The effect of renal function on the pharmacokinetics and pharmacodynamics of enavogliflozin, a potent and selective sodium-glucose cotransporter-2 inhibitor, in type 2 diabetes.

AIMS: To explore the effect of renal function on the pharmacokinetic (PK) and pharmacodynamic (PD) profile and safety of enavogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: An open-label, two-part clinical trial was conducted in T2DM patients, stratified by renal function: Group 1, normal renal function; Group 2, mild renal impairment (RI); Group 3, moderate RI; and Group 4, severe RI. In Part A, Groups 2 and 4 received enavogliflozin 0.5 mg once. In Part B, Groups 1 and 3 received enavogliflozin 0.5 mg once daily for 7 days. Serial blood and timed urine samples were collected to analyse the PK and PD characteristics of enavogliflozin. Pearson's correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL). RESULTS: A total of 21 patients completed the study as planned. The area under the curve (AUC) for enavogliflozin was not significantly correlated with CrCL, although the maximum concentration slightly decreased as renal function decreased. By contrast, daily urinary glucose excretion (UGE) was positively correlated with CrCL after both single- (r = 0.7866, p < 0.0001) and multiple-dose administration (r = 0.6606, p = 0.0438). CONCLUSIONS: Systemic exposure to oral enavogliflozin 0.5 mg was similar among the patients with T2DM regardless of their renal function levels. However, the glucosuric effect of enavogliflozin decreased with RI. Considering the UGE observed and approved therapeutic use of other SGLT2 inhibitors, the efficacy of enavogliflozin with regard to glycaemic control could be explored in patients with mild and moderate RI (estimated glomerular filtration rate ≥30 or ≥45 mL/min/1.73 m2) in a subsequent larger study.

Pharmacokinetics and Pharmacodynamics of Esomezol DR, a New Dual Delayed-Release Formulation of Esomeprazole 20 Mg or 40 Mg, in Healthy Subjects.

Background: Esomeprazole, a proton pump inhibitor (PPI), is widely used to treat acid-related disorders, but it has short plasma half-life which can cause insufficient gastric acid suppression, such as nocturnal acid breakthrough. A new dual delayed-release (DR) formulation of esomeprazole (Esomezol DR), was developed to extend the duration of gastric acid suppression. Purpose: This study aimed to evaluate the pharmacokinetics (PKs) and pharmacodynamics (PDs) of esomeprazole for the DR formulation compared to a conventional enteric-coated (EC) formulation (Nexium) in healthy male subjects. Methods: Two randomized, open-label, multiple-dose, two-way crossover studies with esomeprazole 20 mg and 40 mg were conducted. Subjects received the DR formulation or the EC formulation once daily for 7 days in each period with a 7-day washout. Serial blood samples were collected up to 24 hours after the 1st dose, and 24-hour intragastric pH was continuously monitored before the 1st dose as baseline and after the 1st and the 7th dose. Results: In 20 mg and 40 mg dose groups, 38 and 44 subjects completed the study, respectively. The DR formulation exhibited the dual-release pattern of esomeprazole, resulting in more sustained plasma concentration-time profiles compared to the EC formulation. The systemic exposure of esomeprazole for the DR formulation was comparable to that for the EC formulation, showing the similar area under the plasma concentration-time curve. The 24-hour gastric acid suppression was also similar between the two formulations, while the inhibition during night-time (22:00-06:00) showed a better tendency in the DR formulation. Conclusion: The sustained exposure of esomeprazole in the DR formulation led to well-maintained and higher acid inhibition compared to the EC formulation, especially during the night-time. These results suggest that the DR formulation can be an alternative formulation to the conventional EC formulation, expecting the potential of relieving nocturnal acid-related symptoms.

Pharmacokinetics of Ginsenoside Compound K From a Compound K Fermentation Product, CK-30, and From Red Ginseng Extract in Healthy Korean Subjects.

Natural protopanaxadiol ginsenosides exhibit low absorption in the human intestine. However, ginsenoside compound K (CK) with 1 conjugated glucose molecule exhibits favorable absorption. The purpose of this study was to compare the pharmacokinetics of ginsenoside CK from a CK fermentation product, CK-30, and from a red ginseng extract. A randomized, open-label, 2-treatment, 2×2 crossover study was conducted. The volunteers were randomly divided into 2 groups. One group received CK-30, and the other group received 2.94 g of a red ginseng extract. After a 7-day washout period, the subjects received an alternative treatment for a single dose. The pharmacokinetic parameters, including the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to time of last measurable concentration, were calculated. The median time to reach Cmax of ginsenoside CK after administration of CK-30 was 3.0 hours, whereas the corresponding value of the red ginseng extract was 10.0 hours. Compared with the red ginseng extract, CK-30 resulted in a higher systemic exposure to ginsenoside CK, with a 118.3-fold increase in Cmax and a 135.1-fold increase in area under the plasma concentration-time curve from time 0 to time of last measurable concentration. The systemic exposure to ginsenoside CK was significantly higher after administration of CK-30 than red ginseng extract.

Pharmacogenomic information from CPIC and DPWG guidelines and its application on drug labels.

There are several hurdles to overcome before implementing pharmacogenomics (PGx) in precision medicine. One of the hurdles is unawareness of PGx by clinicians due to insufficient pharmacogenomic information on drug labels. Therefore, it might be important to implement PGx that reflects pharmacogenomic information on drug labels, standard of prescription for clinicians. This study aimed to evaluate the level at which PGx was being used in clinical practice by comparing the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines and drug labels of the US Food and Drug Administration (FDA) and the Korea Ministry of Food and Drug Safety (MFDS). Two PGx guidelines and drugs labels were scrutinized, and the concordance of the pharmacogenomic information between guidelines and drug labels was confirmed. The concordance of the label between FDA and MFDS was analyzed. In FDA labels, the number of concordant drug with guidelines was 24, while 13 drugs were concordant with MFDS labels. The number of drugs categorized as contraindication, change dose, and biomarker testing required was 7, 12 and 12 for the FDA and 8, 5 and 4 for the MFDS, respectively. The pharmacogenomic information of 9 drugs approved by both FDA and MFDS was identical. In conclusion, pharmacogenomic information on clinical implementation guidelines was limited on both FDA and MFDS labels because of various reasons including the characteristics of the guidelines and the drug labels. Therefore, more effort from pharmaceutical companies, academia and regulatory affairs needs to be made to implement pharmacogenomic information on drug labels.

Evaluation of the pharmacokinetics and food effects of a novel formulation tamsulosin 0.4 mg capsule compared with a 0.2 mg capsule in healthy male volunteers.

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 (Cmax) 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 Cmax 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. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02529800.

Pharmacodynamics of tegoprazan and revaprazan after single and multiple oral doses in healthy subjects.

BACKGROUND: Potassium-competitive acid blockers (P-CABs) are emerging as novel treatments for acid-related disorders including gastroesophageal reflux disease. Tegoprazan and revaprazan are approved P-CABs in South Korea, but the pharmacodynamics and safety/tolerability of the two drugs have never been compared. AIMS: To evaluate the pharmacodynamics and safety/tolerability of tegoprazan and revaprazan after single and multiple oral doses METHODS: A randomised, open-label, active-controlled study was conducted in Helicobacter pylori-negative healthy Korean male subjects. Tegoprazan 50 mg or revaprazan 200 mg was administered orally, once daily for 7 days; 24-h intragastric pH monitoring and serum gastrin were measured for pharmacodynamic evaluation. Safety parameters including serum microRNA-122 (miR-122) level were also collected. RESULTS: After a single dose, the %Time pH ≥4 for tegoprazan was greater than that for revaprazan (54.5% vs 25.1%). After multiple doses, the %Time pH ≥4 for tegoprazan was also greater than that for revaprazan (68.2% vs 25.3%). %Time pH ≥4 during 12 hours at nighttime for tegoprazan was greater than that for revaprazan (71.8% vs 31.9%). The changes in the serum gastrin were not clinically significant for either drug. Despite the slight increases of serum miR-122 for each drug, tegoprazan and revaprazan were well tolerated considering other safety parameters including AST and ALT levels. CONCLUSION: Tegoprazan 50 mg showed stronger gastric acid suppression than revaorazan 200 mg. Both drugs were well tolerated.