Incorporation of real-world data to a clinical trial: use of external controls

As real-world data (RWD) becomes more available and the methodology for handling RWD evolves, the use of RWD in drug development and drug approval is drawing interest. One of the ways RWD can be applied to a clinical trial is using an external control, a cohort of patients established separately serving as a control group for the clinical trial’s treatment group. Although external controls have the possibility of bias as a result of differences in baseline characteristics between the external control and experimental groups, selecting an appropriate data source and ensuring comparability through proper handling of the data can increase the utility of external controls, raising the efficiency of drug development. This article discusses several topics relevant to using external controls in clinical trials, including the definition of external control, the selection of data sources, the strategy ensuring comparability, current regulatory circumstances, and future directions.

Possibility of pharmacokinetic drug interaction between a DPP-4 inhibitor and a SGLT2 inhibitor

Type 2 diabetes mellitus is a multifactorial condition characterized by high level of sugar in the blood. To control hyperglycemia, combination therapy is recommended if monotherapy fails to achieve glycemic control. The combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a sodium-glucose cotransporter type 2 (SGLT2) inhibitor is a promising option of the combination therapies in terms of safety as well as efficacy. Despite of the value of combination therapy of these two agents, the pharmacokinetic drug interactions between these two classes of agents have been evaluated in a few drugs. Thus, we reviewed the potential pharmacokinetic drug interaction based on the in vitro metabolism- and transporter-mediated drug interaction information as well as drug interaction studies in human, between a DPP-4 inhibitor and a SGLT2 inhibitor which are marketed in South Korea.

Pharmacokinetics of fixed-dose combination of rosuvastatin 20 mg and ezetimibe 10 mg compared to concurrent administration of individual tablets in healthy Korean subjects

This study aimed to compare the pharmacokinetics of fixed-dose combination (FDC) tablet of rosuvastatin 20 mg/ezetimibe 10 mg with that of concurrent administration of individual rosuvastatin 20 mg tablet and ezetimibe 10 mg tablet in healthy subjects. A randomized, open label, single-dose, two-way crossover study was conducted. Subjects randomly received test formulation (FDC tablet of rosuvastatin 20 mg/ezetimibe 10 mg) or reference formulation (co-administration of rosuvastatin 20 mg tablet and ezetimibe 10 mg tablet). After 2 weeks of washout, subjects received the other treatment. Blood samples were collected up to 72 hours post-dose in each period. Plasma concentrations of rosuvastatin, ezetimibe and total ezetimibe (ezetimibe + ezetimibe glucuronide) were analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). The geometric mean ratio (GMR) of Cmax and AUClast (90% confidence interval, CI) for rosuvastatin was 1.036 (0.979–1.096) and 1.024 (0.981–1.070), respectively. The corresponding values for ezetimibe were 0.963 (0.888–1.043) and 1.021 (0.969–1.074), respectively. The corresponding values for total ezetimibe were 0.886 (0.835–0.940) and 0.983 (0.946–1.022), respectively. FDC tablet containing rosuvastatin 20 mg and ezetimibe 10 mg is bioequivalent to the co-administration of commercially available individual tablets of rosuvastatin and ezetimibe as GMR with 90% CI of Cmax and AUClast of rosuvastatin, ezetimibe and total ezetimibe were contained within conventionally accepted bioequivalence criteria.

Comparison of Plasma Concentrations of Posaconazole with the Oral Suspension and Tablet in Korean Patients with Hematologic Malignancies

The posaconazole tablet formulation was developed to have improved bioavailability compared to the oral suspension. Here, we compared posaconazole plasma concentration (PPC) with the posaconazole oral suspension versus the tablet in Korean patients undergoing remission induction chemotherapy for hematologic malignancies. PPC was measured at 3, 8, and 15 days of treatment with the oral suspension (174 patients) or the tablet (40 patients). At all time-points, mean PPC was significantly higher with the tablet compared to the oral suspension. Our findings suggest that posaconazole tablets generate an optimal PPC earlier and in more patients than the oral suspension among Korean patients.

Bioequivalence of the pharmacokinetics between two formulations of 0.2 mg tamsulosin hydrochloride in healthy subjects

Tamsulosin is an effective therapeutic option for lower urinary tract symptoms, as it selectively blocks alpha1A- and alpha1D-adrenoceptors in the bladder and prostate. The purpose of this study was to evaluate the bioequivalence in the pharmacokinetics (PK) of two 0.2 mg tamsulosin formulations when administered as the reference formulation (Yuropa(R) sustained-release tablet) vs. the test formulation (Yutanal(R) capsule) in healthy male subjects. A randomized, open-label, single-dose, two-way, two-period, crossover study was conducted in 37 healthy volunteers. The 0.2 mg of tamsulosin as the test or the reference formulation were administered during each period, and serial blood samples were collected up to 36 hours after dosing for PK analyses. A non-compartmental analysis was used to estimate the PK parameters. Geometric mean ratios (GMR) and 90% confidence inter-vals (CIs) were calculated for the two formulations to compare the maximum concentration (Cmax) and the area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast). The mean Cmax and AUClast for the test formulation were 6.19 microg/L and 71.30 microg.h/L, respectively, and 5.76 microg/L and 70.38 microg.h /L for the reference formulation, respectively. The GMRs (90% CIs) of the Cmax and AUClast between the two formulations were 1.09 (1.01-1.17) and 1.03 (0.96-1.10), respectively. Tamsulosin 0.2 mg as the test formulation exhibited bioequivalent PK profiles to those of the reference formulation. Therefore, the test formulation is expected to be an alternative to the reference formulation without concerns about differences in drug exposure.

Clinical characteristics of children with 2009 pandemic influenza A (H1N1) admitted in a single institution / 소아과

PURPOSE: This study aims to investigate the clinical characteristics of children diagnosed with the novel influenza A (H1N1) in the winter of 2009 at a single medical institution. METHODS: Out of 545 confirmed cases of influenza A (H1N1) in children, using the real time RT-PCR method at Kosin University Gospel Hospital from September to December of 2009, 149 patients and their medical records were reviewed in terms of symptoms, laboratory findings, complications and transmission within a family. RESULTS: Median age of subjects was 7 years (range: 2 months-18 years). New cases increased rapidly from September to reach a peak in November, then declined rapidly. Most frequently observed symptoms were fever (96.7%), cough (73.2%), rhinorrhea (36.9%) and sore throat (31.5%). Average body temperatures on the 1st, 2nd and 3rd hospital day were 38.75+/-0.65degrees C, 38.08+/-0.87degrees C and 37.51+/-0.76degrees C, respectively. Complete blood counts and biochemical tests performed on the first admission day showed within the reference values in most cases. Of the 82 patients with simple chest radiography, 18 (22%) had pneumonic lesions; multi-focal bronchopneumonia in eleven, single or multi-segmental lobar pneumonia in five, and diffuse interstitial pneumonia in two patients. All of the 149 patients improved from their symptoms and discharged within 9 days of admission without any late complication. CONCLUSION: Children with 2009 pandemic influenza A (H1N1) at our single institution displayed nonspecific symptoms and laboratory findings, resembling those of common viral respiratory illnesses, and did not appear to develop more severe disease.

The Changes of Neurologic Injury and Cytokine mRNA Expression according to Spinal Ischemia Time in the Rat / 대한마취과학회지

BACKGROUND: Spinal cord ischemia initiates a deleterious cascade of biochemical events that ultimately result in an increased intracellular calcium concentration. Many papers have been published on this topic but without a clear consensus on the best way of minimizing the problem. For the further study of preventing neurological injury after spinal ischemia, the proper animal model is necessary. In this study we compared spinal ischemia time on neurologic and histopathologic outcome, and inflammatory gene expression in transient spinal ischemia. METHODS: Rats were anesthetized with halothane, and divided into 4 groups:12.5 minutes of spinal ischemia (Group 1), 15 minutes of spinal ischemia (Group 2), 17.5 minutes of spinal ischemia (Group 3), and 20 minutes of spinal ischemia (Group 4). Spinal ischemia was produced by both induced hypotension and thoracic aortic cross clamping. After spinal ischemia neurologic scores were assessed after 1, 3, 6, and 24 hours. After 24 hours, rats were euthanized and spinal cords were removed for histopathologic assessment and an assay of TNF-alpha and IL-1 mRNA. RESULTS: The neurologic scores worsened according to the ischemia time. The histopathologic scores correlated well with the neurologic scores. The TNF-alpha and IL-1 mRNA expression results of group 2 were larger than those of group 1. There were no significant differences between group 2, group 3, and group 4. CONCLUSIONS: Inflammatory gene expressions are increased during transient spinal ischemia. After 15 minutes of ischemia, no further increase of mRNA expression was shown. The 15 minutes of spinal ischemia was sufficient for the spinal ischemic study in rats.