primarily caused by electron transport chain inhibition. At therapeutic doses, no ALT elevations exceeding three times the upper limit of normal were predicted for healthy volunteers. In a metabolic syndrome-associated fatty liver disease (MAFLD) population with compromised mitochondrial function, mild increases in ALT elevation frequency above placebo were observed in all fezolinetant treatment groups and included a single Hy's Law case at 45 and 60 mg once daily. The predicted Hy's Law case in the MAFLD population was mitigated by the incorporation of mitochondrial biogenesis. These predictions aided discussions with internal and external stakeholders regarding dose selection and initiation of the phase 3 clinical studies. Phase 3 studies were subsequently completed and confirmed the efficacy and acceptable liver safety of fezolinetant at 30 and 45 mg QD, leading to drug approval at 45 mg QD.

Clinical trials are essential to understand the benefit-harm profile of new drugs. Lack of adequate representation in age and sex ratio in clinical trials can result, for example, in higher side effects for underrepresented patients. We quantified differences in age and sex ratios between trial and target populations of new drugs approved by the FDA 2011-2022. We used the FDA's database to identify all new drugs and pivotal randomized trials. Information for average age and sex ratio was obtained from clinicaltrials.gov. Each trial's indication was matched with prevalence estimates of the targeted diseases from the global burden of disease study. A total of 458 drugs (773 trials) were included. The trial populations were significantly younger, on average 4.8 years (95% CI [5.4 years, 4.2 years]), and the female ratio significantly smaller, on average 4.3 percentage points (95% CI [5.4 pp, 3.3 pp]), than the target populations. For diseases with average patient age below 40, the trial population was significantly older than the target population but significantly younger 40 years and older. For diseases with average age between 30 and 39, the female ratio in the trial population was significantly higher than in the target population but significantly lower 50 and older. Better age and sex ratio representation in the trial population is indicated to improve safety and efficacy for patients. Trials targeting diseases below 40 should enroll younger participants and increase their male ratio, while the opposite is true for trials targeting diseases with an older age.

Metformin is the most widely prescribed antidiabetic drug, yet adherence remains difficult to objectively assess. Using untargeted metabolomics and lipidomics, we analyzed plasma from 637 patients with type 2 diabetes (T2D) with confirmed metformin use and 143 nondiabetic controls, annotating 614 metabolites. Patients were stratified by plasma metformin into sub-therapeutic, therapeutic, and supra-therapeutic groups, and associations were evaluated by multiple linear regression and composite metabolite ranking. Five previously unannotated features were structurally identified as N-lactoyl-amino acids, whose levels correlated strongly with plasma metformin (ρ = 0.42-0.55, P < 0.0001) and increased up to 7.2-fold in the supra-therapeutic group (> 2000 ng/mL). While N-lactoyl-amino acids were consistently detected in the nanomolar range, they still displayed robust and dose-dependent associations with metformin. Broader metabolic changes in T2D included elevated lactate, organic acids, and branched-chain amino acids, together with reduced urea cycle metabolites. Lipidomics showed increases in saturated triacylglycerols and diacylglycerols and decreases in cholesteryl esters, sphingomyelins, and phospholipids. These findings establish N-lactoyl-amino acids as robust, dose-responsive plasma biomarkers of metformin exposure. Despite being up to four orders of magnitude less abundant than their amino acid precursors, they sensitively reflect mitochondrial lactate overflow and pharmacodynamic adaptation, offering objective assessment of adherence.

Clesrovimab is a half-life extended monoclonal antibody targeting the respiratory syncytial virus fusion protein. Three studies (phase Ib/IIa [MK-1654-002], phase IIb/III [CLEVER], and phase III [SMART]) were conducted to evaluate the efficacy, safety, and pharmacokinetics (PK) of clesrovimab in infants. The objectives of this analysis were to develop an infant population PK model for clesrovimab and to evaluate the influence of intrinsic and extrinsic factors on clesrovimab PK in infants. A total of 5850 samples from 2942 participants were included in the population PK analysis. A two-compartment model with first-order absorption and elimination well described clesrovimab PK in infants. The estimated half-life for clesrovimab was 44.0 days. Clearance, absorption rate constant, and central volume of distribution had low inter-individual variability. Body weight was included as a covariate on all clearance and volume parameters, with estimated allometric scaling exponents centered on a body weight of 5 kg. A maturation function further described the change in clearance with increasing infant age. In addition to body weight and maturation function, the final model contained an effect of race on clearance. Although body weight, age, and race were identified as statistically significant covariates, the magnitude of the effect of these covariates on clesrovimab exposures was small (< 30%). The results of the population PK modeling support intramuscular administration of clesrovimab for the prevention of respiratory syncytial virus (RSV) disease in all infants, including healthy infants and infants at increased risk for severe RSV disease.

Quantitative Systems Pharmacology (QSP) and Pharmacometrics (PMX) have historically existed at the two ends of the model-informed drug development (MIDD) spectrum. The session "Mind the gap - successful bridging of QSP and PMX in drug development" at the 2024 American Conference of Pharmacometrics brought together QSP scientists and pharmacometricians with the aim to develop better understandings of how to bridge this gap. The current perspective is based on the concepts that were presented and the follow-up panel discussion.

Recently, the Chinese government has prioritized enhancing access to rare disease drugs, with the initial objective of addressing the challenge of drugs being "available abroad but not domestically." The United States, a leader in the development of treatments for rare diseases, serves as a benchmark for assessing a nation's progress in this field. This study examined the progression and influencing factors of the availability gap through the application of two principal metrics: "drug loss" and "drug lag" at the indication level. We conducted a retrospective analysis of rare disease indications approved in the United States and China from 2001 to 2024, focusing on diseases listed in China's official Catalogs of Rare Diseases. Our study indicated that "drug loss" in China had continued to escalate, with the total number of unapproved indications reaching 123 by 2024. Although the growth rate had decelerated since 2017, the "drug loss" associated with novel therapies recently approved by the FDA had intensified. Conversely, the "drug lag" in China for indications approved by the FDA after 2015 had decreased in comparison to those approved before 2015, with the median delay reducing from 4,049 to 2,812 days. The principal factors influencing drug availability were the global R&D and commercial strategies of sponsors. This finding highlighted that encouraging multinational sponsors to integrate China into their initial global development plans and to incentivize domestic companies to engage in earlier and more substantial international research and development collaborations were more important for mitigating "drug loss" and "drug lag" in China.