Clinical Evaluation of Digital Therapeutics: Present and Future / 대한의료정보학회지

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.

Therapeutic drug monitoring on the use of transplacental digoxin in fetal tachyarrhythmia: a case report

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.

Comprehensive analysis of important pharmacogenes in Koreans using the DMET™ platform

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.

A meta-analysis: efficacy and safety of anti-epileptic drugs prescribed in Korea as monotherapy and adjunctive treatment for patients with focal epilepsy

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.

Pharmacokinetic comparison between a fixed-dose combination of fimasartan/amlodipine/ hydrochlorothiazide 60/10/25 mg and a corresponding loose combination of fimasartan/amlodipine 60/25 mg and hydrochlorothiazide 25 mg in healthy subjects

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.

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 (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.

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 (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.

Effect of plasma membrane monoamine transporter genetic variants on pharmacokinetics of metformin in humans

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.

A post hoc analysis of intra-subject coefficients of variation in pharmacokinetic measures to calculate optimal sample sizes for bioequivalence studies

Because bioequivalence studies are performed using a crossover design, information on the intra-subject 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 concentration-time 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)

Retraction and Republication: A post hoc analysis of intra-subject coefficients of variation in pharmacokinetic measures to calculate optimal sample sizes for bioequivalence studies

The retraction has been agreed upon due to critical typographical errors throughout the contents from accidents at the manuscript editing step.

Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity

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.

A post hoc analysis of intra-subject coefficients of variation in pharmacokinetic measures to calculate optimal sample sizes for bioequivalence studies

Because bioequivalence studies are performed using a crossover design, information on the intra-subject 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 C(max). Intra-CVs of C(max) were larger than those of area under the concentration-time 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 C(max). 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.

Effects of CYP2C19 Genetic Polymorphisms on PK/PD Responses of Omeprazole in Korean Healthy Volunteers

The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The noncompartmental method was used for the determination of PK parameters. Change of mean pH and proportion (%) of time of gastric pH above 4.0 were estimated. The poor metabolizer (PM) group had the lowest metabolic ratio and exhibited the highest area under the curve (AUC) for omeprazole among the CYP2C19 phenotype groups. The PM group showed the greatest change of mean pH and the highest % time of gastric pH above 4.0. The relationship between AUC of omeprazole and % time of gastric pH above 4.0 was confirmed. The study demonstrates that CYP2C19*2 and *3 influence the PKs and PDs of omeprazole in Korean healthy volunteers. Clinical trial registry at the U.S. National Institutes of Health (https://clinicaltrials.gov), number NCT02299687.

Evaluation of factors associated with drug-induced liver injury using electronic medical records

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.

A Randomized, Placebo Controlled, Double Blind, Parallel Group, Multiple Dosing, Dose Escalation Clinical Study to Evaluate Pharmacokinetics/Pharmacodynamics and Tolerability of Zofenopril in Healthy Korean Subjects

BACKGROUND: Zofenopril is a new Angiotensin Converting Enzyme (ACE) inhibitor for the treatment of the patients with hypertension and congestive heart failure. This study aimed to evaluate the pharmacokinetics (PKs)/pharmacodynamics (PDs) and tolerability of zofenopril in healthy Korean subjects. METHODS: A randomized, double blind, placebo-controlled, multiple dosing parallel group study with two dosage groups (zofenopril 30 mg or 60 mg) was conducted in healthy Korean male subjects. Each dosage group consisted of 10 subjects and they were randomly assigned to receive zofenopril or placebo with a ratio of 4:1. PK characteristics of zofenopril and its active metabolite, zofenoprilat, were evaluated after single or multiple dosing. Serum ACE activities and blood pressures were measured for PD evaluation. Adverse events, clinical laboratory tests, electrocardiograms, vital signs and physical examinations were performed for tolerability evaluation. RESULTS: The PK characteristics of zofenopril and zofenoprilat after single dose and multiple doses were similar to one another. The metabolic ratio of zofenoprilat to zofenopril after single dose and multiple doses were 12.4 and 14.9, respectively, in the 30 mg dosage group, and were 6.8 and 6.6, respectively, in the 60 mg dosage group. Complete serum ACE activity inhibition was observed within 1 hour in both doses but it was maintained longer in the 60 mg dosage group compared to the 30 mg dosage group. There were no clinically significant abnormalities in tolerability evaluations. CONCLUSION: The PK/PD characteristics of zofenopril and zofenoprilat after single or multiple administrations were explored. Zofenopril was well tolerated after multiple administrations in healthy Korean subjects.