Coadministration of Voriconazole and Rifabutin Can Increase the Risk of Adverse Drug Reactions in Patients with Multiple Infections.

BACKGROUND: Coinfection of tuberculosis or nontuberculous mycobacteria and Aspergillus presents a challenge in medication selection because of the pharmacokinetic interactions between rifampin and voriconazole. Some researchers have suggested the use of rifabutin as an alternative to rifampin because of its lower hepatic cytochrome P450 enzyme induction potency despite its contraindication to drug labels. This study presents clinical cases of voriconazole and rifabutin coadministration and their potential risks. METHODS: This retrospective study was conducted using clinical data from patients who met the following criteria: (1) admitted to Seoul National University Hospital between July 2014 and August 2023 and (2) concurrently administered rifabutin and voriconazole for more than 5 days. RESULTS: Among the 6 patients analyzed, 4 experienced adverse drug reactions (ADRs). Three patients experienced visual and auditory hallucinations, lower extremity numbness, or delirious behavior. Two patients had prolonged the time from the start of the Q wave to the end of the T wave intervals, and 1 had elevated aspartate aminotransferase and alanine aminotransferase levels. In addition, 2 patients experienced severe nausea, poor oral intake, and weight loss. Despite receiving 1.81-fold the recommended voriconazole dosage, a therapeutic concentration (1.0-5.5 mg/L) was not achieved because of cytochrome P450 induction by rifabutin. However, during septic shock, the voriconazole concentration increased by 13.7- to 36-fold. CONCLUSIONS: Concurrent use of rifabutin and voriconazole was associated with ADRs, including the time from the start of the Q wave to the end of the T wave prolongation, hallucinations, and severe nausea. Moreover, initially, there was a significant decrease in voriconazole concentrations; however, these concentrations substantially increased during septic shock. Therefore, it is essential to monitor drug concentrations and ADRs during concurrent use of voriconazole and rifabutin.

Exploration of pharmacokinetic differences between East Asians and Caucasians: insights from pharmacokinetic studies in healthy subjects.

Interethnic differences in the pharmacokinetics of drugs result from a complex interplay of environmental, genetic, and demographic factors. Identifying ethnic differences in pharmacokinetics is challenging due to the multifaceted contributions of the underlying factors. To address these challenges, this paper reviews 9 pharmacokinetic studies meeting the following criteria: (A) Conducted at Seoul National University Hospital from 2013 to 2022 as a single-center study. (B) Pharmacokinetic studies involving both East Asians (Korean, Japanese, or Chinese) and Caucasians. (C) Study drugs were administered orally. (D) Raw data was provided for reanalysis. This retrospective analysis aimed to investigate the existence of ethnic differences in drug exposure and understand the possible factors contributing to these variabilities. Pharmacokinetic, demographic, and clinical laboratory test data were analyzed to assess potential pharmacokinetic differences between East Asians and Caucasians. This assessment involved calculating the geometric mean ratio of dose-normalized area under the time-concentration curve (AUC) and dose- and weight-normalized AUC, along with their 90% confidence intervals. Additionally, pharmacological information, including metabolic pathways, was gathered from the investigational brochure or the respective country's drug label. Among 9 studies, 4 studies demonstrated approximately 1.3 to 1.8 times higher drug exposure in East Asians compared to Caucasians. These drugs were primarily eliminated through hepatic metabolism, with less than 5% excreted unchanged in the urine. Two drugs were metabolized by hepatic cytochrome P450 3A4, one by glutathione S-transferase, and specific metabolic pathways for another drug were not identified. Further research is needed to assess the causes of ethnic variability in these drugs.

A randomized study to evaluate the safety and immunogenicity of a pentavalent meningococcal vaccine.

A randomized, active-controlled, double-blind, first-in-human, phase 1 study was conducted in healthy Korean adults to evaluate the safety, tolerability, and immunogenicity of EuNmCV-5, a new pentavalent meningococcal vaccine targeting serogroups A, C, W, X, and Y. Sixty participants randomly received a single dose of either EuNmCV-5 or MenACWY-CRM, a quadrivalent vaccine containing serogroups A, C, W, and Y. Safety was assessed through monitoring anaphylactic reactions, adverse events for 28 days, and serious adverse events over 180 days. Immunogenicity was assessed via rabbit complement-dependent serum bactericidal antibody (rSBA) assay. EuNmCV-5 was safe, well-tolerated, and elicited a substantial antibody titer increase. The seroprotection rates exceeded 96.7%, and the seroconversion rates were over 85% for all the targeted serogroups. It showed higher seroconversion rates against serogroups A and C (p = 0.0016 and 0.0237, respectively) and elicited a substantial increase in GMT for all targeted serogroups compared to the MenACWY-CRM.ClinicalTrials.gov identifier: NCT05739292.

Pharmacokinetics and Pharmacodynamics of a Fixed-Dose Combination of Esomeprazole and Magnesium Hydroxide Compared to the Enteric-Coated Esomeprazole.

PURPOSE: A fixed-dose combination (FDC) of proton pump inhibitors (PPIs) and antacid salts enables rapid acid suppression through the neutralizing effect of the antacid salt and the rapid absorption of PPIs. This study aimed to compare the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a recently formulated FDC of esomeprazole and magnesium hydroxide to the enteric-coated esomeprazole in healthy subjects. METHODS: A randomized, open-label, multiple-dose, two-treatment, two-way crossover design was conducted in healthy subjects. Forty-nine subjects were randomized to one of the two treatment sequences and received either the test drug (esomeprazole/magnesium hydroxide 40/350 mg) or reference drug (enteric-coated esomeprazole 40 mg) for 7 days in the first period and the alternative in the second period with a 14-day washout period. Blood samples were collected for up to 24 hours for PK assessment, and 24-hour gastric pH monitoring was conducted for PD assessment both before and after a single administration, as well as at a steady state after seven consecutive days of administration. The PK and PD parameters were compared between the two drugs. FINDINGS: After multiple administrations, the median value of time to reach maximum concentration was faster in the test drug than in the reference drug, with a difference of 1.68 hours. The overall systemic exposure of the test drug was similar to that of the reference drug, and the PK parameter fell within the equivalence criteria. The test drug demonstrated a shorter time to reach gastric pH ≥ 4 compared to the reference drug (P = 0.0463). A decrease from baseline in integrated gastric acidity over 24 hours, which represents the degree of inhibition of gastric acid secretion, was equivalent between the two drugs. IMPLICATIONS: The fixed-dose combination of esomeprazole and magnesium hydroxide showed rapid absorption and quicker gastric acid suppression than enteric-coated esomeprazole with comparable PK and PD properties. CLINICALTRIALS: gov identifier: NCT04324905 (https://classic. CLINICALTRIALS: gov/ct2/show/NCT04324905).

Evaluation of Safety, Tolerability and Pharmacokinetic Characteristics of SA001 and Its Active Metabolite Rebamipide after Single and Multiple Oral Administration.

Dry eye disease (DED) is one of the most common eye diseases caused by multiple factors. Rebamipide, which is currently used to treat peptic ulcer disease, was shown to enhance secretory function and modulate inflammation in animal disease models. Considering the pathophysiology of DED, SA001 was developed expecting enhanced systemic exposure of rebamipide. Clinical trials to evaluate the safety, tolerability and pharmacokinetic (PK) characteristics of SA001 and its active metabolite rebamipide were conducted. After oral administration of SA001, blood and urine samples were collected for PK analysis of SA001 and rebamipide. PK parameters were compared between SA001 and conventional rebamipide (Bamedin®) and also between fasted and fed. Safety and tolerability were evaluated throughout the study based on adverse events (AEs), physical examinations, vital signs, 12-lead electrocardiography and clinical laboratory tests. SA001 was rapidly absorbed and quickly converted to rebamipide. The systemic exposure of rebamipide was dose-proportional after single and multiple doses. The plasma concentration of rebamipide after administration of SA001 was higher with a dose adjusted AUClast and Cmax 2.20 and 5.45 times higher in the 240 mg dose group and 4.73 and 11.94 times higher in the 600 mg dose group compared to conventional rebamipide. The favorable PK and tolerability profiles support further clinical development.

Development of a Fast Onset Proton Pump Inhibitor: Comparison of Fixed-Dose Combination of Rabeprazole and Sodium Bicarbonate (YPI-011) to the Conventional Enteric-Coated Rabeprazole.

Purpose: Proton pump inhibitors (PPIs) are the first-line therapy for gastroesophageal reflux disorder (GERD). Unlike conventional PPIs, non-enteric coated PPIs with antacid salt enable a faster acid suppression through the rapid absorption of the PPI. YPI-011 is a newly developed fixed-dose combination of a rabeprazole with sodium bicarbonate (NaHCO3). This study compared the pharmacokinetics (PKs) and pharmacodynamics (PDs) of YPI-011 to the conventional enteric-coated rabeprazole (Pariet®). Materials and Methods: A randomized, open-label, two-treatment, two-sequence crossover study was conducted with two different doses (10 and 20 mg) and 44 subjects in each group. They randomly received either a test or reference treatment for 7 days in the first period and the other treatment in the second period. Blood samples for the PK analysis were taken after the single- and multiple-dose. Intragastric pH monitoring for the PD analysis was implemented for baseline and after the single- and multiple-dose. Results: Gastric acid suppression evaluated by the percentage decrease from baseline in the integrated gastric acidity for a 24-hour interval after the multiple-dose was similar between the treatments in both dose groups. The systemic exposure of rabeprazole at steady state after the multiple-dose was also similar between the treatments in both dose groups. The time to reach the maximum rabeprazole concentration was faster in the test treatment. The PK-PD relationship of PPI is well known, and the faster absorption of rabeprazole resulted in a more rapid mode of action in acid suppression. Conclusion: The fixed dose combination of rabeprazole with NaHCO3 showed a faster absorption and consequently, a more rapid gastric acid suppression with a similar systemic exposure of rabeprazole at steady state compared to the conventional enteric-coated rabeprazole.

Comparison of the Pharmacokinetics, Safety, and Tolerability of Two Empagliflozin Formulations in Healthy Korean Subjects.

Purpose: Empagliflozin is a sodium-glucose cotransporter 2 inhibitor that is commonly used for the treatment of type 2 diabetes mellitus. As cocrystal formulation can improve the chemical properties of drugs, CKD-370 was newly developed as a cocrystal formulation of empagliflozin with solvate L-proline. This study aimed to compare the pharmacokinetics, safety, and tolerability of these two empagliflozin formulations in healthy Korean subjects. Methods: A randomized, open-label, two-sequence, two-period crossover study was conducted on healthy Korean participants. The subjects received a single oral 25 mg dose of either test (CKD-370) or reference treatment (Jardiance®) tablet at each period. Plasma empagliflozin concentrations were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic (PK) parameters were analyzed using non-compartmental methods. The primary PK parameters included the maximum concentration (Cmax) and the area under the concentration-time curve from 0 to last (AUClast). The safety of both formulations was monitored and evaluated. Results: A total of 28 healthy Korean adult subjects were randomized, and 27 subjects were included in the PK analysis. The mean ± standard deviation values of the primary PK parameters, Cmax and AUClast after administration of the test treatment, were 442.02 ± 103.37 µg/L and 3131.08 ± 529.30 µg·h/L, respectively, and those after administration of the reference treatment were 436.29 ± 118.74 µg/L and 3006.88 ± 514.21 µg·h/L, respectively. The geometric mean ratio and its 90% confidence interval of test to reference treatment for Cmax and AUClast were 1.0221 (0.9527-1.0967) and 1.0411 (1.0153-1.0677), respectively, which were within the commonly accepted bioequivalence criteria of 0.80 to 1.25. Both treatments were well-tolerated. Conclusion: The two formulations of empagliflozin showed similar PK characteristics and were generally well tolerated in healthy subjects.

Safety, tolerability, pharmacokinetic/pharmacodynamic characteristics of bersiporocin, a novel prolyl-tRNA synthetase inhibitor, in healthy subjects.

Bersiporocin, a novel first-in-class prolyl-tRNA synthetase (PRS) inhibitor currently under clinical development, was shown to exert an antifibrotic effect through the downregulation of collagen synthesis in various pulmonary fibrosis models. The aim of this first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-dose, dose-escalation study was to evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of bersiporocin in healthy adults. A total of 40 and 32 subjects were included in a single- (SAD) and multiple-ascending dose (MAD) study, respectively. No severe or serious adverse events were observed after a single oral dose up to 600 mg and multiple oral doses up to 200 mg twice daily for 14 days. The most common treatment-emergent adverse events were gastrointestinal adverse events. To improve the tolerability, initial bersiporocin solution was changed to the enteric-coated formulation. Afterward, the enteric-coated tablet was used in the last cohort of SAD and in the MAD study. Bersiporocin showed dose-proportional PK characteristics after a single dose up to 600 mg and multiple doses up to 200 mg. Upon reviewing the safety and PK data, the final SAD cohort (800 mg enteric-coated tablet) was canceled by the Safety Review Committee. The levels of pro-peptide of type 3 procollagen were lower after treatment with bersiporocin than after the placebo in the MAD study, whereas no significant change was observed in other idiopathic pulmonary fibrosis (IPF) biomarkers. In conclusion, the safety, PK, and PD profile of bersiporocin supported its further investigation in patients with IPF.

Considerations for clinical evaluation of the effects of bariatric surgery on the pharmacokinetics of orally administered drugs.

Obesity has been a growing worldwide concern, and surgical intervention including bariatric surgery is considered as one of the options for treatment. However, there still is controversy over the change in pharmacokinetics (PKs) of drugs after the surgery. To investigate the potential covariates that can influence the area under the curve (AUC) and maximum plasma concentration (Cmax), the design of previous studies was reviewed based on pre-determined eligibility criteria. Each study calculated the ratios of the AUC and Cmax before and after bariatric surgery. These studies investigated whether the PK parameters were affected by the time after the surgery or by the type of control group. The ratio of the AUC calculated in the early and late follow-up period was similar across Roux-en Y gastric bypass patients. No significant difference in the PK parameters was found between the pre-surgical patients and matched healthy subjects. However, certain control groups could be preferable depending on the purpose of the clinical trial. Although Cmax was inconsistent compared to the AUC, insufficient sampling of the time points may have caused such an inconsistency. This is the first article exploring the appropriate methodology in designing clinical studies for changes in the PK characteristics of orally administered drugs in patients with bariatric surgery.

Comparative Pharmacokinetics/Pharmacodynamics of Fixed-Dose Combination of Esomeprazole and Calcium Carbonate (AD-206) to the Conventional Esomeprazole.

PURPOSE: Proton pump inhibitors (PPIs) are used for the treatment of acid-related disorders. Demands for enhanced stability and faster onset led to the development of AD-206, a fixed-dose combination of a PPI (esomeprazole) with an antacid salt (calcium carbonate). This study compared the pharmacokinetics (PKs) and pharmacodynamics (PDs) of AD-206 (Addpharma) with conventional esomeprazole (Nexium®, AstraZeneca). MATERIALS AND METHODS: A randomized, open-label, two-treatment, two-sequence crossover study was conducted with 2 different doses of esomeprazole at 20 and 40 mg with a fixed calcium carbonate dose of 600 mg in AD-206. Forty-four subjects were included in each dose group and randomly received either AD-206 or the conventional esomeprazole for 7 consecutive days in each period. After a single- and multiple-dose, blood samples for the PK analysis were analyzed, and 24-hour intragastric pH monitoring was conducted. RESULTS: The systemic exposure of esomeprazole after a multiple-dose of AD-206 was similar to that of the conventional esomeprazole in both doses, but the time to reach the peak concentration was faster in AD-206. The percentage decrease from baseline in the integrated gastric acidity for a 24-hour interval after the dose was not significantly different between the AD-206 and the conventional esomeprazole after a single- and multiple-dose for both doses, and the time to reach pH 4 was faster for AD-206. CONCLUSION: AD-206 showed a similar systemic exposure and suppression of gastric acid secretion after a multiple-dose compared to the conventional esomeprazole.