Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of fimasartan, amlodipine, and rosuvastatin using partial replicated design in healthy adult subjects

Oh, Minkyung,Ghim, Jong-Lyul,Park, Sung-Eun,Kim, Eun-Young,Shin, Jae-Gook Dove Medical Press 2018 Drug design, development and therapy Vol.12 No.-

<P><B>Objective</B></P><P>The aim of this study was to compare the pharmacokinetics (PK) and safety profiles of a fixed-dose combination (FDC) formulation of fimasartan, amlodipine, and rosuvastatin with the co-administration of the two products by using a replicated crossover study design in healthy male subjects.</P><P><B>Results</B></P><P>This was an open-label, randomized, three-sequence, three-period replicated crossover study in healthy male subjects. The replicated crossover design was done because of high coefficient of variation of PK parameter for fimasartan, that is, >30%. With a 14 days washout period, an FDC tablet containing 60 mg fimasartan, 10 mg amlodipine, and 20 mg rosuvastatin was administered only once, and separate formulations of fimasartan/amlodipine 60 mg/10 mg FDC tablet and 20 mg rosuvastatin tablet administered twice. Blood samples were collected up to 72 hours following drug administration. The plasma concentrations of fimasartan, amlodipine, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was assessed by evaluating vital signs, clinical laboratory parameters, physical examinations, and medical interviews.</P><P><B>Results</B></P><P>The geometric mean ratios and 90% confidence intervals (CIs) for the maximum plasma concentration (C<SUB>max</SUB>) and area under the curve from time zero to the last measurable sampling time (AUC<SUB>t</SUB>) were 1.0776 (0.9201–1.2622) and 0.9978 (0.9538–1.0439) for fimasartan, 1.0038 (0.9782–1.0301) and 1.0055 (0.9828–1.0288) for amlodipine, and 1.0006 (0.9290–1.0776) and 0.9986 (0.9532–1.0461) for rosuvastatin, respectively. A total of 22 adverse events (AEs) were reported by 60 subjects; there were no significant differences in the incidence of AEs between the two groups.</P><P><B>Conclusion</B></P><P>The 90% CI of the C<SUB>max</SUB> of fimasartan was within the widened acceptance limit, ln(0.6984)–ln(1.4319). The 90% CIs of the other PK parameters for drugs were between ln(0.8) and ln(1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile, to the co-administration of its three constituent drugs.</P>

Associations between HLA-A, -B, and -C alleles and iodinated contrast media– induced hypersensitivity in Koreans

김은영,최석진,Jong-Lyul Ghim,김미영,설정은,Minkyung Oh,Chan Sun Park,신재국 대한임상약리학회 2021 Translational and Clinical Pharmacology Vol.29 No.2

A common cause of drug hypersensitivity reactions is iodinated contrast media (ICM). ICM-induced hypersensitivity had been considered to be a non-immunological reaction,but evidence for an immunological mechanism has increased recently. Thus, we evaluatedwhether HLA-A, -B, and -C alleles were associated with ICM-induced hypersensitivity. Intotal, 126 patients who underwent contrast-enhanced computed tomography studies throughoutpatient clinics at a tertiary referral hospital between 2008 and 2012 were assessed. Sixty-one patients experienced ICM-induced hypersensitivity and the remainder, 65, wereICM-tolerant patients (control). ICM-induced hypersensitivity patients showed 51 withimmediate, 7 with non-immediate, 3 with both or mixed type. HLA-A, -B, and -C genotypingwas performed using a PCR sequence-based typing method. Four kinds of ICM were used:iopromide, iohexol, iobitridol, and iodixanol. The most used ICM among the hypersensitivitypatients was iopromide. Significant difference in the frequency of HLA-B*58:01 (odds ratios[OR], 3.90; p = 0.0200, 95% confidence interval [CI], 1.16–13.07) was observed betweenICM-induced immediate hypersensitivity and control. There were statistically significantdifferences in the frequencies of the HLA-B*38:02 (OR, 10.24; p = 0.0145; 95% CI, 1.09–96.14)and HLA-B*58:01 (OR, 3.98; p = 0.0348; 95% CI, 1.03–15.39) between iopromide-inducedimmediate hypersensitivity and control. The mechanism of ICM-induced hypersensitivityremains unknown, but this study showed associations, although weak, with HLA-B*58:01 allelesfor ICM-induced immediate hypersensitivity and HLA-B*38:02 and HLA-B*58:01 for iopromideinducedimmediate hypersensitivity as risk predictors. Further studies are needed to validate theassociations in larger samples and to identify the functional mechanism behind these results.

Pharmacokinetics and relative bioavailability of fixed-dose combination of clopidogrel and aspirin versus coadministration of individual formulations in healthy Korean men

Choi, Hyang-Ki,Ghim, Jong-Lyul,Shon, Jihong,Choi, Young-Kyung,Jung, Jin Ah Dove Medical Press 2016 Drug design, development and therapy Vol.10 No.-

<P><B>Background</B></P><P>Simultaneous prescription of clopidogrel and low-dose aspirin is recommended for the treatment of acute coronary syndrome because of improvements in efficacy and patient compliance. In this study, the pharmacokinetics of a fixed-dose combination (FDC) of clopidogrel and aspirin was compared with coadministration of individual formulations to clarify the equivalence of the FDC.</P><P><B>Methods</B></P><P>This was a randomized, open-label, two-period, two-treatment, crossover study in healthy Korean men aged 20–55 years. Subjects received two FDC capsules of clopidogrel/aspirin 75/100 mg (test) or two tablets of clopidogrel 75 mg and two capsules of aspirin 100 mg (reference) with a 14-day washout period. Plasma concentrations of clopidogrel, aspirin, and salicylic acid were measured using validated ultraperformance liquid chromatography–tandem mass spectrometry. Bioequivalence was assessed by analysis of variance and calculation of the 90% confidence intervals (CIs) of the ratios of the geometric means (GMRs) for AUC<SUB>last</SUB> and <I>C</I><SUB>max</SUB> for clopidogrel and aspirin.</P><P><B>Results</B></P><P>Sixty healthy subjects were enrolled, and 53 completed the study. Clopidogrel, aspirin, and salicylic acid showed similar absorption profiles and no significant differences in <I>C</I><SUB>max</SUB>, AUC<SUB>last</SUB>, and <I>T</I><SUB>max</SUB> between FDC administration and coadministration of individual formulations. The GMRs (90% CI) for the <I>C</I><SUB>max</SUB> and AUC<SUB>last</SUB> of clopidogrel were 1.08 (0.95, 1.23) and 0.93 (0.84, 1.03), respectively. The GMRs (90% CI) for the <I>C</I><SUB>max</SUB> and AUC<SUB>last</SUB> of aspirin were 0.98 (0.84, 1.13) and 0.98 (0.93, 1.04), respectively. Both treatments were well tolerated in the study subjects.</P><P><B>Conclusion</B></P><P>The FDC of clopidogrel and aspirin was bioequivalent to coadministration of each individual formulation. The FDC capsule exhibited similar safety and tolerability profiles to the individual formulations. Therefore, clopidogrel/aspirin 75 mg/100 mg FDC capsules can be prescribed to improve patient compliance.</P>

Development and validation of a dried-blood spots method for the simultaneous analysis of 21 anti-tuberculosis drugs using LC-MS/MS

( Minyoung Kim ),( Jae-gook Shin ),( Jong-lyul Ghim ),( Eun-young Kim ),( Dong-hyun Kim ) 대한결핵 및 호흡기학회 2019 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.127 No.0

Background: DBS (dry blood spots) method has many advantages as patient friendly, cost-effective than plasma analysis and has been applied to the analysis of anti-tuberculosis drugs. However, there is no currently available DBS analysis to simultaneously measure both first- and second-anti TB drugs. In this study, we developed and validated a method for simultaneous analysis of 21 anti-TB drugs on DBS using HPLC-MS/MS. Method: Selection of filters (Whatman, 903 Protein saver cards) and extraction solvent were initially optimized. 6-Millimeter spots were punched from homogeneous blood spots and extracted using a 50% acetonitrile containing internal standard. The extracts were further processed and injected onto a RP-dC18 column with a gradient elution system. The detection were done by MRM analysis. Results: All drugs were well separated with high specificity. The calibration curves were linear with correlation coefficients (r) greater than 0.99 for all anti-TB drugs over the target concentration ranges. The intra- and inter-day precision was less than 16.2%, and the accuracy was between 82.8 and 111.5%. The recovery of all drugs was higher than 20%. All drugs were stable after 24 h drying in the clean bench and stable after 4 weeks -20 ° C. Conclusion: This report describes the development and validation of a method for simultaneous quantification of 21-anti-TB drugs using the dried blood spots method. This method is simple, fast, and accurate. The developed DBS method can be applied to therapeutic drugs monitoring in patients with tuberculosis.

Antiepileptic drug-induced severe cutaneous adverse reactions and HLA alleles: A report of five cases with lymphocyte activation test

김은영,김미영,Chan Sun Park,최재혁,Jong-Lyul Ghim,Ho-Sook Kim,신재국 대한임상약리학회 2019 Translational and Clinical Pharmacology Vol.27 No.2

Antiepileptic drugs (AEDs) can induce severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. We performed HLA genotyping and lymphocyte activation tests (LATs) for five AED-induced SCAR patients (three males and two females; aged 40-66 years old). Three patients were treated with carbamazepine (CBZ) for pain control, one was treated with phenytoin (PHT) for seizure prevention, and one was treated with valproic acid (VPA) for seizure prevention. One patient was diagnosed with CBZ-induced DRESS syndrome and the remaining patients were diagnosed with SJS. All patients recovered from SCARs after stopping suspicious drugs and supportive care. LATs were conducted to confirm the culprit drug responsible for inducing SCARs; and LAT results were positive for the suspected culprit drugs, in all except in one case. HLA-A, -B, and -C alleles were determined using PCR-sequence-based typing method. The common alleles of HLA were -A*02:01, -B*51:01, and -C*03:04 which were carried by three patients (60%) for each allele. The patient with CBZ-induced DRESS syndrome carried the HLAA* 31:01 allele. One patient with CBZ-induced SJS and one patient with VPA-induced SJS carried the HLA-B*15:11 allele. No patients carried the HLA-B*15:02 allele, which is a known risk allele of AED-induced SCARs. Further investigation of the three common alleles found in the five AED-induced SCARs patients is needed. We demonstrated the usefulness of LAT for confirming the culprit drug.

Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers

Oh, Minkyung,Park, Sung-Eun,Ghim, Jong-Lyul,Choi, Young-Kyung,Shim, Eon-Jeong,Shin, Jae-Gook,Kim, Eun-Young Dove Medical Press 2017 Drug design, development and therapy Vol.11 No.-

<P><B>Objective</B></P><P>This study compared the pharmacokinetic (PK) and safety profiles of a fixed-dose combination (FDC) formulation of telmisartan and S-amlodipine with those of concomitant administration of the two drugs.</P><P><B>Materials and methods</B></P><P>This was an open-label, randomized, crossover study in healthy male Koreans. All subjects were administered an FDC tablet containing 40 mg telmisartan and 5 mg S-amlodipine and were also coadministered the same dose of both drugs given separately. The crossover study design included a 14-day washout period between the two treatments. Blood samples were collected up to 168 h following drug administration. The plasma concentrations of telmisartan and S-amlodipine were determined by liquid chromatography tandem mass spectrometry. PK parameters and plasma concentration–time curves were compared. Safety was assessed by measuring vital signs, clinical laboratory tests, physical examinations, and patient interviews.</P><P><B>Results</B></P><P>The geometric mean ratios and 90% CIs for the maximum plasma concentration (C<SUB>max</SUB>) and area under the curve from time zero to the last sampling time (AUC<SUB>t</SUB>) were 0.8782 (0.8167–0.9444) and 0.9662 (0.9210–1.0136) for telmisartan and 1.0069 (0.9723–1.0427) and 1.0324 (0.9969–1.0690) for S-amlodipine, respectively. A total of 36 adverse events (AEs) were reported by 23 subjects, but no statistical differences were observed between the two treatments. The most frequently reported AE was a mild-to-moderate headache that was generally self-limiting.</P><P><B>Conclusion</B></P><P>For both telmisartan and S-amlodipine, the C<SUB>max</SUB> and AUC<SUB>t</SUB> 90% CIs were between ln (0.8) and ln (1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile to the coadministration of these drugs.</P>

Genetic polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in Vietnamese-Koreans

Ye-Ji Lim,김은영,차은영,정혜은,Jong-Lyul Ghim,이수준,신재국 대한임상약리학회 2014 Translational and Clinical Pharmacology Vol.22 No.2

The Vietnamese-Koreans, especially offspring between a Vietnamese mother and a Korean fatherconstituted the highest proportion (64.2%) of total Kosian population according to a census in 2014. To evaluate genetic characteristics in the Vietnamese-Koreans, a total of 25 alleles from CYP2C9,CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were genotyped using SNaPshot method with DNAsamples of 127 Vietnamese-Koreans. The previous reports on the CYPs of Korean and Vietnamesepopulations were also analyzed for the comparative studies for the frequencies of CYP alleles. Thestatistical significances in allele and genotype frequencies among the ethnics were analyzed by Chisquareor Fisher's exact probability test. Although most of variants analyzed in 5 CYPs did notreach the statistically significant difference between the Vietnamese-Koreans and Vietnamese, somealleles were only found in Vietnamese-Koreans. Compared with Korean population, frequencies ofCYP2D6*1 and CYP2D6*10B were statistically different from Vietnamese-Koreans (p<0.05). Thisis the first report to describe the CYP genotype profiles of Vietnamese-Koreans, which may provideimportant insight for the genotype based prediction of CYP activities of this admixture of Koreanand Vietnamese.

A Simple Dosing Scheme for Intravenous Busulfan Based on Retrospective Population Pharmacokinetic Analysis in Korean Patients

최상민,Gayeong Kim,임형석,Sang-Heon Cho,Jong-Lyul Ghim,Jin Ah Jung,Un-Jib Kim,노규정,배균섭,이동호 대한약리학회 2012 The Korean Journal of Physiology & Pharmacology Vol.16 No.4

Busulfan is an antineoplastic agent with a narrow therapeutic window. A post-hoc population pharmacokinetic analysis of a prospective randomized trial for comparison of four-times daily versus once-daily intravenous busulfan was carried out to search for predictive factors of intravenous busulfan (iBu) pharmacokinetics (PK). In this study the population PK of iBu was characterized to provide suitable dosing recommendations. Patients were randomized to receive iBu, either as 0.8 mg/kg every 6 h or 3.2 mg/kg daily over 4 days prior to hematopoietic stem cell transplantation. In total, 295 busulfan concentrations were analyzed with NONMEM. Actual body weight and sex were significant covariates affecting the PK of iBu. Sixty patients were included in the study (all Korean; 23 women, 37 men; mean [SD] age, 36.5 [10.9] years; weight, 66.5 [11.3] kg). Population estimates for a typical patient weighing 65 kg were: clearance (CL) 7.6 l/h and volume of distribution (Vd) 32.2 l for men and 29.1 L for women. Inter-individual random variabilities of CL and Vd were 16% and 9% . Based on a CL estimate from the final PK model, a simple dosage scheme to achieve the target AUC0-inf 0.5 (defined as median AUC0-inf with a once-daily dosage) of 26.18 mg/lㆍ hr, was proposed: 24.79ㆍ ABW mg q24h, where ABW represents the actual body weight in kilograms. The dosing scheme reduced the unexplained interindividual variabilities of CL and Vd of iBu with ABW being a significant covariate affecting clearance of iBU. W e propose a new simple dosing scheme for iBu based only on ABW .

Development of high-throughput assay method for the simultaneous analysis of 24 anti-tuberculosis drugs using LC-MS/MS

( Minyoung Kim ),( Jae-gook Shin ),( Dong-hyun Kim ),( Eun-young Kim ),( Jong-lyul Ghim ),( Ji- Hye Kim ) 대한결핵 및 호흡기학회 2019 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.127 No.-

Backgrouod: Chemotherapy of multidrug-resistant tuberculosis is prescribed in combination for at least 2 years. According to WHO guideline, at least 5 drugs are simultaneously administered for successful therapy. TDM could be a useful tool for successful clinical practice. In this regards, a high-throughput analytical tool for the simultaneous determination of 24 anti-tuberculosis drugs covering all anti-TB drugs currently prescribed for the treatment of tuberculosis. Method: Two protein precipitation methods were adopted; one with methanol containing 0.13 N HCl for amikacin, kanamycin and streptomycin (group 1) and the other with acetonitrile for amoxicillin, bedaquiline, ciprofloxacin, clarithromycin, clofazimine, cycloserin, delamanid, DM-6705, ethambutol, ethionamide, isoniazid, levofloxacin, linezolid, moxifloxacin, PAS, prothionamide, pyrazinamide, rifabutin, rifampin, rifapentine and roxithromycin (group 2). Separation was done either on an HILIC silica column with a gradient elution (group 1) or a reversed-phase dC18 column with a gradient elution (group 2). Detection was carried out in selected MRM mode. Results: All drugs were well separated with high specificity. The calibration curves were linear over a 50-fold concentration range, with correlation coefficients (r) greater than 0.99 for all drugs. The limits of quantification were between 0.01 and 2.0 μg/ml. The intra- and inter-day precision was less than 14.3%, and the accuracy was between 85.7 and 109.5%. The recovery was more than 25% with RSD less than 16.0%. Most of the tested drugs were stable after 24 hours at room temperature, Freeze Thaw cycles, 12 hours of post-treatment. Delamanid was spontaneously degraded into the metabolite DM- 6705 and stable only within 5 hours at ice condition. Conclusion: This report describes the development and validation of the method for the simultaneous quantification of 24 anti-tuberculosis agents in human plasma by LC-MS/MS. The validated method is simple, fast, accurate, and precise. This assay can be applied to therapeutic drug monitoring in tuberculosis patients.

Comparison of Pharmacokinetics and Safety of Two Formulations of Letrozole (2.5 mg) in Healthy Male Volunteers

Yook-Hwan Noh,Kyun-Seop Bae,Sang-Heon Cho,Jong-Lyul Ghim,Jin Ah Jung,Un-Jib Kim,Hyun-Jung Park,Jung-Chul Kim,Hyeong-Seok Lim,Sangmin Choe 대한임상약리학회 2012 Translational and Clinical Pharmacology Vol.20 No.2

Background: Letrozole is an oral non-steroidal inhibitor of the aromatase enzyme, which has proven to be a useful drug against breast cancer. Methods: This single-dose, randomized 2 × 2 crossover study was conducted in healthy male volunteers. Participants of each sequence group (each 13 volunteers for sequence group) received, in randomized sequence, a single oral 2.5-mg dose of generic letrozole (test) or branded letrozole (reference). Each treatment period was separated by a 5-week washout period. Blood samples were collected for up to 312 hours after drug administration, and drug concentrations were determined using validated LC/MS-MS. Pharmacokinetic properties were obtained using noncompartmental analysis. Drug tolerability was assessed throughout the study, using measurements of vital signs, physical examination, clinical chemistry testing, EKG, and interviews. Results: A total of 26 subjects completed the study. The geometric mean ratios (90% CI) of Cmax and AUClast were 0.92 (0.85 – 0.99) and 1.01 (0.97 – 1.04), respectively. No serious AEs were reported, and there were no clinically significant differences between test and reference groups. Conclusion: The findings from this study suggest bioequivalence between two formulations of letrozole in healthy male volunteers. The safety profile of two formulations had similar characteristics. Background: Letrozole is an oral non-steroidal inhibitor of the aromatase enzyme, which has proven to be a useful drug against breast cancer. Methods: This single-dose, randomized 2 × 2 crossover study was conducted in healthy male volunteers. Participants of each sequence group (each 13 volunteers for sequence group) received, in randomized sequence, a single oral 2.5-mg dose of generic letrozole (test) or branded letrozole (reference). Each treatment period was separated by a 5-week washout period. Blood samples were collected for up to 312 hours after drug administration, and drug concentrations were determined using validated LC/MS-MS. Pharmacokinetic properties were obtained using noncompartmental analysis. Drug tolerability was assessed throughout the study, using measurements of vital signs, physical examination, clinical chemistry testing, EKG, and interviews. Results: A total of 26 subjects completed the study. The geometric mean ratios (90% CI) of Cmax and AUClast were 0.92 (0.85 – 0.99) and 1.01 (0.97 – 1.04), respectively. No serious AEs were reported, and there were no clinically significant differences between test and reference groups. Conclusion: The findings from this study suggest bioequivalence between two formulations of letrozole in healthy male volunteers. The safety profile of two formulations had similar characteristics.