Cts-Clinical and Translational Science最新文献

Zavegepant is a calcitonin gene-related peptide receptor antagonist for acute migraine treatment. This Phase I, open-label, fixed-sequence study evaluated the effects of itraconazole (a strong cytochrome P450 3A4 [CYP3A4] and P-glycoprotein [P-gp] inhibitor) on the pharmacokinetics of intranasal/oral zavegepant and the effects of rifampin (a strong inducer of CYP3A4 and P-gp; and an inhibitor of organic anion transporting polypeptide 1B3 [OATP1B3]) on oral zavegepant in healthy participants. In the intranasal/oral zavegepant–itraconazole cohort, participants received a single 10-mg dose of zavegepant nasal spray on Day 1, followed by oral zavegepant (50 mg) on Day 3. Itraconazole 200 mg once daily was administered from Days 4 to 12. On Day 7 zavegepant nasal spray and on Day 11 oral zavegepant were coadministered with itraconazole. In the oral zavegepant–rifampin cohort, participants received oral zavegepant (100 mg) on Day 1, rifampin 600 mg once daily on Days 2–10, and rifampin with zavegepant on Day 11. No significant change in zavegepant exposure was observed following coadministration of itraconazole with zavegepant nasal spray. For oral zavegepant coadministered with itraconazole, the area under the curve from 0 to infinity (AUC_0−inf) and the maximum observed concentration (C_max) of oral zavegepant increased by 59% and 77%, respectively. For oral zavegepant coadministered with rifampin, the AUC_0−inf and C_max of oral zavegepant increased by approximately 2.3- and 2.2-fold, respectively. These results suggest that OATP1B3 and intestinal P-gp are the more prominent pathways, as opposed to CYP3A4, for a zavegepant drug–drug interaction. Coadministration of OATP1B3 inhibitors with zavegepant nasal spray should be avoided.

The population pharmacokinetics (PK) of quizartinib and its pharmacologically active metabolite AC886 have been previously described in healthy volunteers (HV) and relapsed/refractory (R/R) FLT3-internal-tandem-duplication-positive (FLT3-IDT-positive) acute myeloid leukemia (AML) patients receiving quizartinib monotherapy. In this analysis, we characterized the population PK of quizartinib and AC886 in newly diagnosed FLT3-ITD-positive AML patients receiving standard induction and consolidation chemotherapy as background treatment, using data from the Phase 3 QuANTUM-First trial and 12 earlier studies. Quizartinib PK were best described by a three-compartment model with sequential zero- and first-order absorption and first-order elimination. A two-compartment model with first-order metabolite formation and first-order elimination best fitted AC886 data. The PK of both moieties showed large interindividual variability (approximately 70% coefficient of variation for systemic clearances). The use of strong cytochrome P450 3A (CYP3A) inhibitors had the largest impact on exposure, increasing the steady-state area under the curve during the dosing interval (AUC_ss) by 1.8-fold. This is consistent with observations in HV and R/R AML patients and confirms the need for dose adjustments during coadministration. A novel finding in newly diagnosed AML patients was the phase-dependent change in steady-state quizartinib exposure: dose-normalized AUC_ss values were 0.6-fold during induction, similar during consolidation, and 1.4-fold during continuation compared to R/R AML patients receiving quizartinib monotherapy. The present analysis highlighted the comparison of quizartinib and AC886 PK between newly diagnosed AML patients and previously studied populations, informed dose modifications needed with strong CYP3A inhibitors, and supported the use of derived individual exposure metrics in separate exposure-response analyses.

ESK-001 is a highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2), which plays an essential role in mediating cytokine signaling in multiple immune-mediated diseases. In 2 phase I studies, a first-in-human single ascending dose (SAD) and multiple ascending dose (MAD) study and a multiple-dose (MD) study, we evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered ESK-001 in healthy participants using a randomized, double-blind, placebo-controlled study design. ESK-001 was rapidly absorbed with systemic exposures generally increasing dose-proportionally across all cohorts. The mean terminal half-life ranged from 8 to 13 h with no to minimal accumulation of ESK-001 following q.d. doses and ~2-fold accumulation following Q12 doses. Less than 1% of unchanged ESK-001 was eliminated in urine. ESK-001 inhibited the downstream TYK2 pathway as shown by inhibition of pSTAT1 expression. Transcriptomic analysis of unstimulated whole blood samples confirmed dose-dependent inhibition of Type I IFN-induced genes and SIGLEC1, a novel TYK2-responsive biomarker. By correlating PK exposure data with PD readouts, a strong PK/PD relationship was demonstrated. There were no deaths, serious treatment-emergent adverse events (TEAEs), nor severe TEAEs, and most TEAEs were mild in severity. In conclusion, ESK-001 was generally safe and well-tolerated in healthy participants, showed linear dose-dependent PK characteristics, and maximally inhibited TYK2-dependent pathways with a predictable concentration-dependent PK/PD relationship. These findings were used to select the dose range of ESK-001 for the STRIDE phase II trial in plaque psoriasis and to support further clinical development of ESK-001 in other TYK2-mediated diseases.

In drug discovery and development, estimating therapeutic and subtherapeutic doses is crucial for designing early-phase clinical trials, particularly first-in-human (FIH) studies. While increasing the in vitro pharmacological potency (lowering K_i) of a compound to its target is expected to decrease the therapeutic dose, its benefit is not necessarily clarified. We analyzed in vitro K_i, human in vivo pharmacokinetics (PK) parameters, and therapeutics doses of 144 oral small-molecule drugs approved in Japan (2010–2021). The data on classic drugs were obtained from Goodman and Gilman's textbook, 9th ed. (published in 1996). Modern drugs had lower K_i (2.5 nM) and daily doses (88 μmol/day) than classic drugs (33 nM and 313 μmol/day), but 3.6-fold higher intrinsic clearance (CL_int; 171 vs. 47 L/h), suggest that increasing potency over the years has not resulted in a reduction in dosage as expected. Estimating therapeutic doses using target receptor occupancy (tRO)-optimized approach improved estimation accuracy (63% within 10-fold of observed values) compared with tRO-fixed approaches. Subtherapeutic dose estimations revealed a risk of overdosing in FIH trials, indicating that these estimates are not necessarily as conservative as is generally understood. Notably, the unbound average concentration-to-K_i ratio (C_ave,u/K_i) varied among drugs and correlated negatively with K_i, suggesting the possible necessity of incorporating it into dose estimation methods. This study provides insights into the relationship between in vitro K_i, in vivo PK parameters, and therapeutic dose of modern drugs, proposing strategies and revealing the risk for dose estimation and drug development in the era of highly potent small molecules.

Whilst chemotherapy regimens have proven to be more successful for pediatric cancer patients over the years, their influence on long-term side effects is relatively poorly understood. One of the possible targets is the gonads, with gonadotoxic agents representing those that threaten the patient's ability to have children post surviving the primary disease treatment. Many risk stratification guidelines have categorized these agents based on the severity of their effect on the pre-pubertal testis. While the consensus is that those agents factored with a cyclophosphamide equivalent dosage pose the highest threat to fertility (e.g. alkylating agents), other agents might still contribute to a reduced testis function; especially in the case of combination therapies. Besides, it is important to note that studies deciphering the effect of other non-alkylating agents on the pre-pubertal testis lack standardized conclusions for clinically relevant outcomes. This makes it imperative to ensure the knowledge gap is addressed between the clinic and pre-clinic to understand potential gonadotoxic effects, ultimately leading to improved patient care. Therefore, this review will summarize the key findings in understanding the gonadotoxic effects of the most commonly researched non-alkylating agents: vincristine, etoposide, doxorubicin, and imatinib on the pre-pubertal testis.

Antiplatelet therapy with a P2Y₁₂ receptor inhibitor, in combination with aspirin, is standard of care for medical management of patients with coronary artery disease, and flexibility in prescribing options among these medications offers great potential for individualizing patient care. Previously, we showed that a loss-of-function missense mutation (G143E) in carboxylesterase 1 (CES1), the primary enzyme responsible for clopidogrel degradation, significantly impacts on-clopidogrel platelet aggregation and recurrent cardiovascular event risk. In the current investigation, we conducted a prospective randomized crossover study of clopidogrel (75 mg/day for 7 days) and ticagrelor (180 mg/day for 7 days) in 50 individuals stratified by CES1 G143E genotype (N = 34 143GG and 16 143GE) to determine the effect of drug choice on inhibition of platelet aggregation (IPA). Consistent with prior reports, we observed strong association between G143E and adenosine diphosphate-stimulated platelet aggregation following clopidogrel administration (IPA = 71.6 vs. 48.0% in 143E-allele carriers vs. non-carriers, respectively, p = 3.8 × 10⁻⁵). Similar significant effects on platelet aggregation were also noted between 143E-allele carriers versus non-carriers in response to stimulation with arachidonic acid (45.8 vs. 25.8%, p = 0.04), epinephrine (44.4 vs. 18.8%, p = 0.03), and collagen (5 μg/mL, 25.8 vs. 11.4%, p = 3.7 × 10⁻³). In contrast, no relationship between CES1 G143E and IPA was observed following ticagrelor administration regardless of the platelet agonist used. Collectively, these data suggest that on-clopidogrel platelet aggregation is substantially modified by CES1 G143E genotype, that this variant does not modify ticagrelor pharmacodynamics, and that more consistent inhibition of platelet aggregation may be achieved by using ticagrelor in patients who carry clopidogrel response-modifying alleles in CES1.

Decentralized clinical trials (DCTs), in which all or part of the trial activities are moved to the participants' immediate surroundings, promise to improve trial conduct. However, no evidence is available on what motivates people to participate in DCTs. Our aim was to determine the drivers and perceptions for participation in clinical trials with different decentralization levels in persons with type 2 diabetes mellitus. Five focus groups were conducted utilizing the nominal group technique in the Netherlands (n = 1), Germany (n = 1), and Austria (n = 3) with four to six participants per group. The focus groups were analyzed using thematic analysis. Of the 26 participants (10 females, median age: 66 years [IQR: 62–72]) 42% had previously participated in a trial, and almost all had internet access at home (96%). A total of seven main themes regarding participation in clinical trials (location, time investment, contact with healthcare professionals (HCPs), digital technologies, data collection, perceived risk, and motivation) were identified, of which a total of 20 drivers emerged. Perceptions regarding trial participation differed widely among participants, and individual preferences influenced which drivers were considered more important by participants. Flexibility of location and time spent on the trial were identified as the most motivating factors for participation in DCTs. Some drivers, such as digital infrastructure, digital literacy, home visits, personal interaction, and relationship with HCPs were perceived as both enablers and barriers, depending on personal preferences. However, most of the potential barriers regarding DCTs may be resolved by addressing them in the design of future DCTs.

Controversies regarding the benefits of statin treatment on clinical outcomes in coronary artery spasm (CAS) without obstructive coronary artery disease (CAD) persist due to limited data. In this retrospective nationwide population-based cohort study from the Taiwan National Health Insurance Research Database during the period 2000–2012, the matched cohorts consisted of 12,000 patients with CAS. After propensity score matching with 1:1 ratio, 2216 patients were eligible for outcome analysis in either statin or nonstatin group, with the mean follow-up duration of 4.8 and 4.6 years, respectively. Statin users versus nonusers had a significantly reduced risk of major adverse cardiovascular events (MACEs) (6.7% vs. 9.5%, hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.55–0.84) and all-cause mortality (6.0% vs. 7.6%; HR 0.77; 95% CI 0.61–0.96). While the results of MACEs were mainly contributed by cardiovascular death (1.9% vs. 3.2%; HR 0.56; 95% CI 0.38–0.83) and ischemic stroke (3.8% vs. 5.4%; subdistribution HR 0.69; 95% CI 0.52–0.91), they were primarily driven by reductions in ischemic but not hemorrhagic stroke. The benefit of statins was significantly pronounced in patients with hypertension and diabetes. Nevertheless, the effect on MACEs was consistent irrespective of age, sex, dyslipidemia, and mental disorder. Statins significantly reduced the risk of MACEs and all-cause mortality in CAS patients. The benefit of statin therapy in reducing MACEs appeared to be linear, with greater risk reduction with higher doses and longer duration without upper threshold, reflecting the dose-dependent relationship of statins with MACEs in CAS patients.

Intranasal insulin is a putative neuroprotective therapy after cardiac arrest, but safety in humans at doses extrapolated from animal models is unknown. This phase I, open-label adaptive dose-escalation study explores the maximum tolerated dose of intranasal insulin in healthy human participants. Placebo or insulin at doses from 0 to 1000 units was given to healthy participants intranasally on repeated weekly visits. Serum glucose, insulin, and C-peptide levels were measured serially at 0, 15, 30, 60, 120, 180, and 240 min after administration. Twenty-four participants (12 female, median age 53, IQR 35–61) were enrolled. There was minimal change in average serum glucose after administration of intranasal insulin. Average serum insulin increased slightly in a dose-dependent manner, reaching maximum concentrations at 15 min. C-peptide decreased over time from administration in all groups. One participant had severe hypoglycemia (24 mg/dL at 45 min) and a different participant had mild hypoglycemia (51 mg/dL at 30 min), both after receiving 600 U intranasal insulin. Hypoglycemic episodes were associated with increases in serum insulin. Both participants continued in the study without hypoglycemia after additional doses. High-dose intranasal insulin up to 1000 U was generally well tolerated, with minimal measurable systemic absorption and without significant aggregate changes in mean glucose. Idiosyncratic episodic systemic absorption and hypoglycemia require further study and additional caution in potential clinical application. Further study of its target engagement and efficacy as a neuroprotective therapy after cardiac arrest at these doses is warranted.

The increase in the availability of real-world data (RWD), in combination with advances in machine learning (ML) methods, provides a unique opportunity for the integration of the two to explore complex clinical pharmacology questions. Here we present a recently developed RWD/ML framework that utilizes ML algorithms to understand the influence and importance of various covariates on the use of a given dose and schedule for drugs that have multiple approved dosing regimens. To demonstrate the application of this framework, we present atezolizumab as a use case on account of its three approved alternative intravenous (IV) dosing regimens. As expected, the real-world use of atezolizumab has generally been increasing since 2016 for the 1200 mg every 3 weeks regimen and since 2019 for the 1680 mg every 4 weeks regimen. Out of the ML algorithms evaluated, XGBoost performed the best, as measured by the area under the precision–recall curve, with an emphasis on the under-sampled class given the imbalance in the data. The importance of features was measured by Shapley Additive exPlanations (SHAP) values and showed metastatic breast cancer and use of protein-bound paclitaxel as the most correlated with the use of 840 mg every 2 weeks. Although patient usage data for alternative IV dosing regimens are still maturing, these analyses provide initial insights on the use of atezolizumab and set up a framework for the re-analysis of atezolizumab (at a future data cut) as well as application to other molecules with approved alternative dosing regimens.