Monostory K, Villapalos Garcia G, Koller D
… +11 more, Adams S, Bousman CA, Tsermpini EE, Whirl-Carrillo M, Turner AJ, Lauschke VM, Nagy M, Boone EC, Klein TE, Zubiaur P, Gaedigk A
The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP1A2 gene. CYP1A2 plays a crucial role in the biotransformation of several commonly used drugs, including antipsyc...The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP1A2 gene. CYP1A2 plays a crucial role in the biotransformation of several commonly used drugs, including antipsychotics, antidepressants, anxiolytics, and methylxanthines. The activity of CYP1A2 varies significantly among individuals due to genetic and non-genetic factors. This GeneFocus paper offers an overview of the functional significance of CYP1A2 in drug metabolism, CYP1A2 genetic variation, and presents the updated PharmVar star allele-based nomenclature for CYP1A2. Updates include revisions to previously defined star alleles to align with PharmVar standards, as well as the addition of novel star alleles, providing the pharmacogenetic community with a more comprehensive and high-quality catalog of CYP1A2 genetic variation. We highlight that the common -163C>A (rs762551) variant, which previously defined CYP1A2*1F, is now the sole core variant for a newly established group of CYP1A2*30 alleles. Furthermore, the -163C>A variant, which has been associated with increased expression levels in smokers, has been found on various haplotypes in combination with one or more amino acid changing variants, each of which was assigned a unique star number (e.g., CYP1A2*13, *21, *24, and *31). While all alleles containing -163C>A may have increased expression levels in smokers, it remains unknown whether the presence of one or more amino acids negates the effect of increased expression levels on CYP1A2 activity. Systematic nomenclature that comprehensively describes CYP1A2 variability is essential for future research aimed at assessing the relationship between CYP1A2 variation, drug metabolism, and the clinical utility of CYP1A2 pharmacogenetic testing.
Demonstrating pharmacological effects in early-phase oncology clinical trials remains challenging, largely due to the lack of robust pharmacodynamic markers. Lipopolysaccharide (LPS) is used as an immune challenge agent...Demonstrating pharmacological effects in early-phase oncology clinical trials remains challenging, largely due to the lack of robust pharmacodynamic markers. Lipopolysaccharide (LPS) is used as an immune challenge agent in healthy participants to study drugs for autoimmune conditions. We hypothesized that the intravenous LPS challenge model could be implemented in oncology drug studies in healthy participants to evaluate in vivo pharmacodynamics of new drugs. This open-label study included 13 healthy males who received a single intravenous dose of 1 or 2 ng/kg LPS. Blood and bone marrow samples were collected pre- and post-LPS for bulk RNA sequencing, multiplex cytokine measurements, immunophenotyping, and immunohistochemistry of bone marrow biopsies. Differentially expressed genes were integrated with the OpenTargets Platform and the COSMIC database to assess their tractability and relation to cancer hallmarks. The LPS challenge and bone marrow sampling were safe and well tolerated. In peripheral blood, LPS induced a rapid, transient inflammatory response, with myeloid cell activation and enrichment of inflammation-related pathways. Conversely, bone marrow showed an attenuated cellular response and activation of hematopoietic and cell cycle-related transcriptional programs. We identified 91 LPS-induced oncology-relevant targets in blood and 24 targets in bone marrow. The oncogenic transcription factor MYC was upregulated in the bone marrow, which was confirmed at the protein level by a dose-dependent increase in c-Myc expression. Our findings highlight the potential of immune challenges in healthy participants to pharmacodynamically profile novel oncology agents, with the aim of generating early pharmacological data ahead of pivotal clinical trials in cancer patients.
Archary M, Bies R, Boateng O
… +12 more, Daley R, Gashema P, Karina M, Njuguna E, Nachman S, Nkrumah N, Odula C, Owen A, Weld ED, Venkatasubramanian P, Olagunju A, Community of Practice for Long‐acting Therapeutics for Maternal and Paediatric Health
As use cases for long-acting therapeutics expand across clinical indications, there is a critical need to ensure the inclusion of women who are pregnant or breastfeeding, infants and children-populations with a historica...As use cases for long-acting therapeutics expand across clinical indications, there is a critical need to ensure the inclusion of women who are pregnant or breastfeeding, infants and children-populations with a historical gap in the availability of interventions already approved for use in adults. This White Paper synthesizes insights from a special session during the 1st of July 2025 workshop of the Community of Practice for Long-Acting Therapeutics for Maternal and Paediatric Health. It was hosted by the University of Liverpool Centre of Excellence for Long-acting Therapeutics. Attendees included stakeholders drawn from clinical practice, patient advocacy groups, academia, pharmaceutical industry, regulatory agencies, product development partners, and public health organizations. Four focus groups-centered on maternal health, pediatric health, access, and regulation-addressed three key questions: (i) What are the most urgent gaps that could hinder the adoption of long-acting therapeutics for maternal and pediatric health indications? (ii) What critical actions are needed to address these gaps? (iii) What partnerships must be initiated or strengthened to enable or accelerate these actions? Actionable strategies to accelerate progress were identified. Key themes that emerged from the discussion included the need for inclusive and context-sensitive research designs, harmonized regulatory frameworks, culturally responsive implementation strategies, and sustainable funding mechanisms. Platforms for fostering interdisciplinary collaboration, amplifying diverse stakeholder voices, and promoting transparency in innovation are needed. Partnership models that support inclusive development and equitable deployment will be central to successful integration and to realize the full potential of long-acting therapeutics in advancing maternal and pediatric health.
Moore C, Bourque MS, Halman A
… +14 more, Agúndez JAG, Prows CA, Hikino K, Schwab M, Oxencis CJ, Chauhan D, Diekstra MHM, Long SE, Bell GC, Gaedigk A, Whirl-Carrillo M, Klein TE, Caudle KE, Conyers R
5-hydroxytryptamine type 3 (5-HT) receptor antagonists are used to treat nausea and vomiting and in the prevention of chemotherapy-induced, radiation-induced, and postoperative nausea and vomiting. Most of the 5-HT recep...5-hydroxytryptamine type 3 (5-HT) receptor antagonists are used to treat nausea and vomiting and in the prevention of chemotherapy-induced, radiation-induced, and postoperative nausea and vomiting. Most of the 5-HT receptor antagonists (i.e., ondansetron, tropisetron, dolasetron, palonosetron, and ramosetron) are metabolized by CYP2D6, but the extent of CYP2D6 involvement varies. CYP2D6 genetic variation can influence the metabolism of these medications, particularly ondansetron and tropisetron, thereby affecting drug efficacy. This guideline is an update to the 2016 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron and includes updated information on CYP2D6 genetic testing and evidence tables. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for 5-HT receptor antagonists based on CYP2D6 genotype, particularly where genetic variation is associated with reduced drug efficacy (updates at https://www.clinpgx.org/guideline/PA166251457).
An emerging proposal suggests that prior findings of pharmacokinetic comparability for one product could be applied to other therapeutic protein products that use the same autoinjector platform. We investigated 16 autoin...An emerging proposal suggests that prior findings of pharmacokinetic comparability for one product could be applied to other therapeutic protein products that use the same autoinjector platform. We investigated 16 autoinjectors using one platform and found that (a) pharmacokinetic comparability outcomes varied and (b) these outcomes were not attributable to identified device performance parameters or product viscosity. Further investigations are necessary to support the proposed extrapolation across products sharing the same autoinjector platform.
Kang S, Min KL, Yang S
… +7 more, Hahn J, Kim D, Jin BH, Chae SU, Bae SK, Wi J, Chang MJ
Clin Pharmacol Ther
· 2026 Jul · PMID 41979241
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Although patients with acute coronary syndrome supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO) have a high risk of thrombosis and bleeding, antiplatelet pharmacology in this setting is not well d...Although patients with acute coronary syndrome supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO) have a high risk of thrombosis and bleeding, antiplatelet pharmacology in this setting is not well defined. This prospective observational study investigated the population pharmacokinetics of ticagrelor and its active metabolite AR-C124910XX and explored model-informed dosing strategies among this population. Paired pharmacokinetic sampling was performed at predefined time points during ON- and OFF-ECMO periods. Plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay and analyzed with NONMEM to develop a joint parent-metabolite model and evaluate the effects of VA-ECMO status and flow rate on ticagrelor disposition. Monte Carlo simulations of various ECMO flow-rate scenarios examined alternative loading and maintenance regimens using prespecified trough concentrations of 180-360 ng/mL, as derived from previous exposure-response and exposure-bleeding analyses in non-ECMO populations. A total of 225 ticagrelor and 225 metabolite concentrations (127 ON-ECMO and 98 OFF-ECMO) from 20 patients were analyzed. VA-ECMO support was associated with reduced ticagrelor clearance and increased volume of distribution, while higher flow rates were associated with decreased volumes of distribution. In simulations, an initial loading dose of 120-135 mg followed by a 60 mg maintenance dose once daily most consistently maintained predicted trough concentrations within the target range during VA-ECMO, whereas 90 mg once daily frequently exceeded the upper bound. These findings indicate that VA-ECMO substantially altered ticagrelor pharmacokinetics and provided quantitative, model-informed support for reduced once daily dosing strategies; however, further pharmacokinetic-pharmacodynamic and outcome studies are needed to confirm these findings.
Risperidone is a commonly used antipsychotic for treating psychiatric illness in children and adolescents. There is a large variability in risperidone response and discontinuation rates remain high. Pharmacogenomics offe...Risperidone is a commonly used antipsychotic for treating psychiatric illness in children and adolescents. There is a large variability in risperidone response and discontinuation rates remain high. Pharmacogenomics offers the opportunity to improve risperidone outcomes, yet studies in pediatric populations are limited. We conducted a genome-wide association study (GWAS) to investigate genetic predictors of risperidone response in pediatric patients (n = 161) who received inpatient care at a pediatric hospital in a rural setting. Clinical, demographic, and treatment outcomes data, collected retrospectively, were incorporated into predictive models. While 41.0% of patients discontinued risperidone, patients remained on risperidone longer than other antipsychotics, with the exception of quetiapine. Female patients discontinued more quickly, as did patients in the acute program compared to residential. We identified nine genetic variants associated with risperidone outcomes: duration of risperidone treatment and frequency of risperidone discontinuation (rs10270303, intronic variant, PTPRN2), maximum risperidone dose (rs6014649, intergenic variant between CBLN4 and MC3R; rs56261530, synonymous variant, SHD), time to readmission (rs35722167, intergenic variant between UGT2A3 and UGT2B7; rs62382382, intronic variant, SGCD; rs62466698, intergenic variant between BET1 and GNG11; rs1152938, intronic variant, CPM), and duration of hospital stay (rs117426990, 3'-UTR variant, TMX3; rs5956073, intergenic variant between DOCK11 and LINC01285). Our study is the first GWAS of risperidone response in pediatric populations, which provides insights into the biological complexity of risperidone response, as well as moving toward precision antipsychotic treatment. Our study demonstrates the high value of conducting research in a community-based setting and highlights the need to expand research studies beyond academic medical centers.
Dong J, Moir A, Pepin X
… +4 more, Lowe E, Hopkins S, Tang W, Zhou D
Clin Pharmacol Ther
· 2026 Jul · PMID 41979227
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Although physiologically based pharmacokinetic (PBPK) modeling is increasingly being used to support oral drug formulation bridging, the acceptance by regulatory agencies is low. One of the primary concerns is the absenc...Although physiologically based pharmacokinetic (PBPK) modeling is increasingly being used to support oral drug formulation bridging, the acceptance by regulatory agencies is low. One of the primary concerns is the absence of clinical pharmacokinetic (PK) data from a non-bioequivalent (non-BE) batch during model validation. Such data are strongly recommended by regulatory agencies to demonstrate that the models are sufficiently sensitive to detect formulation-driven changes in drug exposure. Herein, we investigated whether using clinical non-BE batch data is the most effective absorption model validation approach, using the bridging of adult and pediatric olaparib formulations as an example. Two olaparib PBPK models were developed: a "final" model and a "counterpart" model, each with comparable ability to predict the olaparib PK. Both models well predicted the clinical PK of a non-BE batch of 250 mg olaparib-manufactured intentionally with a slower release profile-and its lack of bioequivalence relative to ten 25 mg tablets, formulated for faster release, as a conservative scenario. The final model closely captured both observed intra- and intersubject variabilities in C and AUC, whereas the counterpart model was unable to reproduce the observed intrasubject variability. Our findings indicated that the clinical non-BE data may not be necessary in all cases. In certain scenarios, validation against intrasubject variability may meet the dual objectives of capturing PK variability and confirming sensitivity within the absorption model. Using the final model, we demonstrated BE between adult and pediatric formulations of olaparib in adults and showed minimal food effect on its exposure in pediatrics.
CYP2C19 metabolizes various selective serotonin reuptake inhibitors (SSRIs) and genetic CYP2C19 variants are associated with SSRI tolerability and response. Yet, whether CYP2C19 variability also impacts citalopram respon...CYP2C19 metabolizes various selective serotonin reuptake inhibitors (SSRIs) and genetic CYP2C19 variants are associated with SSRI tolerability and response. Yet, whether CYP2C19 variability also impacts citalopram response remained unclear. We here evaluated associations between CYP2C19 genotypes and citalopram prescription data of 11,079 patients from the UK Biobank. Importantly, CYP2C19 ultrarapid metabolizers (UMs) were more likely to experience therapeutic failure (OR 2.03, P = 0.002) and both CYP2C19 poor metabolizers (PMs) and UMs exhibited an increased likelihood of treatment resistance (PMs, OR 1.85, P = 0.06; UMs, OR 1.74, P = 0.05). Furthermore, inferred CYP2C19 metabolizer status showed significant monotonic trends with citalopram maintenance dose (from 19.7 mg/d in PMs to 24.4 mg/d in UMs; Jonckheere-Terpstra P = 0.017) and time to dose escalation (2.5 years in PMs to 1.7 years in UMs; P = 0.006). Besides CYP2C19, rare variant analyses identified BMP2K as a novel candidate locus for SSRI response. BMP2K variants were significantly associated with therapeutic failure in citalopram patients (P = 5.49 × 10) and this association was replicated in 220 escitalopram users (P = 0.042). Furthermore, higher BMP2K variant burden significantly correlated with lower maintenance dose. These findings provide the first report of a U-shaped association between CYP2C19 metabolizer status and citalopram therapeutic outcomes and pinpoint BMP2K as a novel candidate gene with potential contribution to interindividual differences in citalopram response. Collectively, these results demonstrate that CYP2C19 genotype is significantly associated with citalopram outcomes in a real-world setting in which patient treatment was not guided by pharmacogenetics, thus avoiding open-label awareness, eliminating expectation bias of genetic testing and highlighting the value of large-scale biobank data for advancing precision psychiatry.
Will clinical translational pharmacology (CTP) seize the opportunity to become a leadership discipline driving the next era of patient-centered therapeutics? This white paper, based on input and discussion from the ASCPT...Will clinical translational pharmacology (CTP) seize the opportunity to become a leadership discipline driving the next era of patient-centered therapeutics? This white paper, based on input and discussion from the ASCPT Summit on the Future of Clinical Translational Pharmacology, issues a bold call to action for CTP to define itself as a discipline that embraces its multidisciplinary breadth, demanding a radical shift that visibly inhabits the full scope of its multitudinous identity. We propose a five-priority roadmap-Foundational Principles, Workforce and Leadership, Innovation and Technology, Health Equity and Global Health, and Public Visibility and Scientific Trust-to transform CTP into an engine of therapeutic advancement and optimization. The future of medicine depends on CTP's ability to lead, adapt, influence, and unify across silos, ensuring that scientific breakthroughs translate into real-world benefit for every patient, everywhere. The next decade demands urgency, unity, and unapologetic ambition to move beyond incremental change.
Antoniou T, Yang J, Juurlink DN
… +5 more, Ho JM, Mamdani M, Wu F, Tadrous M, Gomes T
Clin Pharmacol Ther
· 2026 Jul · PMID 41944476
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Fentanyl, hydromorphone, and oxycodone are metabolized by cytochrome P450 3A4 (CYP3A4). Co-administration with CYP3A4-inhibiting macrolides (clarithromycin or erythromycin) may increase opioid concentrations and overdose...Fentanyl, hydromorphone, and oxycodone are metabolized by cytochrome P450 3A4 (CYP3A4). Co-administration with CYP3A4-inhibiting macrolides (clarithromycin or erythromycin) may increase opioid concentrations and overdose risk, but the clinical impact of these interactions is unknown. We conducted three population-based nested case-control studies of Ontario residents aged 15 years or older who were prescribed transdermal fentanyl, oral hydromorphone, or oral oxycodone between 1997 and 2023. We defined cases as individuals who died of or were hospitalized with opioid toxicity and matched each case to up to four controls on age, sex, calendar year, and a disease risk score. We assigned controls random index dates based on the distribution among cases and estimated adjusted odds ratios (aOR) and 95% confidence intervals (CIs) for the association between opioid toxicity and macrolide use in the preceding 14 days. We matched 735 fentanyl-treated (45.3% of eligible cases), 2,506 hydromorphone-treated (64.5%), and 678 oxycodone-treated (50.1%) individuals with opioid toxicity to at least one control. Across all studies, 70 cases and 120 controls were exposed to a macrolide. CYP3A4-inhibiting macrolide exposure was associated with an increased risk of opioid toxicity among patients treated with fentanyl (aOR 3.80, 95% CI: 1.36-11.56), hydromorphone (aOR 3.38, 95% CI: 1.28-8.97), and oxycodone (aOR 3.11, 95% CI: 1.05-9.51). We observed no associations with azithromycin, a non-CYP3A4 inhibiting macrolide. There was no significant effect modification by study period, and findings were robust in bias analyses. These findings likely extend to individuals exposed to clandestinely produced fentanyl and to other CYP3A4 inhibitors.
With the continuous advancement of CGT technologies, therapeutic regimens worldwide are confronting dual challenges: accelerated regulation and innovation in payment models. The United States has established a regulatory...With the continuous advancement of CGT technologies, therapeutic regimens worldwide are confronting dual challenges: accelerated regulation and innovation in payment models. The United States has established a regulatory framework characterized by early-stage acceleration and late-stage evidence supplementation based on the 21st Century Cures Act, matching a market-driven payment model supported by commercial insurance and Medicare pilots. China adheres to technology-first with strict risk control, experiencing three regulatory phases and forming a government-led payment model via prudent national medical insurance and local supplementary coverage. Both countries face common dilemmas of long-term evidence shortage, payment system adaptation, and regional accessibility inequality. This study objectively clarifies the institutional differences between the two countries and subjectively proposes targeted solutions including risk-adapted hierarchical regulation, cross-border collaborative payment sharing, and industrial synergy, aiming to provide a reference for global CGT universal access.
Hamuy Blanco J, Janse van Rensburg DC, van Rensburg AJ
… +1 more, Schellack N
Clin Pharmacol Ther
· 2026 Jul · PMID 41933437
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The Medication Adherence Risk Score (MARS) is an objective adherence-based score, derived from transactional dispensary data. This study provides expert consensus to validate the use of the MARS as a predictor of mortali...The Medication Adherence Risk Score (MARS) is an objective adherence-based score, derived from transactional dispensary data. This study provides expert consensus to validate the use of the MARS as a predictor of mortality risk. A systematic review and assessment of South African health legislation and professional guidelines informed the development of consensus statements regarding the relevance, validity, predictive power, and implementation feasibility of the MARS. A two-round modified Delphi approach using a 5-point Likert scale was employed. Consensus was reached if at least 80% of respondents selected "agree" or "strongly agree." Nonconsensus statements were revised based on qualitative feedback and subsequently reevaluated in a second round. Thirteen clinical, actuarial, and academic experts were successfully recruited. Consensus was achieved for 20 of the 28 statements in Round 1. Five of 18 (27.8%; risk score components), 1 of 3 (33.3%, validity/predictive power), and 2 of 7 statements (26.5%, real-world implementation) did not initially reach consensus. Nonconsensus statements were revised to provide clarity, after which consensus was achieved for all statements by the end of Round 2. Expert consensus supports the inclusion, exclusion, and weighting of MARS risk factors. The panel agreed that the score offers predictive value for mortality outcomes, and that real-world application for enhancing risk stratification and reducing healthcare costs is feasible. Future statistical analysis is necessary to demonstrate its relationship with mortality risk. Developing practical implementation strategies will facilitate incorporation into clinical practice and public health interventions.
Saarukka LSM, Yamileva K, Linden K
… +2 more, Simonen A, Holmström AR
Clin Pharmacol Ther
· 2026 Jul · PMID 41933435
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Financial toxicity, defined as the economic burden experienced by patients due to medication and other healthcare costs and their consequences, such as material, psychosocial and behavioral effects, represents a signific...Financial toxicity, defined as the economic burden experienced by patients due to medication and other healthcare costs and their consequences, such as material, psychosocial and behavioral effects, represents a significant concern for individuals receiving biological medicines. This scoping review synthesizes current evidence on financial toxicity connected to biological therapies and proposes policy interventions to mitigate its impact, while identifying key research gaps. A comprehensive literature search was conducted across databases Scopus, Medline, Web of Science, CINAHL, and EMB Reviews. The initial set of articles was screened in accordance with the PRISMA framework using Covidence software. After title/abstract and full-text screening, 24 studies were included in the final analysis. Data were synthesized guided by Witte's framework of financial toxicity, which distinguishes between objective financial burden (direct and indirect treatment costs) and subjective financial distress (material, psychosocial and behavioral effects). Findings indicate that high out-of-pocket expenses are the primary driver of financial toxicity among patients using biological medicines. These costs are often exacerbated by indirect expenses such as lost income, as well as insurance-related barriers including high co-payments. Although several studies acknowledged the subjective financial distress related to financial toxicity, this dimension was underreported, with few studies incorporating patient-reported outcomes or validated quality-of-life measures. This review reinforces the multifaceted nature of financial toxicity in the context of biological therapies and highlights the urgent need for support systems that address both economic and psychosocial challenges faced by patients. Future research should prioritize strategies to improve access to treatment while minimizing the financial burden.
Scholefield J, Mazhindu TA, Nagy M
… +3 more, Twesigomwe D, Agesa G, Masimirembwa C
Clin Pharmacol Ther
· 2026 May · PMID 41932844
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Genetic variation has a significant impact on patients' response to medicines. Variations in important pharmacogenes have been evaluated in several studies and consequently led to international guidelines from clinical p...Genetic variation has a significant impact on patients' response to medicines. Variations in important pharmacogenes have been evaluated in several studies and consequently led to international guidelines from clinical pharmacogenomics consortia. However, there are limited examples of these being implemented across the African continent despite the increased evidence of how these variants contribute to adverse drug reactions (ADRs) or ineffective treatments. Considering the vast genetic diversity in Africa, there are significant gaps in understanding how much of a negative effect this might be having across healthcare across the continent. We therefore sought to establish the extent of ADRs from a subset of medicines shown to be associated with pharmacogenetic biomarkers from the last 10 years across 47 countries on the African continent. In the absence of pharmacogenetic testing on the African continent, we used international guidelines to derive a subset of definitions associated with published drug-gene-interaction associated ADRs to infer the role of pharmacogenetic variation on the prevalence of ADRs. The data showed that African countries report only 1% of ADRs in the VigiBase database, indicative of weak pharmacovigilance programs on the continent. Our analysis revealed that ADRs were mainly caused by anti-infectives such as efavirenz. The inferred pharmacogenes associated with high prevalence of ADRs were CYP2B6, CYP2D6, and CYP2C19. Using limited data, this foundational analysis may serve as the basis for stakeholders to prioritize pharmacogenetic interventions across the African continent.
Mazhindu TA, Nagy M, Twesigomwe D
… +3 more, Agesa G, Scholefield J, Masimirembwa C
Clin Pharmacol Ther
· 2026 May · PMID 41932843
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The World Health Organization Model Essential Medicines List and African national essential medicines lists (EMLs) detail drugs intended to be consistently available within national health systems, thereby supporting cli...The World Health Organization Model Essential Medicines List and African national essential medicines lists (EMLs) detail drugs intended to be consistently available within national health systems, thereby supporting clinicians and pharmacists in making evidence-based treatment decisions. At present, these EMLs do not account for pharmacogenomics, despite known drug-gene interactions and the considerable genetic diversity found throughout Africa. In the absence of pharmacogenomic considerations, the medicines lead to sub-optimal treatment outcomes, especially across a continent such as Africa which represents more genetic variation that the rest of the world combined. Herein, we review EMLs from the WHO, and from 52 African countries, highlighting systemic medicines for which actionable pharmacogenomic-biomarker testing recommendations exist. Furthermore, we assess the feasibility of PGx-guided dosing in eight African countries by examining the availability of registered drug formulations that facilitate dose adjustment. The 2023 WHO EML comprised 447 unique systemic medicines, with 58 (13%) categorized as medicines with actionable pharmacogenomic biomarkers. African country EMLs collectively featured 774 such medicines, with an average of 294 per country (range: 125-465). On average, for each country one in every eight medicines in the Essential Medicines List was associated with established pharmacogenomic guidance. PGx recommendation. Cumulatively in African EMLS the most frequent drug classes with this designation are anti-infectives (25.6%), immunomodulators/antineoplastics (16.7%), and medicines for mental and behavioral disorders (14.1%). Analysis of eight African countries determined that implementability ranged from 75% to 96% based on product formulation and strength availability to enable drug or dose modification. We provide data that contributes towards a foundation of increasing evidence showing that integrating pharmacogenomic knowledge into the selection processes for essential medicines and ensuring the availability of appropriate drug formulations can enhance treatment safety and efficacy across Africa.
Intractable cases of atopic dermatitis often exhibit recurrent exacerbations, with the primary treatment being topical steroids. However, prolonged use of steroids can lead to steroid addiction or iatrogenic disease. Wit...Intractable cases of atopic dermatitis often exhibit recurrent exacerbations, with the primary treatment being topical steroids. However, prolonged use of steroids can lead to steroid addiction or iatrogenic disease. Withdrawal from steroids once the condition becomes uncontrollable is known to be challenging. Herein, we explore the strategies for overcoming steroid addiction and mitigating its adverse effects. One approach involves combining the anti-allergic drug tranilast, which inhibits mast cell degranulation, with the unique macrolide antibiotic roxithromycin, known for its T helper type 2 (Th2) suppressive effect. Moreover, we examine the methods for managing steroid-dependent atopic dermatitis, a condition that poses significant challenges in terms of withdrawal.
Clin Pharmacol Ther
· 2026 Jul · PMID 41922922
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We compared the initial efficacy of denosumab (Dmab) and zoledronate (ZOL) in treatment-naive patients with osteoporosis. This cohort study, based on TriNetX data, evaluated the risks of fractures and mortality using Kap...We compared the initial efficacy of denosumab (Dmab) and zoledronate (ZOL) in treatment-naive patients with osteoporosis. This cohort study, based on TriNetX data, evaluated the risks of fractures and mortality using Kaplan-Meier survival analyses, with hazard ratios (HRs) and 95% confidence intervals (CIs). Propensity-score matching generated 10,811 well-balanced patient pairs. Compared with initiation of annual ZOL, initiation of Dmab with the second dose administered within 7 months of the first injection (no or ≤ 1 month delay) was associated with higher risks of osteoporotic fractures (HR = 1.512, 95% CI = 1.277-1.790), vertebral fractures (HR = 1.609, 95% CI = 1.130-2.293), and lumbar fractures (HR = 2.225, 95% CI = 1.168-4.239). Fracture protection with Dmab declined markedly at 6-7 months but remained stable when two injections were administered within 6 months (no delay). Subgroup analyses showed higher risks of osteoporotic and vertebral fractures among Dmab users without diabetes, without prior steroid exposure, and with an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m. Additionally, among patients with prior steroid exposure, Dmab users had a higher risk of osteoporotic fractures compared with ZOL users. In treatment-naive patients with osteoporosis, Dmab provided less initial protection against osteoporotic and vertebral fractures than ZOL, and delayed dosing further increased fracture risk.