Cts-Clinical and Translational Science最新文献

{"title":"Increased coproporphyrin serum levels in healthy volunteers treated with the cholesterol uptake inhibitor ezetimibe","authors":"Jonny Kinzi,&nbsp;Markus Grube,&nbsp;Isabell Seibert,&nbsp;Werner Siegmund,&nbsp;Henriette E. Meyer zu Schwabedissen","doi":"10.1111/cts.70041","DOIUrl":"10.1111/cts.70041","url":null,"abstract":"<p>Ezetimibe undergoes glucuronidation that results in the active metabolite ezetimibe phenoxy-glucuronide (ezetimibe-glucuronide). This phase-II metabolite was shown to interact with the clinically relevant hepatic transporter organic anion transporting polypeptide (OATP) 1B1. In recent years, coproporphyrin I (CPI) was established as a Tier 1 biomarker for OATP1B-mediated interactions among other endogenous substrates like CPIII. To evaluate whether levels of the biomarker are affected by ezetimibe treatment, we assessed the impact of ezetimibe and ezetimibe-glucuronide on OATP1B1-mediated transport of CPs in vitro. Then, we quantified CP levels in serum samples of healthy volunteers treated with a single oral dose of ezetimibe (20 mg) alone or in combination with rifampin (600 mg). Results from our in vitro experiments showed a significant reduction in cellular CPI accumulation in the presence of ezetimibe-glucuronide with an IC₅₀ of 1.97 μM [95% CI: 1.04 to 3.96], while CPIII accumulation was impacted by 10 μM and above. In the in vivo study, we observed peak CP concentrations 1.33 h after dosing, which is closest to the <i>t</i>_max of the ezetimibe metabolite. Co-administration of ezetimibe with rifampin resulted in even higher serum CP levels. The AUC_0–24h of CPI and CPIII increased two- and threefold, respectively, after concomitant dosing compared to ezetimibe alone. Moreover, we quantified CP levels in cumulative urine from both study phases where the renally excreted amount (<i>A</i>_e) of CPI and CPIII increased after ezetimibe and rifampin co-administration compared to ezetimibe alone. In conclusion, our findings indicate that rifampin co-administration results in additional inhibition of OATP1B1 in vivo.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Examining the effects of the HIV-1 protein Tat and morphine on antiretroviral accumulation and distribution within the brain","authors":"Austin M. Jones,&nbsp;Kara M. Rademeyer,&nbsp;Elias P. Rosen,&nbsp;Silas Contaifer,&nbsp;Dayanjan Wijesinghe,&nbsp;Kurt F. Hauser,&nbsp;MaryPeace McRae","doi":"10.1111/cts.70035","DOIUrl":"10.1111/cts.70035","url":null,"abstract":"<p>Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, neuro-acquired HIV (neuroHIV) remains a significant problem and approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND). Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, neuronal injury and synaptodendritic culling, viral replication, and potentially altering antiretroviral concentrations within the brain. The present study examined the effects of HIV and morphine co-exposure on the accumulation and spatial distribution of antiretroviral drugs across multiple regions within the brain in an HIV-1 Tat transgenic mouse model by using infrared-matrix-assisted laser desorption electrospray ionization mass spectrometry imaging (IR-MALDESI MSI). Morphine exposure uniquely decreased antiretroviral concentrations in anterior cerebral (primary motor and somatosensory) cortices, corpus collosum (anterior forceps), caudoputamen, nucleus accumbens, and posterior regions including the hippocampus, corpus callosum (main body), cerebral cortex (somatosensory and auditory cortices), thalamus, and hypothalamus. Interestingly, male mice experienced greater morphine-associated decreases in antiretroviral concentrations than females. The study also assessed whether changes in antiretroviral concentrations were linked with inflammation in astroglia, assessed through the measurement of astroglial activation using glial fibrillary acidic protein (GFAP) as a marker. Alterations in antiretroviral concentrations co-registering with areas of astroglial activation exhibited sex-specific treatment differences. This study highlights the intricate interplay between HIV, opioids, and antiretroviral drugs within the CNS, elucidating distinct regional and sex variations in responsiveness. Our findings emphasize the identification of vulnerabilities within the neural landscape and underscore the necessity of carefully monitoring opioid use to maintain the efficacy of antiretroviral therapies.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11462598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, pharmacokinetics, and pharmacodynamics of ART-648, a PDE4 inhibitor in healthy subjects: A randomized, placebo-controlled phase I study","authors":"Akira Tanaka,&nbsp;Hiroshi Nagabukuro,&nbsp;Kanako Kuniyeda,&nbsp;Haruhi Ando,&nbsp;Toshinori Higashi,&nbsp;Hirokazu Wakuda,&nbsp;Naoyuki Otani,&nbsp;Hideo Kudo,&nbsp;Masae Kuranari,&nbsp;Hidetoshi Furuie,&nbsp;Naoto Uemura","doi":"10.1111/cts.70024","DOIUrl":"10.1111/cts.70024","url":null,"abstract":"<p>Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad-spectrum anti-inflammatory mechanism. However, securing clinically efficacious doses with sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART-648 is an orally available PDE4 inhibitor being developed for the treatment of inflammatory diseases. According to the estimated clinical doses based on an in vitro whole-blood assay, a phase I study was designed. The purpose of this phase I study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following single and multiple administration of ART-648 in healthy subjects. PD was assessed by suppression of lipopolysaccharide-induced TNFα release in ex vivo whole-blood assay. In the single rising dose study, ART-648 was safe and well tolerated with a dose-proportional increase in exposures up to 4 mg. Single doses of ART-648 demonstrated dose-dependent PD response, indicating target engagement at 2-8 mg doses. In the multiple rising dose study, doses up to 4 mg BID after careful titration were well tolerated, while doses up to 6 mg BID were tolerated not in all but the majority of subjects. In conclusion, ART-648 exhibits a favorable PK profile with robust target engagement at clinically safe and tolerated doses identified in healthy subjects.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between statin use and dry eye disease in patients with hyperlipidemia: A population-based retrospective cohort study","authors":"Yong-Wei Wang,&nbsp;Sian-De Liu,&nbsp;Guan-Ling Lin,&nbsp;Evelyn-Jou-Chen Huang,&nbsp;Joseph Jordan Keller,&nbsp;Li-Hsuan Wang","doi":"10.1111/cts.70039","DOIUrl":"10.1111/cts.70039","url":null,"abstract":"<p>Higher serum cholesterol levels have been associated with an increased risk of dry eye disease (DED). The relationship between statin (HMG-CoA reductase inhibitor) use and DED in patients with hyperlipidemia remains unclear. To investigate the association between statin use and the risk of DED in patients with hyperlipidemia, we conducted a population-based retrospective cohort study utilizing data from Taiwan's Longitudinal Generation Tracking Database. Patients were categorized into statin users and nonusers, with a 5-year follow-up period. The study identified patients with newly diagnosed hyperlipidemia, excluding those with prior DED diagnoses. Matching and adjustments for covariates resulted in 41,931 individuals in each group. Patients receiving statin therapy were compared with those unexposed. Cumulative exposure doses were also evaluated to assess dose–response relationships. The primary outcome was the incidence of DED diagnosed during the follow-up period. Cox proportional hazards regression models estimated the risk of DED, and conditional logistic regression analyzed the dose–response effect of statin exposure. Among 41,931 matched pairs, statin users exhibited a slightly increased risk of developing DED compared with nonusers (adjusted hazard ratio, 1.06; 95% CI, 1.02–1.11; <i>p</i> &lt; 0.01). However, no dose–response relationship was observed between statin exposure and DED risk. Statin use among patients with hyperlipidemia is associated with a marginally higher risk of DED. These findings underscore the importance of regular eye examinations in this patient population to facilitate early detection and management of DED.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is there a possibility that P-glycoprotein reduces reproductive toxicity in males but breast cancer resistance protein does not?","authors":"Zhiheng Yu,&nbsp;Wei Liu,&nbsp;Ziyu Wang,&nbsp;Yidong Chen,&nbsp;Jie Yan,&nbsp;Leslie Z. Benet,&nbsp;Suodi Zhai","doi":"10.1111/cts.70027","DOIUrl":"10.1111/cts.70027","url":null,"abstract":"<p>In traditional understanding, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are regarded as efflux transporters that can decrease the concentration of their substrates in the testis, thereby reducing reproductive toxicity in males (RTM) and protecting spermatogenesis. However, there is currently no direct pharmacological evidence demonstrating that P-gp and BCRP can reduce the occurrence of drug-induced RTM. In this study, we chose small molecule targeted anti-tumor agents as model drugs and systematically retrieved and collected information on the transporters and RTM for these drugs, followed by correlation analysis. The results showed a lower incidence of RTM for P-gp substrate drugs, which aligns with previous knowledge. Surprisingly, BCRP substrate drugs exhibited higher rates of RTM in various dimensions, contradicting previous notions. This discrepancy may be attributed to the differential distribution and transport directions of P-gp and BCRP on the blood–testis barrier (BTB). For the first time, this study may provide clues that BCRP may facilitate the passage of exogenous compounds across the BTB, increasing the occurrence of RTM, rather than protecting spermatogenesis as traditionally believed. Furthermore, this study provides the first direct verification of the role of P-gp in reducing RTM and protecting spermatogenesis.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic model-guided enoxaparin dosing in the Neonatal ICU: Retrospective cohort study to plan for prospective feasibility trial","authors":"Haden Bunn,&nbsp;Catherine Schentag,&nbsp;Leonardo R. Brandão,&nbsp;Vijay Ivaturi,&nbsp;Tamorah Lewis","doi":"10.1111/cts.70040","DOIUrl":"10.1111/cts.70040","url":null,"abstract":"<p>Traditional milligram per kilogram (mg/kg) dosing of enoxaparin in neonates frequently fails to achieve target anti-Xa levels promptly, necessitating repeated laboratory monitoring and dose adjustments. This study investigated whether a personalized dosing strategy based on predicted individual clearance and volume of distribution could improve outcomes, comparing standard-of-care (SOC) mg/kg dosing to pharmacokinetic (PK) model-informed precision dosing (MIPD). A retrospective analysis was conducted on hospitalized neonates treated with enoxaparin at less than 44 weeks postmenstrual age from 2019 to 2022. Data on demographics, drug dosing, PK model covariates, and clinical outcomes were extracted from electronic health records and analyzed using the Pumas-AI Lyv dosing tool. The primary focus was on comparing the initial SOC dose to the MIPD-recommended dose. The secondary outcome measured was the time required to achieve therapeutic anti-Xa levels. The study included 168 neonates with a median postnatal age of 15 days (range 1–149) and a median dosing weight of 3.1 kg (range: 0.82–5.2). MIPD-recommended initial doses were 20%–60% higher than SOC doses in 32% of the cases and over 60% higher in 11% of cases. Neonates who received SOC doses that were much lower than the MIPD recommendation showed the longest delays in reaching therapeutic anti-Xa levels. The results indicate that PK model-informed of enoxaparin dosing leads to higher initial dosages than SOC in neonates, potentially reducing the time to therapeutic anti-Xa levels. These findings are being utilized to define dosing limits for a prospective trial of MIPD in neonatal intensive care settings.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic comparison of subcutaneously administered CT-P13 (biosimilar of infliximab) via autoinjector and pre-filled syringe in healthy participants","authors":"Ye Chan Park,&nbsp;Jae Hoon Kim,&nbsp;Sung Hyun Kim,&nbsp;Ju Hyun Lee,&nbsp;Jang Hee Hong,&nbsp;Jin-Gyu Jung,&nbsp;Jung Sunwoo","doi":"10.1111/cts.70037","DOIUrl":"10.1111/cts.70037","url":null,"abstract":"<p>CT-P13, a biosimilar of infliximab, is used to treat inflammatory diseases that arise from immune system complications, resulting in excessive and persistent inflammation. The subcutaneous (SC) formulation of CT-P13 overcomes the drawback of prolonged administration associated with the intravenous (IV) infliximab biosimilar, necessitating autoinjector (AI) administration. This randomized, open-label, two-arm, parallel-group, single-dose clinical pharmacology study aimed to evaluate the pharmacokinetics (PK) and safety of CT-P13 SC administration via AI compared with the existing pre-filled syringe (PFS) method. A total of 147 healthy participants were randomized into two groups, of which 139 completed the study. Blood samples were collected from before CT-P13 SC administration to 2016 h after the start of the administration. Serum concentrations were analyzed using the Meso Scale Discovery electrochemiluminescence method. Geometric mean ratios (90% confidence interval) of the AUC_inf (areas under the concentration–time curve from zero to infinity) and <i>C</i>_max (The maximum serum concentration) for CT-P13 SC AI versus CT-P13 SC PFS groups, were 94.15% (85.02%–104.26%), 92.48% (84.66%–101.01%), respectively. CT-P13 SC AI and CT-P13 SC PFS achieved comparable PK because the 90% CI was within the predefined equivalence margin. At the end of the study, immunogenicity results revealed that 70 (97.22%) and 73 (98.65%) participants tested positive for anti-drug antibody (ADA) in the CT-P13 SC AI and CT-P13 SC PFS groups, respectively. They were tested positive for neutralizing antibodies. No other significant safety differences were observed between the treatment groups. In conclusion, both administrations demonstrated PK equivalence and were both safe and well-tolerated.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mass balance and pharmacokinetic characterization of zavegepant in healthy male subjects","authors":"Rajinder Bhardwaj,&nbsp;Mary Donohue,&nbsp;Jennifer Madonia,&nbsp;Matt S. Anderson,&nbsp;Kyle Matschke,&nbsp;Richard Bertz,&nbsp;Robert Croop,&nbsp;Jing Liu","doi":"10.1111/cts.70015","DOIUrl":"10.1111/cts.70015","url":null,"abstract":"<p>Zavegepant, a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist, is approved as a nasal spray for acute treatment of migraine in adults. This phase I, open-label, single-center, single-period, nonrandomized study in six healthy male subjects assessed mass balance recovery after a single 15-min intravenous (IV) infusion dose of carbon-14 ([¹⁴C])-zavegepant. Blood, urine, and fecal samples were collected over 192 h for analysis of zavegepant in plasma and urine; total radioactivity (TR) in plasma, whole blood, urine, and feces; and zavegepant metabolite profiling and structural identification in plasma, urine, and feces. An average of 96.6% of radioactivity administered was recovered in excreta. Most TR (mean 84.9%) was recovered in the feces, indicating that biliary/fecal elimination was the main route. Volume of distribution of zavegepant based on the terminal phase (129 L) was higher than total body water (42 L), indicating substantial distribution into tissue. Total plasma clearance of zavegepant (220 mL/min) is identical to whole blood clearance given the blood/plasma partition ratio of 1, lower than typical hepatic blood flow (1450 mL/min). The observed plasma terminal half-life of zavegepant was 6.8 h. Exposure to zavegepant accounted for ~90% of circulating plasma TR, suggesting that very low levels of uncharacterized circulating metabolites were present. Metabolite profiling did not identify any metabolites representing ≥10% of radioactivity in plasma, urine, or feces. A single IV infusion of 5 mg [¹⁴C]-zavegepant was well tolerated in healthy male subjects. Disposition findings of IV [¹⁴C]-zavegepant are applicable to the disposition of the approved zavegepant nasal spray.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between aortic calcification and cytokine levels in patients with peripheral artery disease","authors":"Ville Rantasalo,&nbsp;Dan Laukka,&nbsp;Veikko Nikulainen,&nbsp;Juho Jalkanen,&nbsp;Jarmo Gunn,&nbsp;Tuomas Kiviniemi,&nbsp;Harri Hakovirta","doi":"10.1111/cts.70036","DOIUrl":"10.1111/cts.70036","url":null,"abstract":"<p>Aortic calcification—a marker of advanced atherosclerosis in large arteries—associates with cardiovascular mortality and morbidity. Little is known about the soluble inflamJarmatory profiles involved in large artery atherosclerosis. We investigated the correlation between aortic calcification in the abdominal aorta and cytokine levels in a cohort of peripheral artery disease patients. Aortic calcification index was measured from computed tomography exams and circulating cytokine levels were analyzed from blood serum samples of 156 consecutive patients prior to invasive treatment of peripheral artery disease. The study included 156 patients (mean age 70.7 years, 64 (41.0%) women). The mean ankle-brachial index (ABI) was 0.64 and the mean aortic calcification index (ACI) was 52.3. ACI was associated with cytokines cutaneous T-cell-attracting chemokine CTACK (<i>β</i> 23.08, SE 5.22, <i>p</i> &lt; 0.001) and monokine induced by gamma-interferon MIG (<i>β</i> 9.40, SE 2.82, <i>p</i> 0.001) in univariate linear regression. After adjustment with cardiovascular risk factors, CTACK and MIG were independently associated with ACI, <i>β</i> 17.9 (SE 5.22, <i>p</i> &lt; 0.001) for CTACK and <i>β</i> 6.80 (SE 3.33, <i>p</i> 0.043) for MIG. CTACK was significantly higher in the patients representing the highest ACI tertile (highest vs. middle, 7.53 vs. 7.34 Tukeys HSD <i>p</i>-value 0.023 and highest vs. lowest tertile 7.53 vs. 7.29, Tukeys HSD <i>p</i>-value 0.002). MIG was significantly higher in the highest tertile versus lowest (7.65 vs. 7.30, Tukeys HSD <i>p</i>-value 0.027). Cytokines CTACK and MIG are associated with higher ACI, suggesting that CTACK and MIG reflect atherosclerotic disease burden of the aorta. This might further suggest the possible association with other cardiovascular morbidities.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to “Inadequate representation of individuals of African ancestry in pharmacogenetics of tamoxifen research”","authors":"Bianca Kruger,&nbsp;Collet Dandara","doi":"10.1111/cts.70031","DOIUrl":"10.1111/cts.70031","url":null,"abstract":"<p>We acknowledge the points raised by Nthontho et al.<span>¹</span> We concur with the statement that there is an “inadequate representation of individuals of African ancestry in pharmacogenetics of tamoxifen research.” Indeed, the complex genetic and disease landscape across the continent necessitate that tamoxifen pharmacogenetic studies encompass diverse populations across the entirety of Africa.</p><p>Furthermore, we agree with the observation that the focus of tamoxifen pharmacogenetic studies should be directed toward the inclusion of variants relevant to African populations, and not only investigating genetic variation in CYP2D6 but also incorporating other genes coding for enzymes participating in the different pathways of tamoxifen disposition, including phase II genes coding for sulfotransferases (SULTs), uridine 5′-diphospho-glucuronosyltransferases (UGTs) and other cytochrome P450 (CYP) genes. The benefit of including variants common to Africans in pharmacogenetic studies is already evident in research that have improved our understanding of the variability in treatment response in African patients.<span>^{2, 3}</span> As mentioned by Nthontho et al.,<span>¹</span> findings from similar studies could serve as a foundation for advancing tamoxifen pharmacogenetic research.</p><p>For tamoxifen pharmacogenetic studies to be informative, research should be conducted through well-designed clinical studies that incorporate big data to include as many populations as possible across the continent, capturing a wide range of genetic and environmental biomarkers common to African populations. Leveraging “omics” technologies will significantly enhance our understanding of pharmacogenetics in African populations. As highlighted in the response, there is a critical need for funding and organizational support to advance not only tamoxifen pharmacogenetic research but also pharmacogenomics research in Africa.</p><p>The African Pharmacogenomics Consortium/Network (APN) was established to address the lack of pharmacogenomics studies in Africa and among African populations.<span>⁴</span> The APN aims to strengthen the capacity for research and implementation of pharmacogenomics by consolidating the continent's expertise and technological platforms. Achieving this requires strategic collaboration among African researchers and the involvement of international partners.</p><p>We advocate for increased collaboration within Africa to enable the continent to advance in pharmacogenomic research. By fostering these partnerships, Africa can build its capacity, contribute valuable insights to the global field, and become a leading force in pharmacogenomics.</p><p>No funding was received for this work.</p><p>The authors declared no competing interests for this work.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}