Comparison of international guidelines for early-phase clinical trials of cellular and gene therapy products

Cellular and gene therapies (CGT) are promising fields that are bringing significant clinical benefits to patients by directly targeting the underlying cause of disease. In line with this trend, regulatory agencies in every country have been making efforts to accelerate CGT product development. For acceleration, it is necessary to increase the efficiency of clinical trials, thus the early-phase clinical trials for CGT products should be elaborate and productive. The guidelines of international regulatory agencies were compared and analyzed to examine the considerations for the design of early-phase CGT products. The guidelines described a safety evaluation, preliminary evidence of effectiveness gathering, dose exploration, and a feasibility assessment as common objectives of early-phase clinical trials for CGT products. In addition, the considerations for the design of early-phase CGT products included pretreatment effects and problems in the manufacturing and administration process. The guidelines also covered selection of a study population, control group/blinding, and dose/regimen planning. There were differences in the degree of detail, description, and the scope of the content covered by each guideline. The guideline published by FDA was the most specific. However, when compared with the previous guidelines for designing earlyphase clinical trials for small molecules and biologics, the current guidelines need to be revised to suggest more detailed and practical principles and rules.

Bioequivalence of the pharmacokinetics between tofacitinib aspartate and tofacitinib citrate in healthy subjects

Tofacitinib is an oral disease-modifying anti-rheumatic drug to selectively inhibit Janus kinases. Tofacitinib is a representative small molecule inhibitor that is used to treat many diseases including rheumatoid arthritis and various autoimmune conditions.Unlike biological agents, tofacitinib has several advantages, including the ability to be administered orally and a short half-life. This study aimed to evaluate the bioequivalence of the pharmacokinetics (PK) between tofacitinib aspartate 7.13 mg (test formulation) and tofacitinib citrate 8.08 mg (reference formulation; Xeljanz ® ) in healthy subjects. A randomized, open-label, single-dose, 2-sequence, 2-period, 2-treatment crossover trial was conducted in 41 healthy volunteers. A total of 5 mg of tofacitinib as the test or the reference formulation was administered, and serial blood samples were collected up to 14 hours after dosing for PK analyses. The plasma concentration of tofacitinib was determined by ultraperformance liquid chromatography-tandem mass spectrometry. A non-compartmental analysis was used to estimate the PK parameters. A total of 35 subjects completed the study and the study drug was well-tolerated. The mean maximum concentration (Cmax ) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast ) for the test formulation were 52.67 ng/mL and 133.86 ng·h/mL, respectively, and 50.61 ng/mL and 133.49 h·ng/mL for the reference formulation, respectively. The geometric mean ratios (90% confidence intervals) of the Cmax and AUClast between the 2 formulations were 1.041 (0.944–1.148) and 1.003 (0.968–1.039), respectively. Tofacitinib aspartate exhibited bioequivalent PK profiles to those of the reference formulation.Trial Registration: ClinicalTrials.gov Identifier: NCT04278391

Bioequivalence of the pharmacokinetics between tofacitinib aspartate and tofacitinib citrate in healthy subjects

Tofacitinib is an oral disease-modifying anti-rheumatic drug to selectively inhibit Janus kinases. Tofacitinib is a representative small molecule inhibitor that is used to treat many diseases including rheumatoid arthritis and various autoimmune conditions.Unlike biological agents, tofacitinib has several advantages, including the ability to be administered orally and a short half-life. This study aimed to evaluate the bioequivalence of the pharmacokinetics (PK) between tofacitinib aspartate 7.13 mg (test formulation) and tofacitinib citrate 8.08 mg (reference formulation; Xeljanz ® ) in healthy subjects. A randomized, open-label, single-dose, 2-sequence, 2-period, 2-treatment crossover trial was conducted in 41 healthy volunteers. A total of 5 mg of tofacitinib as the test or the reference formulation was administered, and serial blood samples were collected up to 14 hours after dosing for PK analyses. The plasma concentration of tofacitinib was determined by ultraperformance liquid chromatography-tandem mass spectrometry. A non-compartmental analysis was used to estimate the PK parameters. A total of 35 subjects completed the study and the study drug was well-tolerated. The mean maximum concentration (Cmax ) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast ) for the test formulation were 52.67 ng/mL and 133.86 ng·h/mL, respectively, and 50.61 ng/mL and 133.49 h·ng/mL for the reference formulation, respectively. The geometric mean ratios (90% confidence intervals) of the Cmax and AUClast between the 2 formulations were 1.041 (0.944–1.148) and 1.003 (0.968–1.039), respectively. Tofacitinib aspartate exhibited bioequivalent PK profiles to those of the reference formulation.Trial Registration: ClinicalTrials.gov Identifier: NCT04278391

Increasing Prevalence and Mortality of Asthma With Age in Korea, 2002–2015: A Nationwide, Population-Based Study

PURPOSE: The prevalence of asthma is increasing globally as the world population increases; however, and the prevalence and mortality of asthma have not been extensively investigated. Also, the effects of severity and aging on asthma prevalence and mortality are unknown. We aimed to investigate trends of the prevalence and mortality of asthma as well as health care uses and costs over 14 years according to disease severity by using real-world data in Korea.METHODS: Using the National Health Insurance Sharing Service database, we extracted asthmatic patients having diagnosis codes of asthma and prescription records of antiasthmatic medications from 2002 to 2015 and categorized them according to asthma exacerbation and regular treatment. We defined asthma-associated death in terms of patients' prescription records within 3 months before all-cause death, then linked with the Cause of Death Statistics. The annual asthma-related health care uses and costs were analyzed.RESULTS: The prevalence rates of asthma (1.6% to 2.2%) and severe asthma (SA; 3.5% to 6.1% among total asthmatics) have increased steadily over the decade in Korea, where the proportion of elderly asthmatics having increased. The asthma-related health care uses and costs had increased during the study period with the highest uses/costs in SA. The asthma mortality had a steady rising trend from 16.2 to 28.0 deaths per 100,000 with the highest mortality in SA.CONCLUSIONS: The prevalence and mortality of asthma as well as SA increases along with the burden of health care uses/costs. More active interventions, including changes in health care policies, are needed to reduce the prevalence and mortality of asthma, especially SA.

Trabecular Bone Score Is More Sensitive to Asthma Severity and Glucocorticoid Treatment Than Bone Mineral Density in Asthmatics

PURPOSE: In asthmatic patients, treatment with corticosteroids, in addition to conventional risk factors for osteoporosis, may lead to bone loss. Trabecular bone score (TBS) is an indirect new parameter of bone quality. This study aimed to evaluate TBS in asthmatics in comparison to propensity score-matched controls and to investigate correlations between TBS and cumulative systemic and inhaled corticosteroid doses 1 year prior to bone mineral density (BMD) measurement in patients with asthma. METHODS: In total, 627 patients with asthma and the same number of non-asthmatic controls matched for sex and age were included in this retrospective cohort study. TBS was calculated in the lumbar region, based on 2 dimensional projections of dual-energy X-ray absorptiometry. RESULTS: Patients with severe asthma exhibited lower vertebral TBS values (1.32 ± 0.1) than those with non-severe asthma (1.36 ± 0.1, P = 0.001), with non-active asthma (1.38 ± 0.1, P < 0.001), and without asthma (1.39 ± 0.1, P < 0.001). No significant differences in BMD were noted among the study groups. TBS was significantly correlated with cumulative systemic and inhaled corticosteroid doses as well as asthma duration, lung function and airway hyper-responsiveness. A generalized linear model revealed that age, severe asthma, and frequency of oral corticosteroid burst were significant predictors for TBS levels. CONCLUSIONS: TBS can be used as an early indicator of altered bone quality stemming from glucocorticoid therapy or, possibly, more severe asthma.

Erratum: Pharmacokinetics and bioequivalence of two different 20 mg olmesartan tablets: A randomized, single-dose, two-period crossover study in healthy Korean male volunteers

In the published version of this article, an error in the sponsor's identity was discovered in the acknowledgment section.

Pharmacokinetics and bioequivalence of two different 20 mg olmesartan tablets: A randomized, single-dose, two-period crossover study in healthy Korean male volunteers

Olmesartan is an angiotensin receptor blocker (ARB) and is widely used in clinical practice to treat hypertension. To compare the pharmacokinetic (PK) parameters and tolerability of two oral formulations of olmesartan (test drug: OMETAN(R) 20 mg tablet, reference drug: OLMETEC(R) 20 mg tablet) and assess their bioequivalence, a randomized, single dose, two-treatment crossover clinical study was conducted. At each period, 40 subjects received the test drug or the reference drug. Blood samples were collected at pre-dose and up to 48 h after study drug administration of each period. Plasma concentrations of olmesartan were measured using liquid chromatography-tandem mass spectrometry. To evaluate PK profiles, maximum plasma concentration (C(max)) and area under the concentration-time curve from zero to last measurable time (AUC(last)) were estimated using a non-compartmental method. Tolerability was evaluated based on the incidence of adverse events, vital signs, electrocardiograms, and laboratory tests. A total of 39 subjects completed the study. The geometric mean ratio and 90% confidence intervals (CI) of test drug to reference drug were 1.027 (0.969-1.088) for C(max) and 1.014 (0.957-1.074) for AUC(last), respectively. There were no serious adverse events and both formulations of olmesartan were well tolerated. The OMETAN 20 mg tablet was judged to be bioequivalent to the OLMETEC 20 mg tablet.

Pharmacokinetics, Pharmacodynamics and Safety of JES9501 after Single and Multiple Oral Administration in Healthy Subjects

BACKGROUND: JES9501 is dehydroevodiamine, the extract of Evodia rutaecarpa, expected to be a new therapeutic for Alzheimer disease. This study aims to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of JES9501 after single or multiple dosing. METHODS: A double-blind, randomized, placebo-controlled, dose ascending, parallel study was conducted in healthy subjects. A single dose of JES9501 50.100.200.400 or 800 mg and multiple doses of JES9501 100.200 or 400 mg once-daily for 7days was administered. Serial blood and urine samples for PK evaluation were collected. Acetylcholinesterase (AChE) activity was measured for PD evaluation in multiple dose group. RESULTS: In the single dose study, means of dose-normalized peak concentration (Cmax) of 100.200.400 and 800 mg dose group are comparable except 50 mg dose group. Means of dose-normalized area under the plasma concentration-time curve (AUC) from dosing to the last quantifiable concentration of corresponding dose group were similar. At steady state in the multiple dose study, means of dose-normalized Cmax and AUC for dosing interval of 100.200 and 400 mg dose group decreased as the dose increased, however those were not relevant. There was no significant difference of AChE activity between three dosage groups and placebo group. Adverse events related to study drug were all mild and there were no remarkable findings. CONCLUSION: JES9501 was safe and well-tolerated after single or multiple doses in healthy male subjects. Further studies are warranted to evaluate the PK of optimized dosage form and to prove the drug effect in clinical trials for Alzheimer disease patients.