Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are an effective class of lipid-lowering drugs in patients with primary hypercholesterolemia or mixed dyslipidemia. New evidence supported the early use of PCSK9i in patients with atherosclerotic cardiovascular disease without prior ischemic events and not achieving the low-density lipoprotein-cholesterol targets despite being treated with other lipid-lowering therapies. The aim of the study is to evaluate the cost effectiveness of PCSK9i monoclonal antibodies (mAbs) as an add-on treatment in this population over the lifetime horizon from the Italian National Health Service perspective. A Markov model with a 1-year cycle length was developed to evaluate the incremental cost and effectiveness of maximum tolerated statins plus ezetimibe (MTS+E) with versus without PCSK9i mAbs in high-risk patients with atherosclerotic cardiovascular disease without prior ischemic events. Baseline cardiovascular risk and relative cardiovascular risk reduction attributed to PCSK9i mAbs for major adverse cardiovascular events (i.e., acute coronary syndrome, ischemic stroke, and all-cause mortality) were based on analysis using the US Optum Research database. Costs of drugs and management of cardiovascular events were considered in the analysis. Utility values were sourced from the existing literature. Both deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the result. The simulated cohort's mean age was 68 years and mean baseline low-density lipoprotein-cholesterol level was 129.7 mg/dL, with female individuals and diabetes mellitus accounting for 50.1% and 34.8%, respectively. The incremental cost and quality-adjusted life-year (QALY) gained of MTS+E with added PCSK9i mAbs versus without PCSK9i mAbs were €61,334 and 2.42 QALY, equivalent to €25,350 per QALY gained. At a willingness-to-pay threshold of €33,000 per QALY gained, MTS+E plus PCSK9i mAbs had about 65% probability of being cost effective versus MTS+E alone. The results demonstrated that PCSK9i mAbs as an add-on therapy to MTS+E are likely to be cost effective when compared with MTS+E alone in high-risk patients with atherosclerotic cardiovascular disease without prior ischemic events from the Italian National Health Service perspective.

Liver cirrhosis profoundly alters pharmacokinetics and is frequently associated with medication-related problems. Stage-specific dosing guidance remains inconsistent, and prescribing information often lacks clarity. As a result, treatment decisions rely on individual clinical judgement and may differ between professional groups. This study assessed drug-selection and dose-adjustment practices among hepatologists, clinical pharmacologists, and clinical pharmacists, quantified consensus across Child-Pugh stages, and evaluated alignment with prescribing information as a basis for harmonised dosing guidance. Twelve experts from hepatology, clinical pharmacology, and clinical pharmacy evaluated prioritised drugs for patients with liver cirrhosis across Child-Pugh stages A-C in a structured survey. For each drug, experts indicated whether they would apply no dose adjustment, modify the dose, or avoid administration. Consensus was defined as at least 75% agreement, and interrater agreement was assessed by pairwise percentage agreement. Consensus recommendations were compared with the dosing information provided in each drug's Summary of Product Characteristics. Consensus or strong consensus was achieved for only 20% of 177 recommendations, mainly for no dose adjustment or avoidance. Agreement decreased with disease severity (Child-Pugh A 83%; B 47%; C 41%). Of 36 consensus recommendations, 18 matched the summary of product characteristics, while six diverged from it. Pharmacists and clinical pharmacologists more often recommended dose adjustments, especially in Child-Pugh B and C, whereas hepatologists preferred standard dosing or avoidance. Expert recommendations for dosing in cirrhosis showed marked variability and limited concordance with prescribing information, underscoring the need for harmonised interdisciplinary guidance integrating pharmacokinetic evidence and clinical feasibility.

Prurigo nodularis (PN) is a chronic, pruritic skin disorder characterized by significant morbidity and historically limited treatment options. The recent approval of biologic therapies has rapidly changed the treatment landscape, with dupilumab and nemolizumab now Food and Drug Administration (FDA)-approved for PN. This article provides a clinically relevant overview of completed randomized trials, highlighting differences in efficacy, timing of response, and symptom targets. Data were extracted from six compound randomized clinical trials (two dupilumab trials and four nemolizumab trials) identified on ClinicalTrials.gov through January 2025. Across phase 3 studies, dupilumab demonstrated sustained reductions in itch severity and lesional disease, with approximately 58-60% of patients achieving a ≥ 4-point improvement in Worst Itch Numeric Rating Scale (WI-NRS) scores and 45-48% achieving Investigator Global Assessment for Prurigo Nodularis-Stage (IGA PN-S) success by week 24. Nemolizumab showed a more rapid onset of antipruritic effect, with 41-56% of patients achieving a ≥ 4-point improvement in Peak Pruritus Numeric Rating Scale (PP-NRS) scores as early as week 4, along with clinically meaningful improvements in sleep disturbance by week 16. Both therapies demonstrated manageable safety profiles, with predominantly mild to moderate adverse events and low rates of serious adverse events, although nemolizumab was associated with higher overall rates of mild to moderate adverse events. These findings suggest that dupilumab may offer greater lesional clearance at later time points, whereas nemolizumab may provide faster itch relief and less sleep disturbance. These findings support a phenotype-guided approach to biologic selection while highlighting the need for further comparative studies.

Chronic lymphocytic leukaemia (CLL) is a common adult leukaemia, and selecting the most effective first-line treatment is crucial for optimising patient outcomes and managing healthcare costs. While chemoimmunotherapy (CIT) has been the standard approach, targeted therapies offer promising alternatives for treatment-naïve CLL patients. The objective of this study was to evaluate the cost effectiveness of chemoimmunotherapy compared to targeted therapies for treatment-naïve CLL patients in South Africa. A cost-effectiveness analysis was conducted using a Markov model based on three health states: progression-free survival (PFS), progression, and death. The model employed a 15-year time horizon and a 1-month cycle length. Patient-level data were reconstructed, and parametric estimation was used to project long-term clinical outcomes. Cost estimates were derived from national tariffs, reflecting a South African public healthcare perspective, while utilities were sourced from published literature. Outcomes were measured in total costs and quality-adjusted life years (QALYs). Incremental cost-effectiveness ratios (ICERs) were calculated and compared to a willingness-to-pay (WTP) threshold, and sensitivity analyses were conducted to test the robustness of the results. Among the evaluated treatment strategies, chlorambucil-plus-obinutuzumab (ClbO) had the lowest cost and served as the reference comparator. Both CIT regimens were cost effective, with fludarabine, cyclophosphamide, and rituximab (FCR) yielding an ICER of US$1645.52 per QALY gained and bendamustine-plus-rituximab (BR) had an ICER of US$1716.79 per QALY gained, both below the US$3407 WTP threshold, under the model assumptions. Ibrutinib generated the highest QALYs but at a higher cost, resulting in an ICER of US$19,679.52 per QALY gained and a 0% probability of being cost effective at the WTP threshold, while venetoclax-plus-obinutuzumab (VenO) was extendedly dominated, and therefore eliminated from the results. Sensitivity analyses confirmed the robustness of the findings across variations in key parameters. In the South African public healthcare setting, CIT regimens (FCR and BR) represent cost-effective first-line treatment strategies for symptomatic, treatment-naïve CLL. Bendamustine-plus-rituximab emerged as the most decision-robust option under uncertainty, while FCR yielded the lowest point-estimate ICER. Among CIT regimens, FCR may be preferred in fit patients, while BR represents a more decision-robust option in older or unfit populations. Targeted therapies such as ibrutinib and VenO, despite superior clinical efficacy, are not cost effective at current prices. Substantial price reductions, generic entry, or targeted use in high-risk subgroups may improve their value and enable equitable access within South Africa's resource-constrained health system.

Alopecia areata (AA) is a chronic autoimmune disorder characterized by non-scarring hair loss, which may extend to total scalp (AA totalis) or whole-body hair loss (AA universalis). Nail involvement, though often underestimated, occurs in up to 66% of cases, especially in severe forms and in children. This retrospective study evaluated the efficacy of baricitinib 4 mg/day, a Janus kinase 1/2 inhibitor, in treating nail manifestations associated with severe AA. Thirty-seven patients with very severe AA (Severity of Alopecia Tool [SALT] score > 50) and nail involvement were treated with baricitinib for 48 weeks. Nail changes assessed included trachyonichia, pitting, leukonychia, and others. Clinical assessments were performed at baseline and at 12, 24, 36, and 48weeks using the SALT score, onychoscopy, and the Clinician Reported Outcome (ClinRO) for nail appearance. A significant improvement in both hair regrowth and nail abnormalities has been shown. The mean SALT score decreased from 100 to 16.3, and the average number of affected nails reduced from 6.4 to 2.1 (p < 0.001). ClinRO scores also significantly improved (p < 0.001). However, the correlation between hair and nail improvement was weak and not statistically significant (r = 0.15, p = 0.6). This suggests differential responsiveness of hair and nail units. The findings support baricitinib as a promising treatment for nail involvement in AA, highlighting the need for routine nail assessment and development of more refined evaluation tools. Limitations include small sample size and lack of long-term data.

CT-P39 [Omlyclo® (omalizumab-igec)] is a biosimilar of the reference monoclonal anti-immunoglobulin E (IgE) antibody omalizumab. It is approved for use in all indications for which reference omalizumab is approved, including allergic asthma, chronic rhinosinusitis with nasal polyps, chronic spontaneous urticaria (CSU) and (in the USA) IgE-mediated food allergy. CT-P39 has similar physicochemical and pharmacodynamic properties to those of reference omalizumab, and the pharmacokinetic equivalence and comparability of the agents has been demonstrated in healthy volunteers and patients with CSU, respectively. CT-P39 demonstrated clinical efficacy equivalent to that of reference omalizumab in patients with CSU and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of CT-P39 were similar to those of reference omalizumab, and switching from reference omalizumab to CT-P39 appeared to have no impact on efficacy or safety. The role of reference omalizumab in the management of allergic asthma, chronic rhinosinusitis with nasal polyps, CSU and IgE-mediated food allergy is well established and CT-P39 provides an effective alternative for patients requiring omalizumab therapy.

Dotinurad is a selective uricosuric drug for patients with gout with hyperuricemia. To our knowledge, this is the first study to evaluate the pharmacokinetics (PK) of dotinurad, following single and multiple oral doses in healthy Chinese adults. This single-center, open-label, parallel group, phase 1 study had 3 cohorts: A (1-mg single dose), B (single and multiple doses of 4 mg once daily for 7 days), and C (10-mg single dose). Dotinurad was administered on an empty stomach. Healthy nonsmoking Chinese adults aged 18-45 years with body mass index 19-24 k/m2 and weight ≥ 50 kg were enrolled; Cohort B required serum urate ≥ 5.5 mg/dL at screening. In total, 26 subjects were included. After single oral doses of 1, 4, and 10 mg, mean ± standard deviation (SD) plasma dotinurad concentration reached maximum observed plasma concentration (Cmax) of 104 ± 18.5, 365 ± 35.2, and 964 ± 101 ng/mL at 3.00-3.50 h, respectively. The mean ± SD terminal elimination phase half-life was 10.1 ± 1.26, 9.87 ± 1.47, and 10.9 ± 1.53 h for the 1, 4, and 10 mg doses, respectively; both area under the plasma concentration-time curve and Cmax increased in a dose-proportional manner across the 1-10-mg dose range. During once-daily doses for 7 days, steady state was reached by the2nd day after the initiation of multiple dosing, with an average steady-state plasma concentration of 186 ± 31.8 ng/mL, indicating minimal accumulation. Treatment-emergent adverse events (TEAEs) occurred in four subjects (15.4%); all were mild and resolved without treatment. No dose-dependent TEAEs were observed. Single- and multiple-dose PK of dotinurad in healthy Chinese adults showed rapid absorption, rapid elimination, linear PK, and no accumulation with once-daily dosing. Dotinurad was well-tolerated during the 7-day treatment course. ClinicalTrials.gov: NCT05278676.

This study was conducted to examine disproportionality, times to onset, incidence rates, and outcomes of trastuzumab deruxtecan-associated pulmonary adverse events (AEs) using the Japanese Adverse Drug Event Report database. We analyzed data for the period from April 2004 to December 2024. Data on pulmonary AEs were extracted, and the relative disproportionality of AEs was estimated using reporting odds ratios (RORs). Of the 3,221,393 reports analyzed, we identified 1561 reports of AEs associated with trastuzumab deruxtecan, including 505 pulmonary AEs. Only 474 reports were identified as signal-positive: interstitial lung disease, pulmonary toxicity, pneumonitis, and Pneumocystis jirovecii pneumonia. Among these, interstitial lung disease was the most frequently reported (26.6%) and included several fatal cases. Histograms of median times to onset for the four detected pulmonary AE signals showed that AEs occurred at a median of 7-27.5 days after trastuzumab deruxtecan administration. Weibull distributions showed that interstitial lung disease occurred early after administration (early failure type), but pulmonary toxicity occurred constantly throughout the exposure period (random failure type). We focused on pulmonary AEs associated with trastuzumab deruxtecan as postmarketing AEs. Serious outcomes can arise after trastuzumab deruxtecan administration. Patients should be monitored for signs of onset of these AEs not only at the start of administration but also over an extended period.

Iclepertin is a selective inhibitor of glycine transporter 1 recently investigated as a novel treatment for cognitive impairment associated with schizophrenia. Iclepertin is a potential mild inducer of liver cytochrome P450 3A4, which metabolises ethinylestradiol and levonorgestrel, which are used in combined oral contraceptives (OCs). This trial investigated the potential drug interaction effect of steady-state iclepertin on the steady-state pharmacokinetics of combined OCs. This phase I, non-randomised, open-label, two-period, fixed-sequence trial was conducted in healthy pre-menopausal female volunteers aged 18-35 years. In period 1, participants received a combined OC (ethinylestradiol 30 µg/levonorgestrel 150 µg once daily; reference treatment). In period 2, participants received a combined OC and iclepertin 10 mg once daily (test treatment). Primary pharmacokinetic endpoints of ethinylestradiol or levonorgestrel in plasma at steady state over a uniform dosing interval τ were area under the concentration-time curve (AUCτ,ss) and maximum and minimum measured concentration (Cmax,ss and Cmin,ss); drug interaction potential was estimated by geometric mean ratios (test treatment/reference treatment) with two-sided 90% confidence intervals (CIs) using analysis of variance. Safety assessments included monitoring adverse events (AEs). In total, 19 participants entered the trial; 17 were treated (periods 1 and 2). Steady-state pharmacokinetics of ethinylestradiol and levonorgestrel were similar with and without iclepertin; geometric mean ratios for AUCτ,ss, Cmax,ss, and Cmin,ss were slightly above 100%, and 90% CIs were within standard bioequivalence boundaries (80-125%). The number of on-treatment AEs was similar in period 1 (n=13) and period 2 (n=15); AEs were of mild-to-moderate severity. Iclepertin 10 mg had no meaningful effect on the pharmacokinetics of ethinylestradiol and levonorgestrel, suggesting that these drugs can be administered concomitantly. ClinicalTrials.gov (NCT05613777; registered on 18 October 2023).