ABSTRACT Background Further dose optimization is required for patients with moderate-to-severe plaque psoriasis who do not benefit from the approved secukinumab dose regimen. This study aimed to develop an exposure-response model for secukinumab to recommend dose regimens for patients of different body weights. Methods We searched the PubMed and Cochrane Library databases for randomized controlled trials using PASI 75 and PASI 90 response rates as primary outcomes. A model-based meta-analysis was developed to quantitatively analyze the distribution of six secukinumab dose regimens in patients weighing 50–120 kg. Results Sixteen trials involving 6,197 subjects were included in the analysis. The established model accurately described the time-course characteristics of PASI 75 and PASI 90 response rates over 52 weeks. Simulations indicated that maintenance doses could be reduced to 150 mg every 4 weeks and to 150 mg every 3 weeks for patients weighing 50 and 60 kg, respectively. In contrast, maintenance doses of 300 mg every 3 weeks should be selected for patients weighing 120 kg. Patients weighing 70–110 kg remained on approved maintenance doses of 300 mg every 4 weeks. Conclusions Based on patient body weights, the exposure-response model recommends efficacious and economical dose regimens for patients with moderate-to-severe plaque psoriasis.

ABSTRACT Background The present study aimed to explore the quantitative effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on liver functions in patients with nonalcoholic fatty liver disease (NAFLD). Research design and methods A total of 4771 patients with NAFLD were included for analysis by means of nonlinear mixed effect modeling, where the change rates of liver functions were taken as the evaluation indexes so as to eliminate the potential baseline effects. Results For ALT and AST, the Emax of SGLT-2 inhibitors was −17.8% and −13.9%, respectively, and the ET50 was 6.86 weeks and 10 weeks, respectively. Furthermore, the duration time to achieve 25%, 50%, 75%, and 80% Emax were 2.3 weeks, 6.86 weeks, 20.6 weeks, 27.5 weeks in ALT, 3.4 weeks, 10 weeks, 30 weeks, 40 weeks in AST, respectively. Thus, to realize the plateau period (80% of Emax) of SGLT-2 inhibitors on ALT and AST in patients with NAFLD, 100 mg/day canagliflozin (or 10 mg/day dapagliflozin or 10 mg/day empagliflozin) needs to be taken for 20.6 weeks and 30 weeks, respectively. Conclusions The present study explored the quantitative effects of SGLT-2 inhibitors on liver functions and recommends a therapeutic regimen in patients with NAFLD.

ABSTRACT Introduction This meta-analysis aims to systematically analyze the efficacy and toxicity of mirvetuximab soravtansine (MIRV) as second-line and above treatment for advanced or recurrent ovarian cancer. Methods Candidate studies were identified in PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases up to 1 May 2023. Objective response rate (ORR), progression-free survival (PFS), the incidence of adverse events (AEs), and incidence of grade ≥ 3 AEs were extracted and calculated by meta-analysis of merging ratios or mean to describe the efficacy and toxicity of MIRV. Results Seven eligible prospective studies were included in this meta-analysis, including 605 patients with advanced ovarian cancer who received second-line or higher therapy. ORR of MIRV was 34.2% (95% confidence interval [CI] 25.0–43.5), and PFS was 5.82 months (95%CI 4.47–7.18). The overall incidence of AEs was 87.4% (95%CI 52.9–100.0) and the incidence of grade ≥ 3 AEs was 27.1% (95%CI 18.9–36.1). The most common AEs were vision blurring, nausea, and diarrhea, with incidence of 46.7% (39.6–53.8), 41.8% (34.0–49.9), and 41.3% (30.4–52.5), respectively. Conclusions MIRV has definite efficacy and good safety as a novel choice for second-line and above treatment of advanced or recurrent FRα positive ovarian cancer. This may have promising application in patients with platinum-resistant diseases. PROSPERO registration number CRD42023428599

ABSTRACT Introduction Metabolic syndrome (MetS), i.e. the cluster of cardiometabolic risk factors comprising visceral obesity, impaired glucose metabolism, arterial hypertension and atherogenic dyslipidemia, is prevalent globally and exacts a heavy toll on health care expenditures. Areas covered The pathophenotypes of individual traits of the MetS in adults are discussed first, with strong emphasis on nonalcoholic fatty liver disease (NAFLD) and sex differences. Next, I discuss recent studies on phenotypic and outcome heterogeneity of the MetS, highlighting the role of NAFLD, sex, reproductive status, and depressive disorders. In the second half of the article, the therapeutic implications of the variable MetS types and features are analyzed, focusing on the most recent developments, and guidelines. Expert opinion I have identified physiological, pathological, social and medical sources of phenotypical heterogeneity in the MetS and its constitutive traits. Improved understanding of these variables may be utilized in the setting of future precision medicine approaches in the field of metabolic disorders and target organ damage.

ABSTRACT Introduction Unlike conventional antibodies, bispecific antibodies (bsAbs) are engineered antibody- or antibody fragment-based molecules that can simultaneously recognize two different epitopes or antigens. Over the past decade, there has been an explosion of bsAbs being developed across therapeutic areas. Development of bsAbs presents unique challenges and mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling has served as a powerful tool to optimize their development and realize their clinical utility. Areas covered In this review, the guiding principles and case examples of how fit-for-purpose, mechanism-based PK/PD models have been applied to answer questions commonly encountered in bsAb development are presented. Such models characterize the key pharmacological elements of bsAbs, and they can be utilized for model-informed drug development. We also include the discussion of challenges, knowledge gaps and future direction for such models. Expert opinion Mechanistic PK/PD modeling is a powerful tool to support the development of bsAbs. These models can be extrapolated to predict treatment outcomes based on mechanisms of action (MoA) and clinical observations to form positive learn-and-confirm cycles during drug development, due to their abilities to differentiate system- and drug-specific parameters. Meanwhile, the models should keep being adapted according to novel drug design and MoA, providing continuous opportunities for model-informed drug development.

ABSTRACT Introduction Few agonists of the third isotype of beta-adrenergic receptors, the β3-adrenoreceptor, are currently used clinically, and new agonists are under development for the treatment of overactive bladder disease. As the receptor is expressed in human cardiac and vascular tissues, it is important to understand their beneficial (or adverse) effect(s) on these targets. Areas covered We discuss the most recent results of clinical trials testing the benefit and safety of β3-adrenoreceptor activation on cardiovascular outcomes in light of current knowledge on the receptor biology, genetic polymorphisms, and agonist pharmacology. Expert opinion While evidence from small clinical trials is limited so far, the β3-agonist, mirabegron seems to be safe in patients at high cardiovascular risk but produces benefits on selected cardiovascular outcomes only at higher than standard doses. Activation of cardiovascular β3-adrenoreceptors deserves to be tested with more potent agonists, such as vibegron.

ABSTRACT Introduction In the past several years, there have been numerous advances in pharmacotherapeutics for the management of uveitis and other ocular inflammatory diseases, including newer therapeutic agents and ocular drug delivery systems. One of the most attractive modes of drug delivery is the intravitreal route since it has proven to be safe and efficacious and prevents unwanted systemic adverse events related to the agent. Areas covered In this review, intravitreal delivery of various pharmacotherapeutic agents for noninfectious uveitis has been described. An extensive review of the literature was performed using specific keywords on the PubMed database to identify clinical studies employing various pharmacotherapeutic agents with intravitreal drug delivery for noninfectious uveitis. The mode of action, safety, efficacy, and tolerability of these drugs have also been elucidated. Expert opinion Several agents, including biologic response modifier agents, have been found to be safe and efficacious for various indications of uveitis, such as cystoid macular edema, active uveitis, and other conditions such as retinal vasculitis and vitreous haze. The use of intravitreal biological therapies, especially infliximab, has been fraught with potential safety signals such as photoreceptor toxicity. However, pharmacotherapeutic agents such as corticosteroids and anti-vascular endothelial growth factor agents are now widely used in the clinical management of uveitis and its complications.

ABSTRACT Introduction Tenofovir alafenamide (TAF), a prodrug of tenofovir, achieves higher intracellular concentrations of tenofovir-diphosphate and 90% lower plasma concentrations of tenofovir compared to tenofovir disoproxil fumarate (TDF). TAF is associated with improved renal and bone safety outcomes. Areas covered We review the efficacy and safety of TAF-containing regimens in adults and pediatrics. We highlight safety data during pregnancy, drug interactions during co-administration with tuberculosis treatment, and critical knowledge gaps to be addressed for the successful implementation of TAF in low- and middle-income countries. We performed a search on MEDLINE PubMed and conference websites for relevant articles published from January 2010 to March 2023. Expert Opinion Current evidence demonstrates that TAF has similar efficacy and tolerability, superior bone and renal safety, and higher rates of dyslipidemia and weight gain, compared with TDF. However, there are several knowledge gaps, in specific sub-populations, that require action. Emerging data suggests that TAF is safe during pregnancy, although fuller safety data to support TAF use in pregnancy is needed. Similarly, there is a lack of evidence that TAF can be used in combination with rifamycin-based tuberculosis treatment in PWH and TB. Further studies are needed to fill knowledge gaps and support the wider rollout of TAF.

ABSTRACT Introduction Congenital anomalies of the kidney and urinary tract (CAKUT) can be associated with proteinuria, possibly leading to a decline of kidney function. The aim of this review is to evaluate evidence on the efficacy of renin-angiotensin-aldosterone system inhibitors (RAASi) in children affected by CAKUT with proteinuria or chronic kidney disease (CKD). Areas covered We conducted a bibliographic search between 1 December 2022 and 20 February 2023, including randomized controlled trials, case-control studies, observational studies, meta-analyses, and systematic reviews dealing with the efficacy of RAASi in reducing proteinuria and slowing the decline of kidney function in children. Expert opinion RAASi are effective in reducing proteinuria and slowing CKD progression in many renal conditions, however, the efficacy of these drugs in patients affected by CAKUT with proteinuria is still unknown. While waiting for more evidence, when facing a child with CAKUT with isolated proteinuria or with proteinuria and CKD, a 6–12-month trial with RAASi with gradual increase to the maximal tolerated dose should be considered. If no improvement of proteinuria is obtained, the RAASi should be discontinued.