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Abstract Deriving pediatric doses for locally acting drugs (LADs) presents a unique challenge because limited systemic exposure hinders commonly used approaches such as pharmacokinetic matching to adults. This study systematically evaluated drug development practices used for pediatric dose selection of LADs approved by the U.S. Food and Drug Administration from 2002 to 2020. The three study objectives were: (1) to determine the dose selection approach for the labeled pediatric dose, (2) to examine the studied pediatric dose(s), and (3) to evaluate the characteristics of the pediatric clinical programs used to support the labeled pediatric dose. A total of 187 pediatric submissions were characterized for the labeled and studied pediatric doses of LADs. The pediatric dose was predominantly labeled as a flat dose (91%) and at a single‐dose level (67%) similar to adults. The majority (68.4%) of the submissions had the same labeled dose for pediatrics and adults. Independent pharmacodynamic/efficacy studies in pediatric patients commonly (64.2%) provided supportive evidence for the labeled pediatric dose. Inhalation, nasal, and injectable submissions had the highest number of clinical trials, lowest usage of an extrapolation of efficacy approach, and utilized diverse approaches in selecting the studied pediatric doses. This article highlights approaches for LAD dosing in pediatric patients and can be used to inform drug development of these products in the pediatric population.

Abstract The risk of severe adverse events related to thiopurine therapy can be reduced by personalizing dosing based on TPMT and NUDT15 genetic polymorphisms. However, the optimal genetic testing platform has not yet been established. In this study, we report on the TPMT and NUDT15 genotypes and phenotypes generated from 320 patients from a multicenter pediatric healthcare system using both Sanger sequencing and polymerase chain reaction genotyping (hereafter: genotyping) methods to determine the appropriateness of genotyping in our patient population. Sanger sequencing identified variant TPMT alleles including *3A (8, 3.2% of alleles), *3C (4, 1.6%), and *2 (1, 0.4%), and NUDT15 alleles including *2 (5, 3.6%) and *3 (1, 0.7%). For genotyped patients, variants identified in TPMT included *3A (12, 3.1%), *3C (4, 1%), *2 (2, 0.5%), and *8 (1, 0.25%), whereas NUDT15 included *4 (2, 1.9%) and *2 or *3 (1, 1%). Between Sanger sequencing and genotyping, no significant difference in allele, genotype, or phenotype frequency was identified for either TPMT or NUDT15. All patients who were tested using Sanger sequencing would have been accurately phenotyped for either TPMT (124/124), NUDT15 (69/69), or both genes (68/68) if they were assayed using the genotyping method. Considering 193 total TPMT and NUDT15 Sanger Sequencing tests reviewed, all tests would have resulted in an appropriate clinical recommendation if the test had instead been conducted using the comparison genotyping platforms. These results suggest that, in this study population, genotyping would be sufficient to provide accurate phenotype calls and clinical recommendations.

Abstract Human radiolabeled mass balance studies are an important component of the clinical pharmacology programs supporting the development of new investigational drugs. These studies allow for understanding of the absorption, distribution, metabolism, and excretion of the parent drug and metabolite(s) in the human body. Understanding the drug's disposition as well as metabolite profiling and abundance via mass balance studies can help inform the overall drug development program. A survey of the US Food and Drug Administration (FDA)‐approved new drug applications (NDAs) indicated that about 66% of the drugs had relied on findings from the mass balance studies to help understand the pharmacokinetic characteristics of the drug and to inform the overall drug development program. When such studies were not available in the original NDA, adequate justifications were routinely provided. Of the 104 mass balance studies included in this survey, most of the studies were conducted in healthy volunteers (90%) who were mostly men (>86%). The studies had at least six evaluable participants (66%) and were performed using the final route(s) of administration (98%). Eighty‐five percent of the studies utilized a dose within the pharmacokinetic linearity range with 54% of the studies using a dose the same as the approved dose. Nearly all studies were performed as a single‐dose (97%) study using a fit‐for‐purpose radiolabeled formulation. In this analysis, we summarized the current practices for conducting mass balance studies and highlighted the importance of conducting appropriately designed human radiolabeled mass balance studies and the challenges associated with inadequately designed or untimely studies.

Abstract Clinical pharmacology is an integral discipline supporting the development, regulatory evaluation, and clinical use of drugs for the treatment of both common and rare diseases. Here, we evaluated the recommendations and information available from select clinical pharmacology studies in the therapeutic product labeling of new molecular entities (NMEs) approved from 2017 to 2019 for both common and rare diseases. A total of 151 NMEs, including 72 orphan and 79 non‐orphan drugs, were analyzed for recommendations and information available related to food–drug interaction, drug–drug interaction, renal impairment, hepatic impairment, QT assessment, and human radiolabeled mass balance studies using data collected from the original labeling and other regulatory documents. The analysis showed no statistically significant difference in the recommendations between orphan and non‐orphan drugs except for renal impairment related recommendations in section 8 of the labeling. Although not significant, fewer hepatic impairment labeling recommendations were available for orphan drugs when compared with non‐orphan drugs. At the time of initial approval, 79 postmarketing requirements (PMRs) and postmarketing commitments (PMCs) for 33 orphan drugs and 39 PMRs and PMCs for 19 non‐orphan drugs were established; with most difference observed for drug–drug interaction, hepatic impairment, and QT assessment. Overall, although there was a trend for more labeling recommendations and fewer postmarketing studies and clinical trials for non‐orphan drugs, there appeared to be no substantial differences in how these select clinical pharmacology studies are leveraged during the development and approval of orphan and non‐orphan drugs.

Abstract Background and Aims Retro walking has been shown to acquire a greater metabolic cost, placing a higher cardiopulmonary demand on the body, when compared with forward walking at a similar speed. The aim of this study was to compare the effect of retro walking with that of forward walking on C‐reactive protein (CRP) levels, body mass index (BMI) and blood pressure (BP) and to understand the influence of independent factors namely systolic blood pressure (SBP), diastolic blood pressure (DBP) and BMI on CRP in untrained overweight and obese young adults. Methods This was a randomised controlled trial whereby 106 participants underwent either retro walking (n = 53) or forward walking (n = 53) treadmill training four times a week for 12 weeks before and after which CRP, BMI, and BP levels were measured. Comparison of the measured values before and after intervention and between the groups was done and influence of BMI and BP on CRP levels was determined. Results Both groups recorded a significant decrease (p

Abstract Drought and heat stresses are the major abiotic stress factors detrimental to maize (Zea mays L.) production. Much attention has been directed toward plant responses to heat or drought stress. However, maize reproductive stage responses to combined heat and drought remain less explored. Therefore, this study aimed to quantify the impact of optimum daytime (30°C, control) and warmer daytime temperatures (35°C, heat stress) on pollen germination, morpho‐physiology, and yield potential using two maize genotypes (“Mo17” and “B73”) under contrasting soil moisture content, that is, 100% and 40% irrigation during flowering. Pollen germination of both genotypes decreased under combined stresses (42%), followed by heat stress (30%) and drought stress (19%). Stomatal conductance and transpiration were comparable between control and heat stress but significantly decreased under combined stresses (83% and 72%) and drought stress (52% and 47%) compared with the control. Genotype “Mo17” reduced its green leaf area to minimize the water loss, which appears to be one of the adaptive strategies of “Mo17” under stress conditions. The leaf reflectance of both genotypes varied across treatments. Vegetation indices associated with pigments (chlorophyll index of green, chlorophyll index of red edge, and carotenoid index) and plant health (normalized difference red‐edge index) were found to be highly sensitive to drought and combined stressors than heat stress. Combined drought and heat stresses caused a significant reduction in yield and yield components in both Mo17 (49%) and B73 (86%) genotypes. The harvest index of genotype “B73” was extremely low, indicating poor partitioning efficiency. At least when it comes to “B73,” the cause of yield reduction appears to be the result of reduced sink number rather than the pollen and source size. To the best of our awareness, this is the first study that showed how the leaf‐level spectra, yield, and quality parameters respond to the short duration of independent and combined stresses during flowering in inbred maize. Further studies are required to validate the responses of potential traits involving diverse maize genotypes under field conditions. This study suggests the need to develop maize with improved tolerance to combined stresses to sustain production under increasing temperatures and low rainfall conditions.

Synthetic nucleotides that utilize RNA‐centric pharmacology can target diseases at the RNA level, thus altering protein expression in ways previously inaccessible to small molecules and therapeutic biologics. Recognizing that the unique pharmacology of oligonucleotides may require specific considerations in pre‐approval assessment, clinical and nonclinical pharmacology studies being conducted for a selected set of oligonucleotide therapies in a 6‐year period were assessed. This investigation focused primarily on the four following areas: (i) drug‐drug interaction (DDI) potential, (ii) organ impairment (i.e., renal and hepatic impairment), (iii) immunogenicity, and (iv) cardiac safety. Data were summarized and assessed from 14 Investigational New Drug programs and 7 New Drug Applications submitted to the US Food and Drug Administration (FDA) from the period of January 2012 to August 2018, encompassing 152 unique studies. The assessment of DDI potential was largely consistent with the recommendations of current DDI‐relevant guidances. Limited data were available to provide recommendations across organ impairment categories. Limited data on immunogenicity indicate impact on pharmacokinetic, the impact on safety and efficacy, although not extensively evaluated, appeared negligible. Cardiac safety evaluation indicated a potential for discordant translation of risk from nonclinical studies to clinical findings. Continued experience with synthetic oligonucleotide therapies will help inform the development of best practices to support their development and regulatory approval.

Switchgrass ( is a perennial native North American grass present in two ecotypes: upland, found primarily in the northern range of switchgrass habitats, and lowland, found largely in the southern reaches of switchgrass habitats. Previous studies focused on a diversity panel of primarily northern switchgrass, so to expand our knowledge of genetic diversity in a broader set of North American switchgrass, exome capture sequence data were generated for 632 additional, primarily lowland individuals. In total, over 37 million single nucleotide polymorphisms (SNPs) were identified and a set of 1.9 million high-confidence SNPs were obtained from 1169 individuals from 140 populations (67 upland, 65 lowland, 8 admixed) were used in downstream analyses of genetic diversity and population structure. Seven separate population groups were identified with moderate genetic differentiation [mean fixation index (Fst) estimate of 0.06] between the lowland and the upland populations. Ecotype-specific and population-specific SNPs were identified for use in germplasm evaluations. Relative to rice ( L.), maize ( L.), soybean [ (L.) Merr.], and Gaertn., analyses of nucleotide diversity revealed a high degree of genetic diversity (0.0135) across all individuals, consistent with the outcrossing mode of reproduction and the polyploidy of switchgrass. This study supports the hypothesis that repeated glaciation events, ploidy barriers, and restricted gene flow caused by flowering time differences have resulted in distinct gene pools across ecotypes and geographic regions. These data provide a resource to associate alleles with traits of interest for forage, restoration, and biofuel feedstock efforts in switchgrass.