SzM protein of Streptococcus equi ssp. zooepidemicus triggers the release of neutrophil extracellular traps depending on GSDMD.

Streptococcus equissp.zooepidemicus (SEZ) is a crucial pathogen and contributes to various infections in numerous animal species. Swine streptococcicosis outbreak caused by SEZ has been reported in several countries in recent years. SzM protein is a cell membrane-anchored protein, which exhibits as an important virulence factor of SEZ. Effects of SzM protein on host innate immune need further study. Here, recombinant SzM (rSzM) protein of the SEZ was obtained, and mice were intraperitoneally injected with rSzM protein. We discovered that rSzM protein can recruit neutrophils into the injected site. In further study, neutrophils were isolated and treated with rSzM protein, NETs release were triggered by rSzM protein independently, and GSDMD protein was promoted-expressed and activated. In order to investigate the role of GSDMD in NETs formation, neutrophils isolated from WT mice and GSDMD-/- mice were treated with rSzM protein. The results showed that GSDMD deficiency suppressed the NETs release. In conclusion, SzM protein of SEZ can trigger the NETs release in a GSDMD-depending manner.

Neutrophil accumulation raises defence against Streptococcus equi ssp. zooepidemicus in the absence of Gasdermin D.

Streptococcus equi ssp. zooepidemicus (SEZ) predominantly acts as a zoonotic pathogen, capable of infecting a diverse range of animal species including human. Gasdermin D (GSDMD) exhibited comprehensive functions in host against different pathogenic microorganism. This study aimed to investigate the role of GSDMD in host against SEZ. Mice were administrated with SEZ via intranasal intubation for 24 h (3 × 106CFU), GSDMD protein expression significantly increased in the lung tissue of mice infected with SEZ. For further research on the role of GSDMD during SEZ infection, GSDMD-/- mice and WT mice were treated with SEZ via intranasal intubation for 24 h (3 × 106CFU). GSDMD-/- mice showed less severe lung tissue due to fewer bacteria colonization. Numerous neutrophils were recruited into lung tissues in GSDMD-/- mice, related to the release of CXCL1 and CXCL2 regulated by p65 phosphorylation. In further study, neutrophils of WT and GSDMD-/- mice were isolated and treated with SEZ (multiplicity of infection, MOI = 10, 4 h). The absence of GSDMD alleviated the death of neutrophils, in addition, GSDMD deficiency could promote translocation of p65 from the cytoplasm into the nucleus in neutrophil, which may contribute to the release of IL-1ß and TNF-α. This study demonstrated a novel function of GSDMD in host immune response to SEZ invading, indicating that GSDMD deficiency ameliorated SEZ infection through enhancing neutrophil accumulation into infected site, and activating NF-κB pathway in neutrophil to release cytokines against SEZ. Our study suggested that inhibition of host GSDMD may be an effective method against SEZ.

Model-Informed Approaches to Support Drug Development for Patients With Obesity: A Regulatory Perspective.

Obesity, which is defined as having a body mass index of 30 kg/m2 or greater, has been recognized as a serious health problem that increases the risk of many comorbidities (eg, heart disease, stroke, and diabetes) and mortality. The high prevalence of individuals who are classified as obese calls for additional considerations in clinical trial design. Nevertheless, gaining a comprehensive understanding of how obesity affects the pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of drugs proves challenging, primarily as obese patients are seldom selected for enrollment at the early stages of drug development. Over the past decade, model-informed drug development (MIDD) approaches have been increasingly used in drug development programs for obesity and its related diseases as they use and integrate all available sources and knowledge to inform and facilitate clinical drug development. This review summarizes the impact of obesity on PK, PD, and the efficacy of drugs and, more importantly, provides an overview of the use of MIDD approaches in drug development and regulatory decision making for patients with obesity: estimating PK, PD, and efficacy in specific dosing scenarios, optimizing dose regimen, and providing evidence for seeking new indication(s). Recent review cases using MIDD approaches to support dose selection and provide confirmatory evidence for effectiveness for patients with obesity, including pediatric patients, are discussed. These examples demonstrate the promise of MIDD as a valuable tool in supporting clinical trial design during drug development and facilitating regulatory decision-making processes for the benefit of patients with obesity.

FDA Approval Summary: Mirvetuximab Soravtansine-Gynx for FRα-Positive, Platinum-Resistant Ovarian Cancer.

On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% [95% confidence interval (CI), 22.9-41.6] with a median duration of response of 6.9 months (95% CI, 5.6-9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx.

Gene Therapy Strategies Targeting Aging-Related Diseases.

Rapid advancements have taken place in gene therapy technology. However, effective methods for treating aging- or age-related chronic diseases, which are often closely related to genes or even multiple genes, are still lacking. The path to developing cures is winding, while gene therapy that targets genes related to aging represents an exciting research direction with tremendous potential. Among aging-related genes, some candidates have been studied at different levels, from cell to organismal levels (e.g., mammalian models) with different methods, from overexpression to gene editing. The TERT and APOE have even entered the stage of clinical trials. Even those displaying only a preliminary association with diseases have potential applications. This article discusses the foundations and recent breakthroughs in the field of gene therapy, providing a summary of current mainstream strategies and gene therapy products with clinical and preclinical applications. Finally, we review representative target genes and their potential for treating aging or age-related diseases.

Engineered Extracellular Vesicle-Delivered CRISPR/CasRx as a Novel RNA Editing Tool.

Engineered extracellular vesicles (EVs) are considered excellent delivery vehicles for a variety of therapeutic agents, including nucleic acids, proteins, drugs, and nanomaterials. Recently, several studies have indicated that clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) delivered by EVs enable efficient DNA editing. However, an RNA editing tool delivered by EVs is still unavailable. Here, a signal peptide-optimized and EVs-delivered guide RNA (gRNA) and CRISPR/CasRx (Cas13d) system capable of rapidly inhibiting the expression of targeted genes with quick catabolism after performing their functions is developed. EVs with CRISPR/CasRx and tandem gRNAs targeting pivotal cytokines are further packed whose levels increase substantially over the course of acute inflammatory diseases and find that these engineered EVs inhibit macrophage activation in vitro. More importantly, this system attenuates lipopolysaccharide (LPS)-triggered acute lung injury and sepsis in the acute phase, mitigating organ damage and improving the prognosis in vivo. In summary, a potent tool is provided for short-acting RNA editing, which could be a powerful therapeutic platform for the treatment of acute diseases.

Preliminary study on the effect of catabolite repression gene knockout on p-nitrophenol degradation in Pseudomonas putida DLL-E4.

P-nitrophenol (PNP) is a carcinogenic, teratogenic, and mutagenic compound that can cause serious harm to the environment. A strain of Pseudomonas putida DLL-E4, can efficiently degrade PNP in a complex process that is influenced by many factors. Previous studies showed that the expression level of pnpA, a key gene involved in PNP degradation, was upregulated significantly and the degradation of PNP was obviously accelerated in the presence of glucose. In addition, the expression of crc, crcY, and crcZ, key genes involved in catabolite repression, was downregulated, upregulated, and upregulated, respectively. To investigate the effect of the carbon catabolite repression (CCR) system on PNP degradation, the crc, crcY, and crcZ genes were successfully knocked out by conjugation experiments. Our results showed that the knockout of crc accelerated PNP degradation but slowed down the cell growth. However, the knockout of crcY or crcZ alone accelerated PNP degradation when PNP as the sole carbon source, but that knockout slowed down PNP degradation when glucose was added. The results indicate that the CCR system is involved in the regulation of PNP degradation, and further work is required to determine the details of the specific regulatory mechanism.

Older Adults' Access to and Satisfaction With Primary Hospitals Based on Spatial and Non-spatial Analyses.

In order to improve the health and quality of life of older adults, the Chinese government is dedicated to establishing an equilibrium level of primary healthcare services for all communities. However, little attention has been paid to measuring the accessibility of primary hospitals to older adults, nor to understanding the seniors' satisfaction with and needs for primary healthcare services. Therefore, this study sought to investigate the spatial accessibility of primary hospitals to older adults, and also to examine the impact of walking distances on the seniors' satisfaction with their healthcare services. A two-step floating catchment area method was applied to measure the spatial accessibility of primary hospitals to older adults at the level of subdistricts. In order to investigate the actual opinions of older adults and verify the results of spatial analysis, a large-scale questionnaire survey was also conducted. The analyses found that (1) primary hospitals were not equally distributed; (2) most older adults did not have access to primary hospitals within a threshold walking distance of 1,000 m, but they usually could reach a hospital in their subdistrict within a threshold distance of 2,000 m; (3) older adults' satisfaction levels with primary hospitals were significantly different among subdistricts; (4) long walking distances negatively influenced older adults' satisfaction with primary hospitals; (5) the satisfaction of older adults was highest with a threshold distance of 500 m; and (6) a piecewise regression model indicated that older adults' satisfaction with primary hospitals would decrease with an increase in walking distance to the hospital. When the walking distances exceeded 1,000 m, the slope of the linear regression model increased significantly compared with the slope for walking distances less than 1,000 m. By adopting multiple research methods and capturing older adults' behaviors and satisfaction, our results provide (1) data on the importance of accessibility of primary hospitals to older adults, and (2) insights for future planning to achieve equity in primary healthcare and enhance the spatial distribution of primary hospitals.

FDA Approval Summary: Tivozanib for Relapsed or Refractory Renal Cell Carcinoma.

On March 10, 2021, the FDA granted regular approval to tivozanib for treatment of patients with relapsed or refractory (R/R) advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Approval was based on the TIVO-3 study, a randomized trial of tivozanib versus sorafenib in patients with R/R advanced RCC. In TIVO-3, patients were randomized to receive either tivozanib 1.34 mg orally once daily for 21 consecutive days of every 28-day cycle or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival (PFS) per RECIST v1.1. Tivozanib demonstrated efficacy compared with sorafenib with an improvement in PFS [HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.016]. The estimated median PFS was 5.6 months and 3.9 months in the tivozanib and sorafenib arms, respectively. There was no evidence of a detrimental effect on overall survival: HR, 0.97 (95% CI, 0.75-1.24). The most common grade 3 to 4 adverse reaction on the tivozanib arm was hypertension (24%). Compared with sorafenib, tivozanib was associated with lower rates of grade 3 to 4 diarrhea, rash, and palmar-plantar erythrodysesthesia. Patients receiving tivozanib in TIVO-3 had lower rates of dose reduction, interruption, or permanent discontinuation than those receiving sorafenib.

FDA Approval Summary: Margetuximab plus Chemotherapy for Advanced or Metastatic HER2-Positive Breast Cancer.

On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59-0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.

Do Age-Friendly Rural Communities Affect Quality of Life? A Comparison of Perceptions from Middle-Aged and Older Adults in China.

The aging population in rural areas of China faces serious challenges due to urban-rural disparities. In order to improve the active aging of rural older adults, the establishment of age-friendly communities is encouraged. However, globally, the focus is on age-friendly communities in urban areas, not reflecting rural communities. Hence, we addressed the importance of age-friendly rural communities (AFRCs) and aimed to investigate their impact on the quality of life (QoL) of older adults. We examined different perceptions of AFRCs among older adults (aged over 60) and middle-aged people (45-60) in rural communities with questionnaire surveys (n = 470 and 393, respectively). Several statistical methods, such as Chi-squared test, t-test, reliability test, and multiple regression, were adopted to investigate and compare the perceptions of these two. The results indicated that (1) middle-aged people were more satisfied with AFRC components and had a higher QoL than older adults; (2) the QoL of middle-aged people was predicted by housing, accessibility, and outdoor spaces; (3) the QoL of older adults was affected by housing, outdoor spaces, social participation, and public transportation. These findings aid in our understanding of rural communities and the QoL of rural residents. They are helpful for urban planners and policymakers to improve the planning of AFRCs and supplement research on age-friendly communities in rural areas. Practical implementations are proposed for the planning of AFRCs, such as the passive design of residential housing, grouping of community facilities together, and improvement in the hygiene of outdoor spaces in rural areas.

Model-Informed Drug Development in Pediatric Dose Selection.

Model-informed drug development (MIDD) has been a powerful and efficient tool applied widely in pediatric drug development due to its ability to integrate and leverage existing knowledge from different sources to narrow knowledge gaps. The dose selection is the most common MIDD application in regulatory submission related to pediatric drug development. This article aims to give an overview of the 3 broad categories of use of MIDD in pediatric dose selection: leveraging from adults to pediatric patients, leveraging from animals to pediatric patients, and integrating mechanism in infants and neonates. Population pharmacokinetic analyses with allometric scaling can reasonably predict the clearance in pediatric patients aged >5 years. A mechanistic-based approach, such as physiologically based pharmacokinetic accounting for ontogeny, or an allometric model with age-dependent exponent, can be applied to select the dose in pediatric patients aged ≤2 years. The exposure-response relationship from adults or from other drugs in the same class may be useful in aiding the pediatric dose selection and benefit-risk assessment. Increasing application and understanding of use of MIDD have contributed greatly to several policy developments in the pediatric field. With the increasing efforts of MIDD under the Prescription Drug User Fee Act VI, bigger impacts of MIDD approaches in pediatric dose selection can be expected. Due to the complexity of model-based analyses, early engagement between drug developers and regulatory agencies to discuss MIDD issues is highly encouraged, as it is expected to increase the efficiency and reduce the uncertainty.

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer.

On December 20, 2019, the FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki [DS-8201a; T-DXd; tradename ENHERTU (Daiichi Sankyo)] for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. Approval was based on data from study DS8201-A-U201 (DESTINY-Breast01) with supportive safety data from study DS8201-A-J101. The primary efficacy endpoint in DESTINY-Breast01 was overall response rate (ORR) based on confirmed responses by blinded independent central review (ICR) using RECIST v1.1 in all participants who were assigned to receive the recommended dose of 5.4 mg/kg while secondary endpoints included duration of response (DoR). The confirmed ORR based on ICR in these 184 patients was 60.3% [95% confidence interval (CI): 52.9-67.4] and the median DoR was 14.8 months (95% CI: 13.8-16.9). Interstitial lung disease, including pneumonitis, was experienced in patients treated with T-DXd and can be severe, life threatening, or fatal. In addition, neutropenia and left ventricular dysfunction were included as Warnings and Precautions in labeling. Other important common adverse reactions were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, diarrhea, and thrombocytopenia. Overall, the totality of efficacy and safety data supported the accelerated approval of T-DXd for the intended indication.

FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma.

On December 18, 2019, the FDA granted accelerated approval to enfortumab vedotin-ejfv (PADCEV; Astellas and Seattle Genetics) for treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 or programmed death ligand 1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Substantial evidence of effectiveness for this application is obtained from Cohort 1 of the single-arm, multicenter Study EV-201. Patients received enfortumab vedotin (EV) 1.25 mg/kg (up to a maximum dose of 125 mg) intravenously on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Confirmed objective response rate in the 125-patient efficacy population determined by blinded independent central review was 44% [95% confidence interval (CI), 35.1-53.2], with complete responses in 12%. Median response duration was 7.6 months (95% CI, 6.3-not estimable). Grade 3-4 adverse reactions occurred in 73% of patients. Hyperglycemia, peripheral neuropathy, ocular disorders, skin reactions, infusion site extravasations, and embryo-fetal toxicity are labeled as warnings and precautions for EV. The article summarizes the data and the FDA thought process supporting accelerated approval of EV. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

FDA Approval Summary: Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf Injection for Subcutaneous Use in Patients with HER2-positive Breast Cancer.

On June 29, 2020, the FDA approved pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection (Phesgo) for the treatment of patients with HER2-positive early-stage and metastatic breast cancer. Patients should be selected for therapy based on an FDA-approved companion diagnostic test. Approval was primarily based on the FeDeriCa trial, a randomized, open-label, multicenter comparability study of pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection compared with intravenous pertuzumab and intravenous trastuzumab administered in the neoadjuvant and adjuvant settings with chemotherapy for the treatment of patients with early breast cancer. The pharmacokinetic endpoints were, first, to demonstrate that the exposure of subcutaneous pertuzumab was not inferior to that of intravenous pertuzumab, and then to demonstrate that the exposure of subcutaneous trastuzumab was not inferior to that of intravenous trastuzumab. The primary endpoints were met with the observed lower limit of the two-sided 90% confidence intervals above the prespecified noninferiority margins. The most common adverse reactions were alopecia, nausea, diarrhea, anemia, and asthenia. The totality of the evidence demonstrated comparability of the subcutaneous product to intravenous, allowing for extrapolation and approval of all breast cancer indications for which intravenous trastuzumab and pertuzumab are approved.

FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer.

On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months [95% confidence interval (CI), 7.5-14.5] compared with 5.7 months (95% CI, 3.7-7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50-0.85; two-sided P = 0.001). The median overall survival was not yet reached for the alpelisib plus fulvestrant arm (95% CI, 28.1-NE) and was 26.9 months (95% CI, 21.9-NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR, 0.85; 95% CI, 0.58-1.25). The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.

FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer.

On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. This was the first new molecular entity evaluated under Project Orbis, an FDA Oncology Center of Excellence initiative, which supports concurrent review of oncology drugs by multiple global health authorities. Approval was based on the HER2CLIMB trial, which randomized patients to receive tucatinib or placebo with trastuzumab and capecitabine. Tucatinib demonstrated efficacy compared with placebo in progression-free survival [PFS; HR: 0.54; 95% confidence interval (CI): 0.42-0.71; P < 0.00001] and overall survival (OS; HR: 0.66; 95% CI, 0.50-0.87; P = 0.00480). Patients with either treated and stable or active brain metastases made up 48% of the study population. PFS in patients with brain metastases confirmed benefit (HR: 0.48; 95% CI, 0.34-0.69; P < 0.00001). The benefit in patients with brain metastases allowed for inclusion of this specific population in the indication. Important safety signals included diarrhea and hepatotoxicity which are listed under Warnings and Precautions. This article summarizes the FDA thought process and data supporting the favorable benefit-risk profile and approval of tucatinib.

Tumor Growth Dynamic Modeling in Oncology Drug Development and Regulatory Approval: Past, Present, and Future Opportunities.

Model-informed drug development (MIDD) approaches have rapidly advanced in drug development in recent years. Additionally, the Prescription Drug User Fee Act (PDUFA) VI has specific commitments to further enhance MIDD. Tumor growth dynamic (TGD) modeling, as one of the commonly utilized MIDD approaches in oncology, fulfills the purposes to accelerate the drug development, to support new drug and biologics license applications, and to guide the market access. Increasing knowledge of TGD modeling methodologies, encouraging applications in clinical setting for patients' survival, and complementing assessment of regulatory review for submissions, together fueled promising potentials for imminent enhancement of TGD in oncology. This review is to comprehensively summarize the history of TGD, and present case examples of the recent advance of TGD modeling (mixture model and joint model), as well as the TGD impact on regulatory decisions, thus illustrating challenges and opportunities. Additionally, this review presents the future perspectives for TGD approach.

Role of Model-Informed Drug Development in Pediatric Drug Development, Regulatory Evaluation, and Labeling.

The unique challenges in pediatric drug development require efficient and innovative tools. Model-informed drug development (MIDD) offers many powerful tools that have been frequently applied in pediatric drug development. MIDD refers to the application of quantitative models to integrate and leverage existing knowledge to bridge knowledge gaps and facilitate development and decision-making processes. This article discusses the current practices and visions of applying MIDD in pediatric drug development, regulatory evaluation, and labeling, with detailed examples. The application of MIDD in pediatric drug development can be broadly classified into 3 categories: leveraging knowledge for bridging the gap, dose selection and optimization, and informing clinical trial design. In particular, MIDD can provide evidence for the assumption of exposure-response similarity in bridging existing knowledge from reference to target population, support the dose selection and optimization based on the "exposure-matching" principle in the pediatric population, and increase the efficiency and success rate of pediatric trials. In addition, the role of physiologically based pharmacokinetics in drug-drug interaction in children and adolescents and in utilizing ontogeny data to predict pharmacokinetics in neonates and infants has also been illustrated. Moving forward, MIDD should be incorporated into all pediatric drug development programs at every stage to inform clinical trial design and dose selection, with both its strengths and limitations clearly laid out. The accumulated experience and knowledge of MIDD has and will continue to drive regulatory policy development and refinement, which will ultimately improve the consistency and efficiency of pediatric drug development.