An adaptive design is a clinical trial design that allows for modification of a structured plan in a clinical trial based on data accumulated during pre-planned interim analyses. This flexible approach to clinical trial design improves the success rate of clinical trials while reducing time, cost, and sample size compared to conventional methods. The purpose of this study is to identify the current status of adaptive design and present key considerations for planning an appropriate adaptive design based on specific circumstances. We searched for clinical trials conducted between January 2006 to July 2021 in the Clinical Trials Registry (ClinicalTrials.gov) using keywords specified in the Food and Drug Administration Adaptive Design Clinical Trial Guidelines. In order to analyze the adaptive designs used in selected cases, we classified the results according to the phase of the clinical trial, type of indication, and the specific adaptation method employed. A total of 267 clinical trials were identified on ClinicalTrials.gov. Among them, 236 clinical trials actually applied adaptive designs and were classified according to phase, indication types, and adaptation methods. Adaptive designs were most frequently used in phase 2 clinical trials and oncology research. The most commonly used adaptation method was the adaptive treatment selection design. In the case of coronavirus disease 2019, the most frequently used designs were adaptive platform design and seamless design. Through this study, we expect to provide valuable insights and considerations for the implementation of adaptive design clinical trials in different diseases and stages.

Fetal tachycardia (FT) is a rare disorder and is associated with significant mortality of fetus. Digoxin is one of the antiarrhythmic agents used to treat FT via transplacental therapy. In this report, we describe a therapeutic drug monitoring (TDM) case of digoxin during the treatment of FT. A 40-year-old woman, gravida 2 para 1, hospitalized to control FT as the fetal heart rate (FHR) showed over 200 bpm on ultrasonography at 29 weeks of gestation. She did not have any medical or medication history and showed normal electrolytes level on clinical laboratory test results. For the treatment of FT loading and maintenance dose of intravenous digoxin (loading dose: 0.6 mg; maintenance dose: 0.3 mg every 8 hours) were administered. To monitor the efficacy and safety of the treatment, TDM was conducted with a target maternal serum trough digoxin concentration of 1.0 to 2.0 ng/mL, as well as ultrasonography and maternal electrocardiogram. The observed digoxin serum concentrations were 0.67, 0.83, and 1.05 ng/mL after 1, 2, and 5 days after the initiation of digoxin therapy, respectively. Although the serum digoxin concentrations reached the target range, the FHR did not improve. Therefore, digoxin was discontinued, and oral flecainide therapy was started. The FHR adjusted to the normal range within 2 days from changing treatment and remained stable. TDM of digoxin along with the monitoring of clinical responses can give valuable information for decision-making during the treatment FT.

Objectives: Digital therapeutics (DTx) are software-based therapeutic interventions based on clinical evidence. Randomized clinical trials (RCTs) are often the source of clinical evidence, similar to conventional drugs or medical devices. However, novel approaches such as the use of real-world data or digital biomarkers are also utilized. This article aimed to review how DTx products have been clinically evaluated. Methods: DTx products approved by the US Food and Drug Administration as of 2020 were reviewed and products with sufficient published information were selected. Pivotal clinical trials were analyzed according to the elements of the Consolidated Standards of Reporting Trials (CONSORT) guideline. Case reviews were presented for other clinical evaluation strategies, considering the small number of publications. Results: Most approved DTx products used RCTs for clinical evaluations. Similar to conventional RCTs, parallel-group designs with statistical hypothesis testing were adopted. However, DTx trials were often not blinded due to practical issues and involved various comparator groups. In addition, DTx products could be readily evaluated in home-based settings and delivered through the internet. Other evaluation approaches included retrospective analyses using insurance claims data or usage data, which enabled long-term evaluations of effectiveness. Digital biomarkers obtained from real-time and continuous log data were also used to improve the objectiveness of endpoints. Conclusions RCTs accounted for the majority of DTx evaluations. The designs of DTx trials were comparable to those of drug or device trials, but blinding and comparator elements were often different. Furthermore, the use of real-world data and digital biomarkers are also being tried.

For the treatment of hypertension, fixed-dose combinations (FDCs) of antihypertensive drugs can provide complementary benefits from improved compliance and cost-effectiveness compared with loose combinations of corresponding drugs. A new FDC of fimasartan/ amlodipine/hydrochlorothiazide 60/10/25 mg is undergoing clinical development. A randomized, open-label, single-dose, 3-period, 3-sequence, partially replicated crossover phase 1 study was conducted to compare the pharmacokinetics (PKs) between the FDC of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg and a loose combination of a dual-combination FDC (fimasartan/amlodipine 60/10 mg) and hydrochlorothiazide 25 mg. Sixty healthy subjects were randomized, and 55 subjects completed the study. Serial blood samples were collected, and plasma concentrations of fimasartan, amlodipine and hydrochlorothiazide were measured to analyze PK parameters. The PK profiles of the FDC were similar to those of the loose combinations. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to loose combinations for the maximum plasma concentration (Cmax ) and area under the curve until the last measurable time point (AUClast ) were within the conventional bioequivalent range of 0.80 to 1.25. The GMRs and 90% CIs of fimasartan, amlodipine and hydrochlorothiazide were 1.0163 (0.8681–1.1898), 0.9595 (0.9256–0.9946), and 1.1294 (1.0791–1.1821) for Cmax and 1.0167 (0.9347–1.1059), 0.9575 (0.9317–0.9841), and 1.0561 (1.0170–1.0967) for AUClast , respectively. Both the FDC and loose combinations were well tolerated. In conclusion, the FDC of fimasartan/amlodipine/ hydrochlorothiazide 60/10/25 mg showed similar PK profiles to those of the corresponding loose combination, and both treatments were well tolerated.

Focal epilepsy is the most common type of epilepsy in Korea, and anti-epileptic drugs (AEDs) are the main treatment option for patients. This study aimed to compare the efficacy and safety of AEDs for focal epilepsy through a meta-analysis. The AEDs prescribed in Korea as monotherapy and adjunctive treatment for patients with focal epilepsy were included for analysis. Relevant articles were searched for randomized clinical trials of AEDs and treatment outcomes were analyzed on the basis of the 50% responder rate, seizure-free rate, treatment withdrawal rate, and emergence rates of adverse events (AEs). The odds ratios (ORs) and their 95% confidence intervals (CI) of study outcome were calculated using combined data from multiple studies. A total of 47 studies were included in the meta-analysis. The seizurefree rate, treatment withdrawal rate, and AE rate were not significantly different among the AEDs recommended for monotherapy. Among the AEDs recommended for adjunctive treatment, topiramate and oxcarbazepine yielded the highest OR in comparison with placebo for each efficacy parameter: the 50% responder rate for topiramate = 6.42 (3.76–11.6) and the seizure-free rate for oxcarbazepine = 32.7 (6.05–899). The third-generation AEDs (brivaracetam and perampanel) yielded relatively better safety outcomes than other AEDs. In general, the 50% responder rate and treatment withdrawal rate tended to increase as the dose of the AEDs increased. The results from the current meta-analysis of the efficacy and safety data of various AEDs may provide insight into optimal pharmacotherapy for the treatment of focal epilepsy.

Genetic polymorphisms of enzymes and transporters associated with the absorption, distribution, metabolism, and elimination (ADME) of drugs are one of the major factors that contribute to interindividual variations in drug response. In the present study, we aimed to elucidate the pharmacogenetic profiles of the Korean population using the Affymetrix Drug Metabolizing Enzyme and Transporters (DMET™) platform. A total of 1,012 whole blood samples collected from Korean subjects were genotyped using the DMET™ plus microarray. In total, 1,785 single nucleotide polymorphism (SNP) markers for 231 ADME genes were identified. The genotype and phenotype of 13 clinically important ADME genes implemented in the Clinical Pharmacogenetics Implementation Consortium guidelines were compared among different ethnic groups. Overall, the genotype frequencies of the Korean population were similar to those of the East Asian population. Several genes, notably CYP2C19 and VKORC1, showed marked differences in Koreans compared to Europeans (EURs) or Africans (AFRs). The percentage of CYP2C19 poor metabolizers was 15% in Koreans and less than 3% in EURs or AFRs. The frequencies of causative SNPs of the VKORC1 gene for the low warfarin dose phenotype were 90%, 60%, and 10% in Koreans, EURs and AFRs, respectively. Our findings can be utilized for optimal pharmacotherapy in Korean patients.

Tamsulosin, an alpha-1 adrenoreceptor antagonist, has been used as a primary option for medical treatment of benign prostate hyperplasia. An open-label, single-dose, randomized, three-treatment, three-period, three sequence crossover study was conducted to evaluate the pharmacokinetics (PKs) of 0.2 and 0.4 mg tamsulosin hydrochloride (HCl) in the fed versus the fasted state. Subjects were randomly assigned to three sequences and received one of the following treatments at each period: tamsulosin HCl 0.2 or 0.4 mg in the fed state with a high-fat meal, or tamsulosin HCl 0.4 mg in the fasted state. Blood samples for the PK analysis were collected at pre-dose and up to 48 h post-dose. The PK parameters were calculated by a non-compartmental method. The geometric mean ratio (GMR) and its 90% confidence intervals (CIs) of the plasma maximum concentration (C max ) and area under concentration curve from time zero to last measurable concentration (AUClast) were calculated. Twenty-two subjects completed the study. The systemic exposure of tamsulosin 0.4 mg decreased approximately 9% in the fed state compared to the fasted state, and the time to reach peak concentration was slightly delayed in the fed state. The dose normalized GMR and its 90% CIs of C max and AUClast for 0.2 and 0.4 mg tamsulosin in the fed state were within 0.8 and 1.25 range. Systemic exposure of tamsulosin was decreased in the fed condition compared to the fasted condition. Linear PK profiles were observed between 0.2 and 0.4 mg tamsulosin in the fed state.

Tamsulosin, an alpha-1 adrenoreceptor antagonist, has been used as a primary option for medical treatment of benign prostate hyperplasia. An open-label, single-dose, randomized, three-treatment, three-period, three sequence crossover study was conducted to evaluate the pharmacokinetics (PKs) of 0.2 and 0.4 mg tamsulosin hydrochloride (HCl) in the fed versus the fasted state. Subjects were randomly assigned to three sequences and received one of the following treatments at each period: tamsulosin HCl 0.2 or 0.4 mg in the fed state with a high-fat meal, or tamsulosin HCl 0.4 mg in the fasted state. Blood samples for the PK analysis were collected at pre-dose and up to 48 h post-dose. The PK parameters were calculated by a non-compartmental method. The geometric mean ratio (GMR) and its 90% confidence intervals (CIs) of the plasma maximum concentration (C max ) and area under concentration curve from time zero to last measurable concentration (AUClast) were calculated. Twenty-two subjects completed the study. The systemic exposure of tamsulosin 0.4 mg decreased approximately 9% in the fed state compared to the fasted state, and the time to reach peak concentration was slightly delayed in the fed state. The dose normalized GMR and its 90% CIs of C max and AUClast for 0.2 and 0.4 mg tamsulosin in the fed state were within 0.8 and 1.25 range. Systemic exposure of tamsulosin was decreased in the fed condition compared to the fasted condition. Linear PK profiles were observed between 0.2 and 0.4 mg tamsulosin in the fed state.

In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials.
Chromatography, Liquid ; Drug-Related Side Effects and Adverse Reactions ; Incidence ; Mass Screening ; Mass Spectrometry ; Metabolomics ; Pharmacogenetics* ; Plasma ; Real-Time Polymerase Chain Reaction

BACKGROUND: Current dilemma working with surgically-induced OA (osteoarthritis) model include inconsistent pathological state due to various influence from surrounding tissues. On the contrary, biochemical induction of OA using collagenase II has several advantageous points in a sense that it does not involve surgery to induce model and the extent of induced cartilage degeneration is almost uniform. However, concerns still exists because biochemical OA model induce abrupt destruction of cartilage tissues through enzymatic digestion in a short period of time, and this might accompany systemic inflammatory response, which is rather a trait of RA (rheumatoid arthritis) than being a trait of OA. METHODS: To clear the concern about the systemic inflammatory response that might be caused by abrupt destruction of cartilage tissue, OA was induced to only one leg of an animal and the other leg was examined to confirm the presence of systemic degenerative effect. RESULTS: Although the cartilage tissues were rapidly degenerated during short period of time upon biochemical induction of OA, they did not accompanied with RA-like process based on the histology data showing degeneration of articular cartilage occurred only in the collagenase-injected knee joint. Scoring evaluation data indicated that the cartilage tissues in non-induced joint remained intact. Neutrophil count transiently increase between day 8 and day 16, and there were no significant change in other complete blood count profile showing a characteristics of OA disease. CONCLUSION: These study shows that biochemically induced cartilage degeneration truly represented uniform and reliable OA state.
Animals* ; Blood Cell Count ; Cartilage ; Cartilage, Articular ; Clothing ; Collagenases* ; Digestion ; Inflammation ; Joints ; Knee Joint ; Leg ; Models, Animal* ; Neutrophils ; Osteoarthritis* ; Regeneration