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Optimization of secukinumab dose regimens in patients with moderate-to-severe plaque psoriasis via exposure-response modeling

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.

The efficacy and toxicity of mirvetuximab soravtansine, a novel antibody-drug conjugate, in the treatment of advanced or recurrent ovarian cancer: a meta-analysis

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

Open Access
Mechanism-based pharmacokinetic and pharmacodynamic modeling for bispecific antibodies: challenges and opportunities

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.

Intravitreal immunotherapy in non-infectious uveitis: an update

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.

Broadening access to tenofovir alafenamide for the treatment and prevention of HIV-1 infection

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.