Cts-Clinical and Translational Science最新文献

To plan future steps for the implementation and regulation of pharmacogenetic testing, any issue in the management of pharmacogenetic information by regulatory bodies must be identified. In this paper, an analysis of pharmacogenetic information in the summary of product characteristics (SmCPs) of drugs approved by Italian Drug Agency (AIFA) was conducted. Among 4214 SmCPs of 1063 active ingredients, 53.2% (n = 2240) included pharmacogenetic information in at least one section, most frequently for drugs in the Anatomical Therapeutic Chemical category “Antineoplastic and immunomodulatory agents”. To contextualize these data in the international scenario, a pharmacogenetic level of actionability, based on AIFA SmCPs, was assigned to 608 drug/gene pairs included in FDA's “Table of Pharmacogenomic Biomarkers in Drug Labels”, according to PharmGKB (The Pharmacogenomics Knowledge Base). Approximately 67% of drug/gene pairs were deemed classifiable: Based on SmCPs phrasing, for half of them the genetic testing was cataloged as “required” or “recommended” (mainly tumor somatic variants), whereas 40% as “actionable” (mostly PK/PD-related germline variants). The comparison with other regulatory agencies highlighted a discordance in the assigned pharmacogenetic levels of actionability ranging from 1% to 14%. This discrepancy may also point out the need to rethink the language used in AIFA-approved SmCPs to clarify whether a pharmacogenetic test is necessary or not and for which subjects it has been recommended. For the first time, a detailed evaluation and comparative analysis of the pharmacogenetic information on Italian SmCPs was presented, placing it in an international context and laying the groundwork for rethinking pharmacogenetic indications in AIFA-approved SmCPs.

Piperaquine tetraphosphate (PQP), a long-acting antimalarial, is being considered in a combination for chemoprevention. Dihydroartemisinin-piperaquine tablets (hard and dispersible) approved for the treatment of acute uncomplicated malaria should be administered in a fasted state, as PQP bioavailability increases with food. A new taste-masked dispersible granules PQP formulation aims to minimize the impact of food on drug exposure. This randomized, open label, parallel group, Phase I pilot study was conducted between 24th July 2023, and 3rd January 2024, at the Ifakara Health Institute, Bagamoyo, Tanzania in 60 healthy African adults (five cohorts of 12). Single-dose pharmacokinetics and relative systemic exposure of the oral PQP dispersible granules formulation prototype (320 mg) was compared to the hard tablet when fasted and PQP granules in three different fed conditions. In the fasted state, the relative exposure of PQP granules versus the tablet was 73.9% (90% CI 48.3, 113.0) for C_max and 86.5% (68.2, 109.6) for AUC_0-t. Following a typical East African low-fat meal, a standard high-fat meal, or 250 mL whole milk, the relative exposure of PQP granules versus the fasted state was 202% (90% CI 132, 311), 275% (193, 391), and 294% (203, 425) for C_max and 164% (124, 217), 184% (148, 228), and 195% (147, 259) for AUC_0-t, respectively. Both formulations were well tolerated with one drug-related adverse event (moderate migraine). No severe or serious adverse events or clinically relevant laboratory or electrocardiograph changes were observed. PQP dispersible granules had lower systemic exposures versus the tablet when fasted, whereas various meals increased drug exposure.

Clearance of an intravenous iohexol dose of 3235 mg is used to assess glomerular filtration rate (GFR), although systematic assessment of its pharmacokinetic (PK) properties is incomplete. The objectives of the present investigations were (i) to assess potential interactions of iohexol with important drug transporters, and (ii) whether a 259 mg dose could replace the current standard dose. In vitro, we evaluated whether iohexol inhibits or is transported by renal transporters (hOAT1/3, hOCT2, and hMATE1/2K) or other transporters (hOATP1B1/3, hOCT1, and hMDR1) using cell-based and vesicle-based systems. In vivo, we conducted a clinical trial with 12 volunteers with the administration of single intravenous doses of 3235 mg (“reference”) and 259 mg (“test”) using a changeover design. Plasma and urine samples were collected up to 24 h postdose. We assessed the dose linearity of iohexol pharmacokinetics using the standard bioequivalence approach and conducted a population PK analysis to characterize its profile. Our in vitro findings indicate that iohexol is neither a substrate nor a significant inhibitor of the transporters, suggesting it is unlikely to participate in transporter-mediated drug–drug interactions in vivo. In the clinical trial, the test/reference ratio for plasma clearance, calculated as dose divided by the area under the plasma concentration–time curve, was 1.01 (90% confidence interval 0.968–1.05), confirming dose linearity. Population PK analysis further supported these results, showing no significant effect of dose on renal clearance and negligible nonrenal clearance of iohexol. Low-dose iohexol is a suitable marker for precise GFR measurement, even when coadministered with other drugs.

5-hydroxytryptamine-3 (5-HT₃) receptor antagonists including ondansetron, tropisetron, dolasetron, palonosetron, granisetron, and ramosetron are commonly used to prevent and treat nausea and vomiting. Most of these medications are at least partially metabolized via the highly polymorphic CYP2D6 enzyme, resulting in variations of metabolism among individuals. Current (2017) international prescribing guidelines for ondansetron/tropisetron use according to genotype provide recommendations for CYP2D6 ultrarapid metabolizers but not intermediate or poor metabolizers. However, multiple studies have been conducted since this guideline was published. This review evaluated all available evidence of an association between CYP2D6 genotype and 5-HT₃ receptor antagonist outcomes, including in patients who are CYP2D6 intermediate/poor metabolizers and pediatric-specific studies. In this review, we confirm that CYP2D6 genotype impacts ondansetron response in a postoperative nausea and vomiting setting, which was supported by a meta-analysis. We also highlight the heterogeneity and limitations of included studies as well as provide future directions for pharmacogenomics research.

High-dose methotrexate (HD-MTX) infusions are commonly used to consolidate remission in children with acute lymphoblastic leukemia (ALL). We investigate the potential role of candidate polymorphisms in SLCO1B1 (rs4149056 and rs2306283), ABCB1 (rs1045642), ABCC2 (rs717620), ABCC3 (rs9895420), and ABCC4 (rs7317112) drug transporters genes on HD-MTX pharmacokinetics and patients' outcome (meant both as relapse and drug-related toxicities) in an Italian cohort of 204 ALL pediatric patients treated according to the AIEOP-BFM ALL 2009 protocol. TaqMan SNP genotyping assays determined patient's genotypes. Measurements of HD-MTX plasma concentration were available for 814 HD-MTX courses in 204 patients; MTX clearance was estimated by a two-compartmental linear pharmacokinetic model with first-order elimination and a Bayesian approach, via ADAPT. Independent contributions of age and ABCC4 SNP rs7317112 (A>G, intronic) on MTX clearance were detected in a multivariate analysis (p = 1.57 × 10⁻⁸ and p = 2.06 × 10⁻⁵, respectively), suggesting a delayed elimination of the drug in older patients and an accelerated one in carriers of the variant GG genotype. After multiple corrections, the association between ABCC2 SNP rs717620 (−24 C>T) and severe hematological toxicity was found (p < 0.005). Moreover, SLCO1B1 SNP rs4149056 (c.521T>C, p.V174A) affected patients' outcomes: carriers of the variant C allele presented a reduced risk of relapse compared to wild-type TT (hazard risk: 0.27, 95% confidence interval [CI]: 0.08–0.90, p = 0.037). Taken together, these data highlighted the importance of variants in drug transporters genes on HD-MTX disposition in the AIEOP-BFM ALL 2009 protocol consolidation phase, and their putative role as predictive markers of outcome.

Coronary artery disease remains a significant global health issue and is a leading cause of mortality. Dual antiplatelet therapy, including clopidogrel, is essential for preventing stent thrombosis after coronary artery stenting. This study assessed the comparative efficacy and safety of generic versus brand-name clopidogrel in a large Taiwanese cohort. A retrospective cohort study was conducted using the National Health Insurance database, identifying patients who underwent coronary stenting and received either generic or brand-name clopidogrel between January 1, 2008, and December 31, 2021. Propensity score matching was employed to balance baseline characteristics. The primary efficacy outcome was a composite of myocardial infarction, ischemic stroke, or cardiovascular death over a two-year follow-up. The primary safety outcome was major bleeding requiring hospitalization. A total of 211,509 patients were included, of which 2686 received generic clopidogrel and 208,823 received brand-name clopidogrel. After matching, 2686 patients from each group were analyzed. The hazard ratio for the primary efficacy outcome was 0.92 (95% confidence interval: 0.78–1.10), indicating no significant difference between the two groups. The subdistribution hazard ratio for the primary safety outcome was 1.06 (95% confidence interval: 0.84–1.33), suggesting no significant difference in bleeding risk. Subgroup analyses showed consistent results across various patient demographics and clinical conditions. In conclusion, among patients undergoing coronary stenting, the risks of ischemic and bleeding events were comparable between those receiving generic and brand-name clopidogrel.

Tramadol, the 41st most prescribed drug in the United States in 2021 is a prodrug activated by CYP2D6, which is highly polymorphic. Previous studies showed enzyme-inhibitor affinity varied between different CYP2D6 allelic variants with dextromethorphan and atomoxetine metabolism. However, no study has compared tramadol metabolism in different CYP2D6 alleles with different CYP2D6 inhibitors. We hypothesize that the inhibitory effects of CYP2D6 inhibitors on CYP2D6-mediated tramadol metabolism are inhibitor- and CYP2D6-allele-specific. We performed comparative analyses of CYP2D6*1, CYP2D6*2, CYP2D6*10, and CYP2D6*17 using recombinant enzymes to metabolize tramadol to O-desmethyltramadol, measured via UPLC-MS/MS. The Michaelis constant (K_m) and maximum velocity (V_max) for each CYP2D6 allele, and IC₅₀ values for different inhibitors were determined by nonlinear regression analysis. Intrinsic clearance was calculated as V_max/K_m. The intrinsic clearance of tramadol was almost double for CYP2D6*2 (180%) but was much lower for CYP2D6*10 and *17 (20% and 10%, respectively) compared to CYP2D6*1. The inhibitor potencies (defined by Ki) for the various inhibitors for the CYP2D6*1 allele were quinidine > terbinafine > paroxetine ≈ duloxetine >>bupropion. CYP2D6*2 showed the next greatest inhibition, with Ki ratios compared to CYP2D6*1 ranging from 0.96 to 3.87. For each inhibitor tested, CYP2D6*10 and CYP2D6*17 were more resistant to inhibition than CYP2D6*1 or CYP2D6*2, with most Ki ratios in the 3–9 range. Three common CYP2D6 allelic variants showed different metabolic capacities toward tramadol and genotype-dependent inhibition compared to CYP2D6*1. Further studies are warranted to understand the clinical consequences of inhibitor and CYP2D6 genotype-dependent drug–drug interactions on tramadol bioactivation.

This analysis assessed the relationship between the plasma concentrations of loperamide and its N-desmethyl loperamide meta- bolite (M1) and the potential QT interval prolongation at therapeutic and supratherapeutic doses. The exposure–response analysis was performed using the data from healthy adults participating in a randomized, double-blind, single-dose, four-way (placebo; loperamide 8 mg [therapeutic]; loperamide 48 mg [supratherapeutic]; moxifloxacin 400 mg [positive control]) crossover study. The electrocardiographic measurements extracted from 12-lead digital Holter recordings were time-matched to pharmacokinetic sampling of loperamide/M1. The primary response variable was placebo-adjusted change from baseline in Fridericia-corrected QT interval (ΔΔQTcF); the exposure variable was loperamide and/or M1 concentration. A total of 53 participants with 1408 time-matched pharmacokinetic and ΔΔQTcF measurements was analyzed. Hysteresis between both loperamide and M1 concentrations and ΔΔQTcF was observed with supratherapeutic dose. The pre-specified linear concentration-ΔΔQTcF relationship was driven by M1 concentrations in the effect compartment. The model-predicted mean ΔΔQTcF at the geometric mean of the maximum concentration in the effect compartment was −0.526 msec (90% CI, −1.51 to 0.462) following 8-mg dose (2.1 ng/mL) and 6.06 msec (90% CI, 3.86–8.27) following 48-mg dose (14.2 ng/mL). The upper bound of two-sided 90% CI was < 10 msec for both doses. The sensitivity analysis considering loperamide concentrations in the effect compartment instead of M1 as input for the concentration-ΔΔQTcF analysis confirmed these findings. The data showed that loperamide or M1 does not have an effect on cardiac repolarization that exceeds the threshold of regulatory concern in healthy participants at doses of 8 and 48 mg.

The Timor-Leste Pharmacovigilance (PV) became an associate member of the WHO Programme for International Drug Monitoring in 2019; however, the adverse drug reaction (ADR) reporting rate remains low, with only nine reports per 1342 million inhabitants over 5 years. This study aimed to evaluate the knowledge, attitude, practice, and barriers related to ADRs, pharmacovigilance, and ADR reporting among healthcare professionals (HCPs) in Timor-Leste. A cross-sectional survey with a validated, self-administered questionnaire was conducted among 600 HCPs, including clinical doctors, nurses, and pharmacy employees from one national referral and five referral hospitals. Of the 461 HCPs who responded (76.8% response rate), 98 were clinical doctors (21.3%), 311 nurses (67.4%), and 52 pharmacy employees (11.3%). The knowledge score on ADRs was 3.81 ± 0.36 out of 8, with clinical doctors, nurses, and pharmacy employees scoring 4.49 ± 0.51, 3.47 ± 0.24, and 4.56 ± 0.26, respectively. On pharmacovigilance and ADR reporting, the score was 3.00 ± 0.16 out of 8, with clinical doctors, nurses, and pharmacy employees scoring 3.36 ± 0.26, 2.81 ± 0.08, and 3.50 ± 0.24, respectively. All scores referred to the number of correctly answered questions. Positive attitudes were observed, with 53.4% agreeing that ADR reporting is crucial for drug safety, although only 22.0% reported observed ADRs. Key barriers included unavailability of reporting forms (81.0%), insufficient financial support (71.9%), and lack of reporting by colleagues (71.4%). These findings highlight the need for increased awareness, training, and resources to improve ADR reporting in Timor-Leste.