Clinical Pharmacology And Therapeutics[JOURNAL]
Sun
200 papers
Preserved Spermatogenesis and Hormonal Function in Men Receiving a Pretomanid Regimen (BPaMZ) for Pulmonary Drug-Resistant Tuberculosis.
Howell P, Lombardi A, Brumskine W … +11 more , Mikiashvili L, Boekelheide K, Moreira J, Holsta A, Betteridge M, Thompson L, Crook A, Bruinenberg P, Beumont M, Sun E, Conradie F
Clin Pharmacol Ther · 2026 Jun · PMID 42312322 · Publisher ↗
Pretomanid is a component of the World Health Organization-recommended treatment regimen for drug-resistant tuberculosis in patients aged ≥ 14 years. While preclinical rodent studies identified testicular toxicity as a p...
Pretomanid is a component of the World Health Organization-recommended treatment regimen for drug-resistant tuberculosis in patients aged ≥ 14 years. While preclinical rodent studies identified testicular toxicity as a potential clinical liability at elevated doses, no corresponding effects were observed in nonhuman primates nor clinical hormone assessments. This phase 2 clinical trial assessed testicular safety of therapy with bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in 26 adult males with drug-resistant tuberculosis recruited from South Africa and Georgia. The study included 26 weeks of treatment followed by 52 weeks of safety monitoring until study week 78. The primary endpoint measured change in total sperm count from baseline at week 26, with secondary endpoints evaluating sperm concentration, semen volume, and reproductive hormone concentrations. Results demonstrated favorable testicular safety outcomes. Mean total sperm count increased from 48.8 to 68.8 × 10 per ejaculate by week 26. Fifteen participants (68%) showed increased sperm counts, while 17 (77%) exhibited higher sperm concentrations from baseline to week-26 Thirteen participants (59%) experienced ≥ 50% improvement in both parameters. Two participants demonstrated > 50% decreases in total sperm count; however, sperm concentration reductions were < 50%, suggesting low semen volume as a factor. Testosterone levels increased from baseline, peaking at week 44, while inhibin B demonstrated steady increases, peaking at week 78. Follicle-stimulating hormone and luteinizing hormone remained stable throughout the study period. All assessable participants achieved sputum culture conversion by week 12. Pharmacokinetic analysis revealed no correlation between pretomanid plasma concentrations and sperm count changes. These findings provide reassurance that pretomanid does not impair human spermatogenesis nor disrupt reproductive hormone homeostasis.
Patient-Centric First-in-Human Dose Selection: An Ex Vivo Minimal Anticipated Biological Effect Level Approach for T-Cell Engagers in Multiple Myeloma.
Kraft TE, Marrer-Berger E, Belli S … +14 more , Haegel H, Schneider A, Giusti AM, Bscheider M, Jacob W, Weisser M, Blanco L, Frances N, Rossmann E, Steiner G, Azpiroz AZ, Paiva B, Martinet L, Fauti T
Clin Pharmacol Ther · 2026 Jun · PMID 42310437 · Publisher ↗
The minimal anticipated biological effect level (MABEL) approach to first-in-human (FIH) dose calculation can lead to long dose-escalation periods before observing clinical activity. We used a novel ex vivo MABEL approac...
The minimal anticipated biological effect level (MABEL) approach to first-in-human (FIH) dose calculation can lead to long dose-escalation periods before observing clinical activity. We used a novel ex vivo MABEL approach to calculate the FIH starting dose for forimtamig, a T-cell bispecific antibody under investigation for the treatment of relapsed/refractory multiple myeloma (RRMM). We used in vitro and ex vivo MABEL approaches to calculate the FIH dose for a Phase 1 trial (NCT04557150) in patients with RRMM. In vitro assays used the OPM-2 MM cell line and peripheral blood mononucleocytes from healthy donors and patients with MM. Ex vivo assays used fresh bone marrow aspirates from MM patient donors. Forimtamig increased tumor cell lysis, cytokine release, and T-cell activation in vitro and ex vivo. Tumor cell lysis was considered the most relevant assay for dose calculation. EC for LDH release (in vitro: mean 0.6 pM; ex vivo: 9 pM for the most sensitive patient) led to calculated FIH starting doses of 0.4 and 6 μg, respectively. FIH starting dose was 6 μg. Clinical activity was observed in the second dosing cohort (18 and 54 μg). The third dosing cohort (54 and 162 μg) showed durable objective responses. Cytokine release syndrome was Grade 1 at the starting dose and absent in the second dosing cohort. Our ex vivo MABEL approach was accepted by regulatory authorities and yielded a tolerated forimtamig FIH starting dose which demonstrated clinical activity in the second dosing cohort. We encourage similar innovative patient-centric approaches to FIH dose calculation.
Use of Clinical Pharmacology in Slowing the Myopia Epidemic.
Novack GD
Clin Pharmacol Ther · 2026 Jun · PMID 42298884 · Publisher ↗
Myopia (nearsightedness) is in epidemic proportions in the world today. The eyecare community has long been desirous of pharmacological treatments to slow myopic progression. Most recently, two proprietary formulations o...
Myopia (nearsightedness) is in epidemic proportions in the world today. The eyecare community has long been desirous of pharmacological treatments to slow myopic progression. Most recently, two proprietary formulations of low-dose atropine were approved. In this article, the author summarizes the challenge to develop therapies for a chronic, preventative, and pediatric treatment, and how clinical pharmacologists' knowledge of pharmaceutics, pharmacokinetics, and therapeutics can optimize the development of therapies to slow myopic progression.
Novel intravenous human IVIG in patients with secondary immunodeficiency: Interim analysis of a multicenter, prospective, non-interventional study.
Bauhofer A, Aigner S, Borte S
Int J Clin Pharmacol Ther · 2026 Jun · PMID 42290269 · Publisher ↗
OBJECTIVE: To evaluate the effectiveness, safety, and tolerability of Yimmug, a novel, highly purified, 10% human plasma-based intravenous immunoglobulin (IVIG) preparation, in patients with secondary immunodeficiency (S...
OBJECTIVE: To evaluate the effectiveness, safety, and tolerability of Yimmug, a novel, highly purified, 10% human plasma-based intravenous immunoglobulin (IVIG) preparation, in patients with secondary immunodeficiency (SID) under real-world conditions. MATERIALS AND METHODS: This interim analysis is based on data from a multicenter, prospective, non-interventional study conducted with out-patients in Germany. Effectiveness was assessed by changes in (i) serum IgG levels, (ii) severe infection rates, (iii) clinical symptoms, and (iv) patient-reported quality of life (QoL) at three treatment intervals (after 3, 12, and 24 IVIG infusions) compared to baseline. Safety was evaluated through documentation of adverse events (AEs), including adverse drug reactions (ADRs), while tolerability was assessed by investigators. RESULTS: A total of 119 SID patients received 726 IVIG infusions at a median (IQR) dose of 0.3 (0.2 - 0.3) g/kg over a median (IQR) duration of 1.4 (0.4 - 2.9) years, with a median interval of 30.1 days between infusions. Serum IgG trough levels increased, with the proportion of patients achieving IgG ≥ 6 g/L rising from 30.3% at baseline to 66.7% after both 12 and 24 infusions. The mean annual rate of infections requiring antibiotics decreased from 2.3 at baseline to 0.0 after 3 and 12, and to 0.4 after 24 infusions, respectively. The new IVIG was well tolerated, and patients' clinical symptoms and QoL improved during treatment. AEs were reported in 20 (16.8%) patients, with 41 events in total, while ADRs occurred in 9 (7.6%) patients, with 16 events. Serious AEs (SAEs) occurred in 4 (3.4%) patients, involving 5 events, but no serious ADRs (SADRs) were reported. CONCLUSION: This interim analysis shows that the risks are minor compared to the benefits of this novel IVIG preparation in the management of SID.
Network meta-analysis of bisphosphonates in the treatment of bone metastases from breast cancer.
Zhang LW, Huang A, Ma HF … +1 more , Shen J
Int J Clin Pharmacol Ther · 2026 Jun · PMID 42290268 · Publisher ↗
OBJECTIVE: Through a network meta-analysis, this study aimed to systematically evaluate the efficacy and safety of bisphosphonates in reducing skeletal-related events in patients with bone metastases from breast cancer,...
OBJECTIVE: Through a network meta-analysis, this study aimed to systematically evaluate the efficacy and safety of bisphosphonates in reducing skeletal-related events in patients with bone metastases from breast cancer, providing clinical guidance for treatment selection. MATERIALS AND METHODS: Randomized controlled trials (RCTs) on bisphosphonate therapy for bone metastases in breast cancer were retrieved from PubMed, Cochrane, and Embase databases from inception to January 2025. Statistical analyses were performed using Stata software. RESULTS: 22 studies involving 14,934 patients were included. The bisphosphonates evaluated were pamidronate, zoledronate, clodronate, and ibandronate. Regarding the reduction of pathological fractures, the efficacy ranking was clodronate > ibandronate > pamidronate > zoledronate. Significant differences were found between clodronate and pamidronate (OR = -1.41, 95% CI: -2.78 to -0.04) and between clodronate and zoledronate (OR = -1.44, 95% CI: -2.85 to -0.04). For hypercalcemia reduction, zoledronate was more effective than clodronate and pamidronate, though differences were not statistically significant (p > 0.05). In terms of safety, ibandronate showed fewer adverse reactions than clodronate and zoledronate, with a significant difference between ibandronate and zoledronate (OR = -1.14, 95% CI: -1.99 to -0.28). CONCLUSION: Clodronate was most effective in reducing pathological fractures, zoledronate was superior in controlling hypercalcemia, and ibandronate demonstrated the best safety profile. Further clinical studies are warranted to clarify the comparative advantages of each bisphosphonate and support individualized treatment decisions.
Pharmacokinetic and bioequivalence study of apremilast tablets in healthy Chinese subjects under fasting and fed conditions.
Lu P, Yao F, Wang J … +4 more , He Y, Liang J, Zhai X, Liu G
Int J Clin Pharmacol Ther · 2026 Jun · PMID 42290267 · Publisher ↗
Apremilast is a pioneering oral selective phosphodiesterase-4 inhibitor for the treatment of psoriasis. To evaluate and compare the pharmacokinetic properties and bioavailability of apremilast tablets manufactured by Nan...
Apremilast is a pioneering oral selective phosphodiesterase-4 inhibitor for the treatment of psoriasis. To evaluate and compare the pharmacokinetic properties and bioavailability of apremilast tablets manufactured by Nanjing Haijing Pharmaceutical Company (Nanjing, China) with apremilast tablets certified by Celgene Europe B.V. (Utrecht, The Netherlands), we conducted a randomized, open-label, single-dose, two-period, crossover study in healthy Chinese subjects under fasted and fed conditions. Eligible subjects were randomly assigned to receive reference or test apremilast tablets in the first treatment period and the other formulation in the second period. Serial blood samples were collected for pharmacokinetic analysis. Adverse events were recorded. A total of 28 healthy subjects were enrolled in the fasting cohort and 36 subjects in the fed cohort. The 90% confidence intervals of the geometric mean ratios of the test to reference formulations were 91.56 - 106.18% for C, 96.08 - 108.18% for AUC, and 96.02 - 107.67% for AUC in the fasting cohort, and 95.15 - 107.05% for C, 105.13 - 113.45% for AUC, and 104.80 - 111.91% for AUCin the fed cohort, all of which were within the bioequivalence range of 80.00 - 125.00%. There were no serious adverse events. The results showed that the test and reference apremilast tablets were bioequivalent and well tolerated in healthy Chinese subjects under fasting and fed conditions.
From Non-Cancer Pain to Cancer Survivorship: Applying Opioid Deprescribing Lessons across the Divide.
Miksad R
Clin Pharmacol Ther · 2026 Jul · PMID 42287623 · Publisher ↗
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Toward the Future: A Race-Agnostic, Bayesian Approach to Defining Glomerular Filtration for Personalized Drug Dosing.
Scheetz MH, Lodise TP, Rhodes NJ … +3 more , Pai MP, Barreto EF, Neely MN
Clin Pharmacol Ther · 2026 Jun · PMID 42274272 · Publisher ↗
Accurate assessment of renal function is fundamental to dosing renally eliminated drugs. For decades, serum creatinine-based estimating equations have been used to approximate glomerular filtration rate (GFR) for this pu...
Accurate assessment of renal function is fundamental to dosing renally eliminated drugs. For decades, serum creatinine-based estimating equations have been used to approximate glomerular filtration rate (GFR) for this purpose. While these equations perform reasonably well at the population level, they exhibit substantial individual-level imprecision and inaccuracy. Simultaneously, recent efforts to remove race from estimating equations addressed important ethical concerns but did not resolve the core limitation of population-based estimation for individual drug dosing. In this perspective, we argue that personalized dosing requires a shift away from demographic surrogates toward direct measurement of renal clearance and clarify when incremental therapeutic complexity is warranted. We review the limitations of endogenous biomarkers, discuss the role of cystatin C, and propose exogenously measured GFR using iohexol integrated within a Bayesian pharmacometric framework as a clinically actionable approach to individualized drug dosing. Practically, this framework can be implemented by administering a small iohexol dose, collecting sparse timed samples, estimating absolute mGFR and its uncertainty with Bayesian software, and using that posterior estimate to refine renal dose selection.
Payload-Based Clinical Pharmacology Review of Approved Antibody-Drug Conjugates: Commonalities and Considerations for Streamlined Development.
Lu S, Xiao Q, Qian L … +4 more , Sun S, Zhou Z, Liao MZ, Li C
Clin Pharmacol Ther · 2026 Jun · PMID 42261138 · Publisher ↗
Antibody-drug conjugates (ADCs) combine the specificity of an antibody with the potency of a cytotoxic drug. Thirteen ADCs, utilizing seven unique cytotoxic payloads and targeting 11 distinct antigens, are currently appr...
Antibody-drug conjugates (ADCs) combine the specificity of an antibody with the potency of a cytotoxic drug. Thirteen ADCs, utilizing seven unique cytotoxic payloads and targeting 11 distinct antigens, are currently approved by the US Food and Drug Administration as of June 2025, representing a rapidly growing and highly promising class of anticancer therapeutics. Monomethyl auristatin E is the most frequently used payload (in five approved ADCs), followed by deruxtecan and calicheamicin. It is noted that ADCs using the same linker and payload often share similar PK and catabolism/metabolism characteristics, and thus providing opportunities for their streamlined development provided the applicant owns or has a right of reference of underlying data when it is necessary. In this review, we summarize the key clinical pharmacology considerations by payload class, using approved ADCs as case examples to support development and regulatory approval. We then compare the data and discuss how to leverage prior experience of ADCs, either qualitatively or quantitatively. These data and strategy insights will help researchers to integrate data from platform ADCs that share the same linker-payload and apply broader ADC-related insights, thereby accelerating future ADC developments.
How Drug-Drug Interaction Studies Inform Drug Labeling: A Survey of US Food and Drug Administration-Approved New Molecular Entities from 1998 to 2022.
Shugg T, Springer AN, Gafari Y … +5 more , Xu J, Marroum P, Desta Z, Powell NR, Younis IR
Clin Pharmacol Ther · 2026 Jun · PMID 42257440 · Publisher ↗
Drug-drug interactions (DDIs) are a major cause of adverse drug events and drug inefficacy. To mitigate their clinical burden, it is essential for drug labeling to provide actionable DDI recommendations to clinicians. Th...
Drug-drug interactions (DDIs) are a major cause of adverse drug events and drug inefficacy. To mitigate their clinical burden, it is essential for drug labeling to provide actionable DDI recommendations to clinicians. This investigation analyzed DDI information included in US Food and Drug Administration (FDA) labeling over the past two decades, focusing on DDI management recommendations and the information sources that served as their basis. Data elements were extracted from drug labels and clinical pharmacology reviews for new molecular entities (NMEs) approved by the FDA between 1998 and 2022. Drug labels for 76.2% of NMEs contained ≥1 DDI recommendation, yielding a total of 8,992 unique DDI pairs. Actionable management strategies were recommended for 48.5% of DDI pairs. The most common sources informing DDI recommendations were predictions based on disposition pathways (43.5%) and clinical pharmacokinetic (PK) DDI studies (36.7%). Antivirals (39.2), psychiatry (24.2), and reproduction (23.1) were the therapeutic areas with the most average recommendations per approval, while oncology (71.9%), nephrology (71.4%), and medical imaging (63.6%) were the therapeutic areas with the highest percentages of actionable recommendations. The underlying mechanisms for 75.2% of DDI recommendations involved drug-metabolizing enzymes or drug transporters, with the most common being CYP3A inducers/inhibitors (38.8% of interactions), CYP3A substrates (24.4%), and CYP2C19 inducers/inhibitors (15.8%). The extent of drug exposure changes in PK DDI studies was positively associated with actionable labeling recommendations (P < 0.001). In conclusion, our findings identify considerations to enhance the efficiency and completeness of studying DDIs and communicating DDI management recommendations in drug labeling.
Virtual Twin Approach Using Physiologically Based Pharmacokinetic Modeling to Support Precision Dosing of Valproic Acid in Geriatric Patients.
Jang YJ, Heo DG, Hong E
Clin Pharmacol Ther · 2026 Jun · PMID 42252689 · Publisher ↗
Personalized dosing is particularly important for drugs with narrow therapeutic indices in geriatric patients, who exhibit substantial physiological variability and limited pharmacokinetic (PK) evidence to guide individu...
Personalized dosing is particularly important for drugs with narrow therapeutic indices in geriatric patients, who exhibit substantial physiological variability and limited pharmacokinetic (PK) evidence to guide individualized dose selection. Valproic acid (VPA) is an effective treatment option for bipolar disorder in older adults, yet dosing largely relies on therapeutic drug monitoring (TDM), which guides adjustment only after steady state is achieved. This study evaluated a physiologically based pharmacokinetic (PBPK)-guided virtual twin (VT) framework to prospectively predict individual VPA exposure in a real-world geriatric population. A PBPK model for extended-release VPA was developed using the Simcyp Simulator (version 25). Clinical data (n = 74) were collected from elderly patients receiving VPA at the Samsung Medical Center. PBPK model performance was validated against published PK data from healthy adults and independent TDM data from the geriatric patients. The model adequately reproduced observed PK of VPA, with predicted PK parameters ranging from 0.73- to 1.37-fold of observed values. Virtual twins were subsequently generated for each patient by incorporating patient-specific demographic characteristics and routinely available physiological parameters. Individual PK profiles were simulated and compared with measured TDM concentrations. Incorporation of demographic and physiological covariates achieved an absolute average fold error of 1.13 (90% CI: 1.10-1.16), with nearly 90% of predictions falling within the 0.8- to 1.25-fold range of the observed concentrations. These findings suggest that PBPK-guided virtual twins can predict individual VPA exposure using routinely available clinical data and may enable prospective dose optimization, complementing conventional TDM to advance precision dosing in geriatric pharmacotherapy.
Strengthening Pharmacovigilance Reporting for Withdrawal Reactions to Support Deprescribing.
Khan Z, Moriarty F
Clin Pharmacol Ther · 2026 Jun · PMID 42249887 · Publisher ↗
Pharmacovigilance plays a crucial role in post-marketing surveillance of medicines and relies on the spontaneous reporting of adverse drug reactions (ADRs). Discontinuation of a drug can cause clinically relevant signs a...
Pharmacovigilance plays a crucial role in post-marketing surveillance of medicines and relies on the spontaneous reporting of adverse drug reactions (ADRs). Discontinuation of a drug can cause clinically relevant signs and symptoms, including withdrawal reactions; however, this subset of ADRs is not fully accommodated in current pharmacovigilance practice. We discuss proposed revisions to current ADR forms that could enhance the capture of withdrawal reaction evidence.
Translating B-Cell and Plasma-Cell Targeting from Oncology to Autoimmunity: Modalities, Quantitative Bridging, and a Development Roadmap.
Yuan M, Xu XS
Clin Pharmacol Ther · 2026 Jun · PMID 42244451 · Publisher ↗
B cells drive B-cell malignancies and diverse autoimmune diseases through autoantibody production, antigen presentation, and cytokine dysregulation, and persistence of pathogenic B-cell or plasma-cell compartments. Acros...
B cells drive B-cell malignancies and diverse autoimmune diseases through autoantibody production, antigen presentation, and cytokine dysregulation, and persistence of pathogenic B-cell or plasma-cell compartments. Across autoimmune diseases, the dominant pathogenic compartment varies, ranging from precursor-dependent states to tissue-compartment inflammation and long-lived plasma cell-weighted autoantibody production. This review synthesizes the biological rationale for B-cell-axis targeting across oncology and autoimmunity and proposes a pathobiological framework spanning precursor-dependent, compartment-dominant, and long-lived plasma cell-weighted archetypes. We outline the mechanisms, lineage coverage, depletion depth, durability, and tolerability of CD20-, CD19-, CD38-, and BCMA-directed antibodies, bispecific T-cell engagers, and chimeric antigen receptor (CAR) T cells, and map these modalities onto biologically defined autoimmune archetypes. We also compare dosing paradigms, pharmacokinetics/pharmacodynamics (PK/PD), exposure-response relationships, and safety trade-offs between oncology-style induction and chronic maintenance in autoimmunity, emphasizing biomarker-guided retreatment, infection-risk mitigation, and regimen adaptation for non-malignant disease. Clinically, therapies developed for lymphoma and myeloma have transformed B-cell cancer care and are now being repurposed for rheumatoid arthritis, multiple sclerosis, neuromyelitis optica spectrum disorder, IgG4-related disease, myasthenia gravis, systemic lupus erythematosus, and related disorders. We summarize pivotal translational inflection points, from rituximab extension beyond lymphoma to approvals of ocrelizumab, ofatumumab, ublituximab, and inebilizumab in neuroimmunology. We further review plasma cell-directed and T-cell-engaging strategies for deep immune resets in refractory disease, while clarifying implications for trial design, long-term safety, and implementation. Finally, we introduce a model-informed roadmap integrating population PK/PD, exposure-response, and quantitative systems pharmacology to optimize indication selection, patient enrichment, and dose/regimen design-supporting confident extrapolation rather than empiricism.
Major Adverse Cardiac Events with Ondansetron: The Role of Observational Evidence to Inform Actionable Safer Prescribing in Cardio-Oncology.
Raschi E, Diemberger I, Poluzzi E … +1 more , De Ponti F
Clin Pharmacol Ther · 2026 Jun · PMID 42244432 · Publisher ↗
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Reducing Exposure Before Birth: An Interrupted Time Series Study of Prenatal Exposure to Fetotoxic Medications Under Risk Management Plans in Canada.
Khan NS, Sheehy O, Leal LF … +2 more , Tchuente V, Bérard A
Clin Pharmacol Ther · 2026 Jun · PMID 42244106 · Publisher ↗
Canada's 2009 risk management plan (RMP) framework has not been evaluated for prenatal exposure impact. Conversely, widely used drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) lack RMPs. We assessed first-tri...
Canada's 2009 risk management plan (RMP) framework has not been evaluated for prenatal exposure impact. Conversely, widely used drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) lack RMPs. We assessed first-trimester exposure to RMP-regulated medications following regulatory interventions and to NSAIDs following safety publications. We conducted interrupted time series analyses using data from the Québec Pregnancy Cohort (1998-2022), including pregnancies among individuals aged 15-45 years with continuous public prescription drug insurance. First-trimester exposure was defined as dispensed prescriptions overlapping or initiated during gestational weeks 0-14. Exposures included RMP-regulated medications (overall, retinoids, and valproic acid) and prescription NSAIDs. RMP dates served as interruption points. Monthly incidence rates were analyzed using segmented Poisson regression to estimate incidence rate ratios (IRRs) with 95% confidence intervals (CIs). Among 559,215 eligible pregnancies, 6,215 and 87,820 involved first-trimester exposure to RMP-regulated medications and NSAIDs, respectively. The Canadian RMP framework was associated with an immediate 45.3% reduction (IRR: 0.547, 95% CI: 0.403-0.743) and a sustained 1.3% monthly decline (IRR: 0.987, 95% CI: 0.981-0.994). Retinoid exposure declined by 12.5% per month post-SMART RMP (IRR: 0.875, 95% CI: 0.772-0.993), with reductions post-iPLEDGE RMP (IRR: 0.949, 95% CI: 0.932-0.966). Valproic acid exposure declined after the strengthened FDA boxed warning (IRR: 0.869, 95% CI: 0.836-0.903) and migraine prophylaxis contraindication (IRR: 0.754, 95% CI: 0.543-1.046). NSAID publications yielded transient effects. RMPs were associated with sustained prenatal exposure reductions, whereas safety publications were associated with transient effects, highlighting the need for reinforced risk-management strategies.
Systematic Evaluation of Data and Trial Fitness for Oncology Trial Emulation: Empirical Findings from the CARE Initiative.
Levy N, Sheridan P, Campbell U … +40 more , Lenis D, O'Doherty I, Estrin A, Gautam N, Iyer M, McDonald S, Belli A, Carrigan G, Chan KA, Chen J, Chia V, Dhopeshwarkar N, Eckert J, Fernandes L, Greshock J, Hendricks-Sturrup R, Huang J, Jiao X, Khosla S, Lunacsek O, McRoy L, Natanzon Y, Ovbiosa O, Pace N, Pinheiro S, Rees M, Rider J, Rimawi MF, Robinson T, Rodriguez-Watson C, Sangli C, Sarsour K, Schneeweiss S, Shapiro M, Stewart M, Taylor A, Wang CK, Wang S, Zhang Y, Madsen A
Clin Pharmacol Ther · 2026 Jun · PMID 42240135 · Publisher ↗
The Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation (CARE) Initiative seeks to advance understanding of when real-world data (RWD) can generate valid treatment effectiveness estimat...
The Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation (CARE) Initiative seeks to advance understanding of when real-world data (RWD) can generate valid treatment effectiveness estimates by emulating completed oncology randomized controlled trials (RCTs). A prerequisite for meaningful RCT emulation insights is the identification and use of RWD with sufficient fitness to satisfy RCT-specific data elements. We conducted a systematic, multi-stage feasibility assessment of six commercially available US electronic health record-based RWD sources across 23 candidate oncology RCTs. Each potential RCT-RWD combination was first screened for availability of the RCT indication, outcomes, and sample size ≥ 1.5-times enrollment for each trial arm. Combinations passing this screen underwent more detailed evaluation of RCT design elements including eligibility criteria, outcomes, and potential confounders. Each data element was rated with respect to availability, missingness, and validity. Final feasibility determination was informed by ratings of essential element capture and refined sample size estimates. Of 54 candidate RCT-RWD combinations assessed, nine advanced to detailed feasibility assessment and three were selected for emulation protocol development. Fit-for-emulation constraints included complex eligibility criteria, biomarker requirements, performance status requirements, and outcome ascertainment. These findings highlight the importance of systematic feasibility evaluation before conducting emulations and may inform data selection for future RWD studies in oncology. Data fitness for oncology RCT emulation could be improved by linking high-quality, oncology-specific RWD sources to broader EHR and claims data sources or through customized data abstraction.
The Framework of Precision Pharmacotherapy in Metabolic Dysfunction-Associated Steatohepatitis: A Network Meta-Analysis.
Chen Y, Yang X, Shen W … +4 more , Zhang P, Yang X, Xu X, Lu D
Clin Pharmacol Ther · 2026 Jun · PMID 42233597 · Publisher ↗
The challenge of precision treatment for metabolic dysfunction-associated steatohepatitis (MASH) is increasingly recognized, for which comparative evidence remains limited. We performed a network meta-analysis of randomi...
The challenge of precision treatment for metabolic dysfunction-associated steatohepatitis (MASH) is increasingly recognized, for which comparative evidence remains limited. We performed a network meta-analysis of randomized controlled trials (RCTs) to examine the relative efficacy of pharmacotherapies in MASH. RCTs investigating pharmacologic treatments were systematically searched. The primary outcomes were fibrosis improvement of ≥ 1 stage without worsening of MASH and MASH resolution without worsening of fibrosis. Random-effects models were used to calculate the odds ratios (ORs) with 95% confidence interval. About 69 RCTs, including 16,180 patients with MASH, were included. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, thyroid hormone receptor-β (THR-β) agonists, incretins, and fibroblast growth factor-21 (FGF21) analogs were associated with improvements in both primary outcomes compared with placebo. Subgroup analyses suggested that treatment responses may vary across clinically relevant populations, such as those defined by cirrhosis status and type 2 diabetes (T2D). FGF21 analogs were associated with higher odds of MASH resolution in cirrhotic MASH patients compared with placebo (OR = 4.25, 95% CI = 1.97-9.17), whereas incretins showed favorable associations with MASH resolution in MASH patients without cirrhosis (OR 5.92, 95% CI = 3.46-10.15). Compared with placebo, SGLT2 inhibitors were associated with higher odds of fibrosis improvement in MASH patients with T2D (OR = 9.48, 95% CI = 2.43-37.00) as well as in MASH population without T2D (OR = 4.67, 95% CI = 1.30-16.79). Although the depth of subgroup evidence is currently limited, these findings provide a comparative framework to inform future stratified trial design and therapeutic development in MASH.
Population Genomics Insights into Pharmacogenomic Differentiation Between East Asians and Europeans.
Chen S, Chen H, Xu S
Clin Pharmacol Ther · 2026 Jun · PMID 42233542 · Publisher ↗
Genetic variation contributes substantially to interindividual and interpopulation differences in drug response, yet most pharmacogenomic studies remain biased toward European populations. Here, we systematically assesse...
Genetic variation contributes substantially to interindividual and interpopulation differences in drug response, yet most pharmacogenomic studies remain biased toward European populations. Here, we systematically assessed pharmacogenomic variation across East Asians (EAS) and Europeans (EUR) using public genomic datasets and investigated the potential evolutionary forces shaping these differences. Our analyses revealed that EAS populations generally harbor a lower frequency of pharmacogenomic variants previously associated with reduced drug response compared with EUR populations, indicating population-level differences in the distribution of PGx variants. Drug-associated genes exhibited threefold higher population differentiation than the genome-wide background (F = 0.18 vs. 0.06). Key transport genes such as SLCO1B3/SLCO1B7 showed striking differences in cumulative allele probability (EAS: 18.69% vs. EUR: 91.60%), suggesting population-level divergence in drug transport and pharmacokinetics. Population genetic analyses revealed stronger signals of positive selection on PGx variants in EAS populations, likely reflecting historical adaptations to pathogen and dietary pressures. For instance, the VKORC1-rs9923231-T allele, which enhances warfarin sensitivity, shows evidence of selection in EAS populations (XP-EHH = 3.58) and may relate to vitamin K intake. Conversely, the EUR-enriched SH2B3-rs3184504-T allele (AF: 0.46 vs. AF: 0.003) has been associated with selection related to blood pressure regulation. Collectively, these findings highlight the importance of incorporating population diversity into pharmacogenomic research and underscore the potential need for population-specific drug response guidelines to advance global precision medicine.
Pirfenidone and nintedanib in fibrosing interstitial lung disease: A retrospective study based on a regional university hospital data registry and literature review.
Sans-Pola C, Boy R, Villar A … +6 more , Ojanguren I, Simeón-Aznar CP, Guillen-Del-Castillo A, Vancells G, Agustí A, Danés I
Int J Clin Pharmacol Ther · 2026 Jun · PMID 42233448 · Publisher ↗
AIMS: To evaluate the effectiveness and tolerability of pirfenidone and nintedanib in idiopathic pulmonary fibrosis (IPF) and other fibrotic lung diseases. MATERIALS AND METHODS: The study was retrospective and monocentr...
AIMS: To evaluate the effectiveness and tolerability of pirfenidone and nintedanib in idiopathic pulmonary fibrosis (IPF) and other fibrotic lung diseases. MATERIALS AND METHODS: The study was retrospective and monocentric based on patients treated between 2015 and 2020 at the Vall d'Hebron University Hospital, the largest public hospital complex in Catalonia, Spain. Effectiveness and tolerability, including the relative change in forced vital capacity (FVC) assessed at 12 months, were evaluated using data for patients with interstitial lung disease retrieved from a registry and the medical records. RESULTS: Antifibrotics were administered to 55 patients: 34 (61.8%) with IPF, 14 (25.5%) with progressive pulmonary fibrosis (PPF), 5 (9.1%) with systemic sclerosis-associated interstitial lung disease (SSc-ILD), and 2 (3.6%) with post-COVID-19 fibrosis. Median age was 69.9 years; 78.2% were male. The median duration of nintedanib and pirfenidone treatment at study end was 12.1 (interquartile range (IQR) 6.9 - 22.8) and 27.6 months (IQR 10.4 - 58.7), respectively. Treatment was discontinued due to toxicity in 48.5% of patients treated with nintedanib and 18.2% of those treated with pirfenidone. At 1 year, 62% of patients with IPF, 64% of those with PPF, and all patients with SSc-ILD were still receiving antifibrotic therapy, and the median change from baseline in FVC was -2% (IQR from -7.1 to 7.2), -9.9% (from -25.4 to -1.6), and -3.3% (from -18.7 to 16.3), respectively. CONCLUSION: Antifibrotic therapy using pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis provides significant stabilization of the disease measured using the change in FVC at 12 months. Treatment withdrawal was mostly attributable to poor tolerance to nintedanib.
Digital Transformation of Medicines Regulation in Africa-Perspectives from a Stakeholder Convening.
Reyneke C, Semete-Makokotlela B, Singh V … +10 more , Nkuku K, Terblanche M, Mukanga ET, Ngum N, Dandajena K, Mhango MC, Wairimu P, Mwangi J, Lagrave D, Pillai GC
Clin Pharmacol Ther · 2026 Jun · PMID 42231040 · Publisher ↗
Regulatory authorities worldwide are developing strategies to integrate artificial intelligence (AI) into the lifecycle of health products, technologies, and medicines. While regulators share goals of improving efficienc...
Regulatory authorities worldwide are developing strategies to integrate artificial intelligence (AI) into the lifecycle of health products, technologies, and medicines. While regulators share goals of improving efficiency, strengthening decision-making, and protecting public health, their approaches differ according to institutional structures, capacity, maturity, and regional priorities. In the United States, the FDA adopts a model-focused approach, treating AI primarily as a regulatory science tool to strengthen analytical components of decisions such as patient selection, biomarker substitution, and predictive modeling. The agency emphasizes credibility and validation through a risk-based framework that evaluates AI models according to their influence on regulatory decisions and potential consequences of error. In Europe, the EMA pursues system-level digital transformation, embedding AI within a broader data and analytics strategy emphasizing interoperability, data structuring, automation, and governance supported by legislation. African national regulatory authorities are advancing AI through pragmatic pilot initiatives. The South African Health Products Regulatory Authority (SAHPRA) is implementing AI within a structured digitization strategy, including AI-assisted dossier screening and automated GMP review to address backlogs and workflow inefficiencies. The Medicines Control Authority of Zimbabwe (MCAZ) deploys AI-driven dossier screening through its in-house digital systems, while Kenya's Pharmacy and Poisons Board has proposed a risk-based framework for regulating AI-enabled medical devices. At the continental level, the African Medicines Agency and AUDA-NEPAD aim to harmonize digital transformation and responsible AI adoption through reliance and cross-border data sharing. This paper summarizes discussions from a convening to identify priorities for digitization and digital transformation of African medicines regulation.
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