Cts-Clinical and Translational Science最新文献

Pharmacokinetics (PK) has long been differentiated from pharmacodynamics (PD) and biomarkers, yet this distinction undervalues PK's translational relevance. In this Perspective, we propose that PK itself functions as a biomarker that bridges dose, exposure, and response. Using examples from target-mediated drug disposition, antidrug antibodies, cerebrospinal fluid PK, high-dose methotrexate therapy, and anti-infective pharmacology, we illustrate how PK serves as a measurable, predictive, and actionable biomarker that informs drug development, guides decisions, and advances precision medicine.

Paclitaxel (Taxol) is a widely used anticancer agent that undergoes extensive hepatic metabolism and that causes a debilitating, dose-limiting peripheral neurotoxicity. We previously reported that the uptake of paclitaxel in hepatocytes and dorsal root ganglion neurons, the site of injury within the nervous system, is mediated by the organic anion transporting polypeptides OATP1B1 and OATP1B3 (Oatp1b2 in rodents), transporters that are highly sensitive to pharmacological inhibition. To facilitate future screens of chemical libraries to identify modulators and imaging-based drug distribution studies, we explored the utility of PB-Gly-Taxol and PB-GABA-Taxol, derivatives of paclitaxel linked to the coumarin-derived fluorophore Pacific Blue, as in vitro and in vivo substitute biomarker probes of paclitaxel. Transport studies in transfected HEK293 cells revealed efficient uptake of these PB-taxoids by human and murine OATP1B/Oatp1b-type transporters, with up to 100-fold increases in uptake relative to values observed in vector control cells, and inhibition of this transport by known inhibitors. Although cell viability assays demonstrated lower cytotoxicity of both PB-taxoids (IC₅₀: 13~80 nM) against a panel of breast cancer cell lines, ensuing investigations confirmed their ability to induce peripheral neurotoxicity phenotypes in mice (p < 0.05), in an Oatp1b2-dependent manner, to the same extent as paclitaxel. These findings imply that PB-taxoids mimic the transport and toxicokinetic features of paclitaxel, and these agents thus offer potential as fluorescent imaging tools for exploring drug–drug interaction liabilities and paclitaxel-related toxicity profiles that involve OATP1B/Oatp1b-type transporters.

ASP1617 is a novel, highly selective inhibitor of cathepsin-S, an important protease for antigen peptide loading onto major histocompatibility complex class II molecules. Preclinically, ASP1617 prevented progression of lupus-like glomerulonephritis in an NZB/W F1 mouse model of systemic lupus erythematosus. In this double-blind, randomized, placebo-controlled, first-in-human study in healthy subjects, ASP1617 was generally well tolerated. Treatment-emergent adverse events of rash and throat tightness were reported in two subjects receiving the highest doses of 110 mg BID in multiple ascending dose (MAD) cohorts, leading to withdrawal of ASP1617 in both subjects. Mean elimination half-life was 10.4–15.9 h in single ascending dose (SAD) cohorts and 13.7–20.5 h in MAD cohorts. ASP1617 exposure increased slightly greater than dose proportionally between SAD cohorts and dose proportionally between MAD cohorts and was similar between Japanese and non-Asian subjects. A high-fat, high-calorie meal slightly decreased peak and total exposure and delayed absorption. Both single and multiple dosing of ASP1617 led to rapid and maximal inhibition (> 80% at 3 h post-dose) of cathepsin-S activity as well as the downstream increase of invariant chain p10 (Lip10) in B cells, indicating target engagement. However, in all MAD cohorts, cathepsin-S activity gradually rebounded during treatment, surpassing baseline levels after the last dose, and cathepsin-S mass increased significantly, fivefold above baseline, and prolonged after treatment. Due to the observed safety events, induction of the cathepsin-S target, and gradual loss of pharmacodynamic effects during repeated dosing, appropriate mitigation strategies are necessary for the further clinical development of ASP1617.

Trial Registration: ClinicalTrials.gov Identifier: NCT04077879

To summarize the available evidence in the literature regarding the effects of exposure to an enriched environment (EE) on the modulation of apoptotic markers in central tissue of rodents under unfavorable conditions. Searches were conducted in three databases: PubMed/Medline (70 articles), Scopus (65 articles), and EMBASE (128 articles), all of which were subjected to eligibility criteria. Of the 263 articles found, 95 duplicates were removed. After evaluating the title and abstract, 147 studies were excluded, leaving 21 articles, 16 of which were included in this systematic review. EE was implemented using various inanimate objects. The disruptive event/condition included social isolation, cerebral ischemia, stroke, postpartum depression, accelerated aging, ischemia/reperfusion, high altitude, Alzheimer's disease, hypobaric hypoxia, infrasound exposure, sepsis, and exposure to sevoflurane. Regarding the expression of apoptotic markers, after EE exposure, there was a reduction in the expression of p-IKKβ/IKKβ and p-P65/P65 in the hippocampus, a reduction in Bax, as well as cleaved Caspase-3, Cytochrome C, a reduction in the Bax/Bcl-2 ratio, and p53. As for anti-apoptotic markers, increased expression of Bcl-2 was observed following EE exposure. This systematic review concludes that the benefits of EE can reduce apoptosis through the modulation of both pro-apoptotic and anti-apoptotic genes. In this regard, EE has been shown to be an important neuroprotective tool in various adverse conditions, mitigating cognitive deficits by reducing apoptosis related to cellular stress.

Fc-engineered antibodies (mAbs) enhancing FcRn binding have rapidly expanded in drug discovery and development. Although an approach exists for predicting the pharmacokinetics of Fc-engineered mAbs after intravenous injections in humans, no methodology has been established for predicting pharmacokinetics after subcutaneous injections. This study aimed to establish a methodology for predicting the pharmacokinetics of Fc-engineered mAbs after subcutaneous injections in humans. First, bioavailability (F) and absorption rate constant (k_a) values following subcutaneous injections in humans were collected and analyzed. Then, AUC after subcutaneous injections in humans was predicted using the geometric mean of reported F and allometrically scaled clearance (CL) from cynomolgus monkeys. Next, plasma concentration-time profiles after subcutaneous injections were predicted using the geometric mean of reported F and k_a values and allometrically scaled two-compartment model parameters from cynomolgus monkeys. The geometric mean of reported F for Fc-engineered mAbs in humans was 0.601, lower than that of normal mAbs. The geometric mean of ka was 0.284/day, comparable to normal mAbs. The prediction accuracy of AUC using the geometric mean of F and scaled CL from cynomolgus monkeys was 95.2% within 2-fold of observed values. Furthermore, C_max and T_max after subcutaneous injections showed 94.1% and 70.6% prediction accuracy within 2-fold of observed values, respectively. Overall, 88.4% and 95.3% of whole plasma concentration-time profiles were predicted within 2-fold and 3-fold of observed values, respectively, demonstrating the high prediction accuracy. This methodology, combining fixed absorption parameters with scaled two-compartment model parameters, can significantly support Fc-engineered mAbs development.

Qiao W., Shahraz A., Vishwanathan K. and Sawant-Basak A. Clinical pharmacology perspective on direct-to-subcutaneous dosing of T cell engagers in oncology first-in-human studies. Clinical and Translational Science. 2026; 19(1):e70461.

In Conflicts of Interest section, the statement of “The authors declare no conflicts of interest” was incorrect.

This should have been “W.Q. was an employee of AstraZeneca when the work was conducted. A.S., K.V., and A.S-B are employees and shareholders of AstraZeneca.”

We apologize for this error.

Intrinsic factors such as age and ethnicity influence statin pharmacokinetics (PK) and may increase the risk of muscle-related adverse events. This study investigated the effect of age on the PK of simvastatin (SV) and its active metabolite, simvastatin acid (SVA), in healthy Thai subjects using an LC–MS/MS assay while accounting for key SLCO1B1 variants known to affect statin exposure. We further compared our results with published data across multiple ethnic populations via meta-analysis and conducted an exploratory pharmacogenetic analysis of SVA disposition-related genes to identify potential candidate variants contributing to PK differences observed between Thai and Caucasian populations. The pharmacokinetic results showed that aging significantly increased SV C_max but did not alter SVA exposure, while SLCO1B1 decreased and poor functions were associated with higher SVA exposure. The meta-analysis revealed that Thai subjects showed significantly higher SVA levels than Caucasians, Chinese, and Japanese. The pharmacogenetic analysis identified functional or promoter variants in SLCO1B1 and PON genes with allele frequency differences directionally consistent with the observed PK differences between Thais and Caucasians. Our results may partly explain the higher incidence of SV-associated rhabdomyolysis previously reported in Thais compared with Caucasians and highlight the relevance of these intrinsic factors in SV and SVA PK, with implications for dosing considerations in Thai patients. Additional studies are warranted to further support the involvement of these polymorphic variants in the observed interethnic differences in SVA PK and adverse outcomes.

Immune checkpoint regulators can improve neurological functions in Alzheimer's disease. However, it remains blurred whether these regulators may ameliorate temporal lobe epilepsy (TLE) and TLE-related cognitive impairment. This study analyzed the bulk transcriptomic data of human TLE hippocampi by bioinformatics. The expression of the potential immune checkpoint regulators in the hippocampus was assessed by immunohistochemical staining; the preoperative seizure severity and postoperative cognitive function were evaluated by the National Hospital Seizure Severity Scale (NHS3) and Telephone Interview for Cognitive Status-Modified (TICS-m); the correlation between the target immune checkpoint regulators and TLE-related cognitive impairment was examined by simple linear regression models and the area under the receiver operating characteristic curve (AUC). We first identified glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) as a key immune checkpoint regulator in TLE patients, with an increased intensity of GITRL in epileptic hippocampus (n = 21) compared with that of the control (n = 3). The GITRL intensity was positively correlated with NHS3 score (r² = 0.503, p < 0.001) and negatively with TICS-m total score (r² = 0.456, p < 0.001), specifically, TICS-m memory score (r² = 0.360, p = 0.004), TICS-m language/attention score (r² = 0.319, p = 0.008), and TICS-m orientation score (r² = 0.312, p = 0.008). The AUC showed that the GITRL intensity presented a good predictive performance in discerning patients with a TICS-m score of ≥ 30 (AUC: 0.875, 95% CI, 0.721–1.00; p = 0.013). These findings highlight hippocampal GITRL as a potential predictive marker for TLE-related cognitive impairment.

The nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) has been identified as a key genetic determinant of 6-mercaptopurine (6-MP)-induced hematopoietic toxicity in populations with a high frequency of NUDT15 variants but a low frequency of thiopurine S-methyltransferase (TPMT) variants. However, evidence remains limited in populations where both genetic variants are prevalent. This study aimed to characterize the impact of NUDT15 and TPMT polymorphisms on 6-MP-induced hematopoietic toxicity in Thai pediatric patients, a population with a high prevalence of both variants. A total of 215 Thai pediatric patients undergoing maintenance-phase therapy with 6-MP were enrolled. Genotyping for TPMT and NUDT15 was performed, and phenotypes were determined based on the genotype data. The results showed that the absolute neutrophil count (ANC), white blood cell (WBC) count, and platelet count during the first 6 months of the maintenance phase were significantly lower in intermediate metabolizers (IM) of NUDT15 compared to normal metabolizers (NM). The risk of 6-MP-induced severe neutropenia increased by 6.8–24.5-fold in IM/PM of NUDT15. The suitable tolerance doses of 6-MP in the IM/PM of NUDT15 were lower than the normal starting dose while the tolerance dose of 6-MP in the indeterminate metabolizers (IDM) of NUDT15 or IM of TPMT was not significantly different from the normal starting dose. In conclusion, NUDT15 plays a more prominent role than TPMT in 6-MP-induced hematopoietic toxicity in Thai pediatric patients. Determining NUDT15 phenotypes is essential to ensure appropriate 6-MP dosage adjustments and to mitigate the risk of severe hematopoietic toxicity in this population.

Efavirenz's effects on cytochrome P450 2C9 (CYP2C9) activity have not been formally characterized in vivo. We conducted the first clinical drug–drug interaction (DDI) study to test the effect of chronic efavirenz dosing on CYP2C9 activity, using tolbutamide as a selective probe. Healthy participants received a single oral dose of tolbutamide (250 mg) with a single 600 mg dose of efavirenz (SD) before and after 600 mg daily efavirenz for 17 days (MD). Tolbutamide, efavirenz, and their metabolites were quantified in plasma and urine samples by LC–MS/MS method. Participants were genotyped for CYP2C9*2 and *3 and for CYP2B6*4, *9, and *18. Pharmacokinetic data were valid for 71 and 59 participants for SD- and MD groups, respectively. MD efavirenz caused more than 50% increase in median tolbutamide AUC_0-∞ and C₂₄ in all subjects, and 1.42–1.46-fold increase in the paired analysis (p < 0.0001); tolbutamide/metabolite ratios were also increased (p < 0.001), while tolbutamide's CL/F/kg, metabolite formation clearance, and metabolite C_max were significantly reduced. CYP2C9 genetic variants were associated with reduced tolbutamide elimination compared to *1/*1 and *1/*2 (slowest, *3/*3; and intermediate, *1/*3, *2/*2, and *2/*3). The lowest percent change occurred in *2/*2 and *3/*3 genotypes, though small sample sizes limited reliable assessment of genotype-specific DDI effects. In conclusion, chronic efavirenz use inhibits CYP2C9 activity in vivo. This inhibition may increase the risk of adverse effects from narrow-therapeutic-index CYP2C9 substrates (e.g., warfarin, phenytoin, and sulfonylureas). Therefore, therapeutic drug monitoring and dose adjustments are warranted when efavirenz is co-administered with these medications.