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This study aimed to estimate individual pharmacokinetic (PK) parameters in an obese hemodialysis (HD) patient receiving gentamicin and to assess the impact of obesity on gentamicin clearance (CL). A 53-year-old obese Korean woman underwent HD and received gentamicin. To estimate individual PK parameters, we employed the POSTHOC option using NONMEM® 7.4.4. A priori model contained HD as a covariate for CL during HD, and creatinine CL (CrCL), normalized by the group mean value from the a priori model, as a covariate for non-HD CL (CLNHD). Individual CLNHD exhibited a substantial reduction from the population CLNHD, with the value corresponding to 36% of the a priori model's population PK (popPK) parameter. The patient's CrCL exceeded the group maximum of the a priori information, suggesting inaccurate renal function representation. After adjusting CrCL to the group mean from the a priori model, the patient's CLNHD was 138% of the population's typical value. The objective function value for each run was 0.53 and -4.49, respectively. The patient's CLNHD was greater than the popPK parameter value but less than the popPK parameter value when estimated using the patient's original CrCL. Meanwhile, another software (Monolix®; version 2024R1) gave similar results. This study shows the importance of individualized PK parameter estimation, particularly in obese HD patients, and highlights the potential impact of factors including obesity on gentamicin CL. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Coproporphyrin (CP)-I and CP-III are the markers of organic anion-transporting polypeptides' (OATPs) activities, and they are porphyrin metabolites that originate from heme synthesis. Furthermore, CP-I and CP-III, which are OATP1B endogenous metabolites, have gradually attracted the attention of scientists and researchers in recent years. Previous studies have also observed CP-I and CP-III levels as clinical biomarkers for predicting OATP1B inhibition in drug-drug interaction studies. To establish an accurate ultra-high performance liquid chromatography-mass spectrometry method for the quantitation of CP-I and CP-III, we reviewed previous methodological publications and applied them to a clinical pharmacology study using a human urine matrix. We used 13.25 M formic acid as a working solution for internal standards (CP-I 15N4 and CP-III d8) to avoid isobaric interference. The calibration curve showed good linearity in the range of 1-100 ng/mL, with a correlation coefficient (R2) higher than 0.996 in each validation batch. Both the between-run and within-run assays achieved good precision and accuracy, and we found that both CP-I and CP-III were stable in the prestudy validation. The method exhibited suitable dilution integrity, allowing for the re-analysis of samples with concentrations exceeding the upper limit of quantification through dilution. Overall, the application of the described method in a clinical study revealed that it can be utilized effectively to monitor drug-drug interactions mediated by OATP1B. [ABSTRACT FROM AUTHOR]

Trimethylamine N-oxide (TMAO) is a small molecular amine oxide generated from dietary choline and carnitine through intestinal microbial metabolism. Recently, TMAO has attracted much public attention as its role in disease progression has been proven in many clinical studies. The plasma concentration of TMAO in humans was found to be positively associated with the increased risk of many diseases including cardiovascular diseases and chronic kidney diseases. To achieve accurate and sensitive quantitation of TMAO for clinical applications, we established and validated a simple quantitative method using a liquid chromatography tandem mass spectrometry (LC-MS/MS) system. We constructed an eight-point calibration curve in an artificial surrogate matrix instead of the commonly used biological matrices to avoid interference from the endogenous TMAO. The calibration curve showed excellent linearity in the range of 1 to 5,000 ng/mL, with a correlation coefficient (R2) higher than 0.996 in each validation batch. Moreover, both the intra-day and inter-day assays achieved satisfactory precision and accuracy results ranging from 1.65-7.15% and 96.36-111.43%, respectively. Further, this method was cross-validated using a human plasma matrix and applied to a clinical pharmacology study. Overall, these results demonstrate that the developed quantitation method is applicable in clinical research for monitoring disease progression and evaluating drug effects. [ABSTRACT FROM AUTHOR]

Cytochrome P450 (CYP) 3A enzymes, the most important phase 1 drug-metabolizing enzymes, are responsible for 50% of the metabolism of clinically used drugs. CYP3A activity varies widely among individuals, which can affect the probability of adverse drug reactions and drug-drug interactions mediated by the induction or inhibition of the enzyme. Hence, it is important to be able to predict CYP3A activity in individuals to reduce the incidence of unexpected drug responses. To specifically and quickly measure CYP3A activity, we developed method based on gas chromatography interfaced with triple-quadrupole mass spectrometry for the quantification of cortisol, cortisone, 6β-hydroxycortisol, and 6β-hydroxycortisone simultaneously in urine and 4β-hydroxycholesterol in plasma. The results were calculated based on charcoal-stripped steroid-free urine and plasma control samples. The accuracy and precision were 93.18% to 110.0% and 1.96% to 5.34%, respectively. This method was then applied to measure endogenous steroids from urine and plasma samples of healthy Korean males and females. The calibration curves of all analytes showed good linearity with a correlation coefficient (r²) that ranged from 0.9953 to 0.9999. Therefore, this validated method can be used to measure endogenous biomarkers to predict CYP3A activity and might be applicable in the prediction of CYP3A-mediated drug interactions of new drug candidates. [ABSTRACT FROM AUTHOR]

This study aimed to assess the pharmacokinetics of cyclosporine A (CsA) in Asian children with renal impairment (RI) by developing a physiologically-based pharmacokinetic (PBPK) model with Simcyp Simulator. The PBPK model of Asian children with RI was developed by modifying the physiological parameters of the built-in population libraries in Simcyp Simulator. The ratio of healthy and RI populations was obtained for each parameter showing a difference between the populations. Each ratio was multiplied by the corresponding parameter in healthy Asian children. The model verification was performed with published data of Korean children with kidney disease given multiple CsA administrations. Simulations were performed with different combinations of ethnicity, age, and renal function to identify the net impact of each factor. The simulated results suggested that the effect of RI was higher in children than adults for both Caucasian and Asian. In conclusion, the constructed model adequately characterized CsA pharmacokinetics in Korean children with RI. Simulations with populations categorized by ethnicity, age, and renal function enabled to assess the net impact of each factor on specific populations. [ABSTRACT FROM AUTHOR]

Digital therapeutics (DTx) is a new subsection of digital health that is primarily driven by software and will be of great interest to clinical pharmacologists. In this article, an overview of DTx, including definition, position in the landscape of therapeutics, product categories, benefits, and challenges, is provided. Discussions from the point of view of clinical pharmacology are presented, as DTx should have exposure-response relationships. The principles of clinical pharmacology can be applied to DTx as they are comparable to pharmacotherapy. Clinical pharmacology has great potential in the development, application, and regulation of DTx. [ABSTRACT FROM AUTHOR]

Metformin, an oral hypoglycemic agent belonging to biguanide class, is widely used to treat type 2 diabetes mellitus, and several drug transporters such as organic cation transporters (OCTs), multidrug and toxin extrusion transporter (MATE), and plasma membrane monoamine transporter (PMAT) are thought to affect its disposition. We evaluated the role of PMAT genetic variations on the pharmacokinetic characteristics of metformin in a Korean population. In this retrospective study, 91 healthy subjects from four different metformin pharmacokinetic studies were analyzed; in each study, the subjects were administered two oral doses of metformin at intervals of 12 hours and dose-normalized pharmacokinetic parameters were compared between the subjects' genotypes. Subjects who had more than one allele of c.883-144A>G single nucleotide polymorphism (SNP) in PMAT gene (rs3889348) showed increased renal clearance of metformin compared to wild-type subjects (814.79 ± 391.73 vs. 619.90 ± 195.43 mL/min, p=0.003), whereas no differences in metformin exposure were observed between the PMAT variant subjects and wild-type subjects. Similarly, subjects with variant rs316019 SNP in OCT2 showed decreased renal clearance of metformin compared to wild-type subjects (586.01 ± 160.54 vs. 699.13 ± 291.40 mL/min, p=0.048). Other SNPs in PMAT and MATE1/2-K genes did not significantly affect metformin pharmacokinetics. In conclusion, the genetic variation of c.883-144A>G SNP in PMAT significantly affects the renal clearance of metformin in healthy Korean male subjects. [ABSTRACT FROM AUTHOR]

Because bioequivalence studies are performed using a crossover design, information on the intrasubject coefficient of variation (intra-CV) for pharmacokinetic measures is needed when determining the sample size. However, calculated intra-CVs based on bioequivalence results of identical generic drugs produce different estimates. In this study, we collected bioequivalence results using public resources from the Ministry of Food and Drug Safety (MFDS) and calculated the intra-CVs of various generics. For the generics with multiple bioequivalence results, pooled intra-CVs were calculated. The estimated intra-CVs of 142 bioequivalence studies were 14.7±8.2% for AUC and 21.7±8.8% for Cmax. Intra-CVs of Cmax were larger than those of area under the concentrationtime curve (AUC) in 129 studies (90.8%). For the 26 generics with multiple bioequivalence results, the coefficients of variation of intra-CVs between identical generics (mean±sd (min ~ max)) were 38.0±24.4% (1.9 ~ 105.3%) for AUC and 27.9±18.2% (4.0 ~ 70.1%) for Cmax. These results suggest that substantial variation exists among the bioequivalence results of identical generics. In this study, we presented the intra-CVs of various generics with their pooled intra-CVs. The estimated intra-CVs calculated in this study will provide useful information for planning future bioequivalence studies. (This is republication of the article 'Transl Clin Pharmacol 2017;25:179-182' retracted from critical typographic errors. See the 'Retraction and Republication section of this issue for further information). [ABSTRACT FROM AUTHOR]

The causes and attributing factors of drug-induced liver injury (DILI) remain unclear as a result of exclusion-based diagnosis and low incidence. The aim of this study was to explore and evaluate potential drug-related causes and factors associated with DILI. Using electronic medical records (EMR) from the Seoul National University Bundang Hospital from 2003 to 2014, patients with DILI events were identified based on liver function test results. All patients with hepatic or biliary diseases were excluded. Patient characteristics, including demographics, clinical patterns, and severity of DILI were summarized and their associations were evaluated. Drugs frequently prescribed to patients exhibiting DILI within the month before their first DILI event compared to the total patient population were identified and the probabilities of hepatotoxicity associated with their use were assessed through examination of available reports. Among the 1,835 patients with laboratory test results, 1,023 were male and 1,053 were 65 years of age or older. Moderate DILI was dominant in older or male patients and cholestatic DILI tended to be more frequently identified in older patients of either sex. Cytarabine was the most frequently prescribed drug in DILI patients, followed by aprotinin and dopamine. Among the 30 most frequently prescribed drugs in DILI patients, 15 (50%) were identified as known hepatotoxic agents. In conclusion, this study evaluated differences in features of DILI among groups based on demographics and explored candidate drugs with possible associations with DILI, which has potential value reflecting real-world clinical practice. [ABSTRACT FROM AUTHOR]

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® 20 mg tablet, reference drug: OLMETEC® 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 (Cmax) and area under the concentration-time curve from zero to last measurable time (AUClast) were estimated using a noncompartmental 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 Cmax and 1.014 (0.957-1.074) for AUClast, 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. [ABSTRACT FROM AUTHOR]

The aging process is linked to changes in the physiological function of organs and changes in body composition that alter the pharmacokinetics of drugs and pharmacodynamic responses. Comorbidity and polypharmacy in the elderly decreases tolerability of drugs, leading to greater vulnerability to adverse drug reactions than that observed in younger adults. In geriatric pharmacotherapy, the general recommendation is dose reduction and slow titration, which is based on pharmacokinetic considerations and concern for adverse drug reactions, rather than clinical trial data. Older patients are under-represented in clinical trials. In the absence of evidence, extrapolation of risk-benefit ratios from younger adults to geriatric populations is not necessarily valid. Sound evidence through prospective clinical trials is essential, and geriatric societies, governments, and patient advocacy groups should collaborate to promote the inclusion of older people in clinical trials. It is believed that all involved in clinical trials have both an obligation and an opportunity to eliminate age discrimination in clinical trial practice. [ABSTRACT FROM AUTHOR]

A correction to the article "Pharmacokinetics and bioequivalence of two different 20 mg olmesartan tablets: A randomized, single-dose, two-period crossover study in healthy Korean male volunteers" that was published in the previous issue is presented.