Hee Youn Choi

Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Gemigliptin, a Dipeptidyl Peptidase-IV Inhibitor: A Crossover Drug-Drug Interaction Study in Healthy Male Korean Volunteers

BACKGROUND Gemigliptin (LC15-0444) is a newly developed selective and competitive inhibitor of dipeptidyl peptidase (DPP)-4 and has potential for the treatment of type 2 diabetes mellitus. Gemigliptin is metabolized by the cytochrome P450 (CYP) 3A4 isozyme to yield the active major metabolite LC15-0636. OBJECTIVE The effects of multiple oral doses of ketoconazole (a potent CYP3A4 inhibitor) and multiple oral doses of rifampicin (a potent CYP3A4 inducer) on the pharmacokinetic properties of a single oral dose of gemigliptin were evaluated in fasting healthy male Korean volunteers. METHODS In this open-label, 2-part, 3-treatment, 1-sequence, 2-period crossover drug-drug interaction study, 1 group of subjects received a single 50-mg oral dose of gemigliptin on 2 separate occasions-once as monotherapy and again after pretreatment with 400 mg of oral ketoconazole once daily for 7 days. The other group of subjects received a single 50-mg oral dose of gemigliptin on 2 separate occasions-once without pretreatment and again after pretreatment with 600 mg of oral rifampicin once daily for 10 days. Blood samples were obtained at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, and 72 hours after gemigliptin dosing. Plasma concentrations were determined using LC-MS/MS. Pharmacokinetic parameters were estimated via noncompartmental methods. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS Twenty-four subjects were enrolled (12 per group). Concurrent administration of ketoconazole was associated with increased total gemigliptin plasma exposure (AUC(0-∞); 2.36-fold [90% CI, 2.19-2.54]) and decreased metabolism of gemigliptin until negligible concentrations of LC15-0636 were detected. Pretreatment with rifampicin was associated with decreased AUC(0-∞) of gemigliptin (by 80% [90% CI, 78%-82%]) and a 2.9-fold increase (mean [SD], 0.18 [0.08] to 0.52 [0.10]) in the metabolic ratio of gemigliptin to LC15-0636. The treatments were well-tolerated, with no severe adverse events reported. Six of the 24 subjects (25%) experienced AEs during the first period of gemigliptin monotherapy administration. Six of 12 subjects (50%) each experienced AEs during concurrent administration with ketoconazole and rifampicin. CONCLUSIONS In this select group of healthy male Korean volunteers, concurrent administration of gemigliptin with ketoconazole or rifampicin was associated with significantly increased or decreased systemic exposure to gemigliptin, respectively. These findings suggest that gemigliptin may require a dose adjustment when concurrently administered with drugs that alter CYP3A4 activity. Concurrent administration of gemigliptin with ketoconazole or rifampicin was well tolerated. ClinicalTrials.gov identifier: NCT01426906.

Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid.

Objective The effects of various polymorphisms in cytochrome P450 (CYP) enzyme and transporter genes on the pharmacokinetics (PK) of simvastatin were evaluated in healthy Korean men. Methods Plasma concentration data for simvastatin and simvastatin acid were pooled from four phase I studies comprising 133 participants. The polymorphisms CYP2D6*4, CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, CYP2C19*2, CYP2C19*3, CYP2A6*7, and CYP2A6*9; SLCO1B1 rs4149056, rs2306283, and rs4149015; ABCB1 rs1128503, rs2032582, and rs1045642; and ABCG2 rs2231142 were evaluated in each participant. Noncompartmental PK results were compared by genotype. Results CYP2D6*5 and CYP2D6*14 were found to be associated with a higher area under the curve (AUC) for simvastatin, whereas the AUC of simvastatin acid was significantly increased in patients with the SLCO1B1 rs4149056, ABCG2 rs2231142, and CYP2D6*41 allele variants. Patients with the CYP2D6*41 variant showed a higher peak serum concentration (Cmax) of both simvastatin and simvastatin acid. The SLCO1B1 rs4149056 and rs4149015 polymorphisms were associated with an increased AUC ratio (i.e. ratio of simvastatin acid to simvastatin), whereas the SLCO1B1 rs4149056 and CYP2D6*5 variants were related to a higher Cmax ratio. Conclusion The CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, SLCO1B1 rs4149056 and rs4149015, and ABCG2 rs2231142 genetic polymorphisms are associated with the PK of both simvastatin and simvastatin acid. This could potentially be used as a basis for individualized simvastatin therapy by predicting the clinical outcomes of this treatment.

Evaluation of Pharmacokinetic and Pharmacodynamic Profiles and Tolerability After Single (2.5, 5, or 10 mg) and Repeated (2.5, 5, or 10 mg BID for 4.5 days) Oral Administration of Ivabradine in Healthy Male Korean Volunteers

BACKGROUND Ivabradine, a selective inhibitor of the pacemaker current in the sinoatrial node, has shown pure heart rate (HR)-reducing effects with anti-ischemic efficacy as well as improvement in heart failure outcomes. OBJECTIVE The purpose of this study was to explore pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and tolerability in healthy male Korean volunteers, as well as to compare them with PK/PD profiles of white subjects. METHODS This was a randomized, double-blind, placebo-controlled Phase I study conducted in healthy male subjects. For each of the 3 dosing groups, 9 subjects were randomized to receive ivabradine and 3 to receive placebo. Subjects received a single oral dose of ivabradine 2.5, 5, or 10 mg and after a 3-day washout period, repeat doses of 2.5, 5, or 10 mg BID for 4.5 days. Blood and urine samples were collected over 72 hours during each period, and levels of ivabradine and its metabolite S18982 were determined by using validated LC-MS/MS, followed by noncompartmental PK analysis. For PD properties and tolerability, 24-hour Holter recordings were obtained: at baseline, after a single dose, after repeated doses, and after the last dose. Serial resting 12-lead ECG assessments were also performed throughout the study. RESULTS Forty-eight subjects were enrolled, and 45 completed the study. After single doses of 2.5, 5, and 10 mg, respective mean Cmax levels of ivabradine were 9, 15, and 39 ng/mL, and mean AUC0-last values were 30, 52, and 121 ng h/mL. At steady state, mean Cmax,ss levels were 11, 19, and 42 ng/mL, reached at a median Tmax of 0.67 hour for all 3 doses. The mean AUC0-τ levels were 43, 58, and 139 ng h/mL, respectively. The PK findings were linear with dose and time. Decreases in mean HR on both the Holter recordings and ECGs were observed in all of the ivabradine groups compared with placebo. After the repeated doses, mean decreases in HR were greater than those for the single doses for the same period. Statistically significant differences were observed between the 5- and 10-mg ivabradine groups and placebo. A total of 3 adverse events were reported in 2 subjects receiving ivabradine; both fully recovered without sequelae. CONCLUSIONS Single and repeated administration of ivabradine were generally well tolerated in these healthy male Korean volunteers. Ivabradine induced significant reductions in HR, especially at doses of 5 and 10 mg. PK/PD characteristics were similar to those found in white subjects, suggesting that the dose concentration-response relationship of ivabradine is similar between Korean and white subjects.

Bioavailability and tolerability of combination treatment with revaprazan 200 mg + itopride 150 mg: a randomized crossover study in healthy male Korean volunteers.

BACKGROUND To date, no definitive treatment of functional dyspepsia (FD) has been proven to be effective and reasonably well-tolerated. Proton pump inhibitors (PPIs) combined with prokinetic agents are considered an effective option. Revaprazan is a selective potassium-competitive acid blocker that reversibly inhibits gastric H(+)/K(+)-ATPase and shows effective acid suppression comparable to PPIs. Itopride is a prokinetic agent that has anticholinesterase activity as well as dopamine D(2) receptor antagonistic activity. For this reason, revaprazan and itopride have been prescribed for FD; however, no available studies have reported the pharmacokinetic interactions of these 2 drugs. OBJECTIVE The objective of this study was to compare the bioavailability and tolerability of revaprazan and itopride combination therapy to those of equally dosed monotherapies to acquire basic drug-drug interaction information about revaprazan. METHODS This multiple-dose, randomized crossover study was conducted in healthy male Korean subjects. Subjects received, in randomized sequence, a 7-day oral dose of revaprazan 200 mg once daily, itopride 50 mg TID, or both. Each treatment period was separated by a 7-day washout period. Blood samples were collected for up to 24 hours following the last dose at steady state, 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, clinical chemistry testing, and interviews. RESULTS A total of 30 subjects were enrolled in the study. Among them, 28 subjects completed revaprazan treatment, and 27 completed the study (3 subjects were withdrawn). The geometric mean ratios (GMRs) (90% CI) of C(max,ss), and AUC(τ,ss) with revaprazan were 0.92 (0.84-1.00) and 0.96 (0.89-1.03), respectively. The GMRs of C(max,ss) and AUC(τ,ss) with itopride were 1.07 (0.96-1.20) and 1.12 (1.06-1.18), respectively. A total of 15 adverse events (AEs) were reported in 8 subjects. All AEs were considered to be mild, and there were no clinically significant differences between treatment groups. CONCLUSION The findings from this study suggest bioequivalence between revaprazan given as monotherapy and in combination with itopride in these healthy Korean male volunteers, with no clinical significant drug-drug interaction. All treatments in this study was generally well tolerated. ClinicalTrials.gov identifier: NCT0133289.

Pharmacokinetic interaction between udenafil and dapoxetine: a randomized, open-labeled crossover study in healthy male volunteers.

Background “Udenafil” is a phosphodiesterase-5 inhibitor indicated for erectile dysfunction. “Dapoxetine” is a serotonin transport inhibitor indicated for premature ejaculation. The aim of the study reported here was to investigate the pharmacokinetic drug interaction between udenafil and dapoxetine in healthy male subjects. Methods An open-label, three-treatment, six-sequence, three-period crossover study was performed in healthy male subjects. In varying sequences, each subjects received single oral doses of udenafil 200 mg, dapoxetine 60 mg, and both treatments. The periods were separated by a washout period of 7 days. Serial blood samples were collected up to 48 hours after dosing. The plasma concentrations of udenafil and dapoxetine were determined using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed throughout the study. Results Twenty-three healthy subjects completed the study. The geometric mean ratios of the area under the plasma concentration–time curve from time 0 to last measurable time point and measured peak plasma concentration for udenafil were 0.923 (90% confidence interval [CI]: 0.863–0.987) and 0.864 (90% CI: 0.789–0.947), respectively. The geometric mean ratios of the area under the plasma concentration–time curve from time 0 to last measurable time point and measured peak plasma concentration for dapoxetine were 1.125 (90% CI: 1.044–1.213) and 0.837 (90% CI: 0.758–0.925), respectively. There were no serious adverse events reported, and none of the subjects dropped out due to adverse events. Conclusion Udenafil was found to have no clinically significant pharmacokinetic interactions with dapoxetine. The concurrent administration of udenafil and dapoxetine was generally well tolerated.

Pharmacokinetic Interaction of Telmisartan With S-Amlodipine: An Open-Label, Two-Period Crossover Study in Healthy Korean Male Volunteers

BACKGROUND Telmisartan belongs to a class of orally active angiotensin II receptor blockers (ARBs), and S-amlodipine is an enantiomer of amlodipine. Amlodipine is a racemic mixture and the calcium channel blocking (CCB) effect is confined to S-amlodipine, whereas R-amlodipine has a 1000-fold lower activity and no racemization occurs in vivo in human plasma. Combination therapy of ARBs with CCBs provides advantages for blood pressure control and vascular protection over monotherapy. OBJECTIVE To investigate the effects of coadministration of telmisartan and S-amlodipine on the steady-state pharmacokinetic properties of each drug as a drug-drug interaction study required before developing the fixed-dose combination agent. METHODS This study comprised 2 separate parts, A and B; each was a multiple-dose, open-label, 2-sequence, 2-period, crossover study in healthy male Korean volunteers. In part A, volunteers were administered 80 mg of telmisartan, either alone or with 5 mg of S-amlodipine. In part B, volunteers were administered 5 mg of S-amlodipine, either alone or with 80 mg of telmisartan. Blood samples were taken on days 9 and 37, following the final dose of each treatment, and at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after administration in part A, and were taken at 0 (predose), 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, and 24 hours after administration in part B. Plasma concentrations were determined using LC-MS/MS. The pharmacokinetic properties of each drug after coadministration of telmisartan and S-amlodipine were compared with those of each drug administered alone. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS Fifty-six volunteers were enrolled (32 in part A and 24 in part B), and all completed except 4 volunteers (3 withdrawn in part A and 1 withdrawn in part B). The geometric mean ratios (GMRs) (90% CI) for the C(max,ss) and AUC(τ,ss) of telmisartan (with or without S-amlodipine) were 1.039 (0.881-1.226) and 1.003 (0.926-1.087), respectively. The GMRs (90% CI) for C(max,ss) and AUC(τ,ss) of S-amlodipine (with or without telmisartan) were 0.973 (0.880-1.076) and 0.987 (0.897-1.085). Total 11 adverse events (AEs) were reported in 7 volunteers (21.9%) in part A. A total of 9 AEs were reported in 6 volunteers (25.0%) in part B. Statistical analysis confirmed that the 90% CIs for these pharmacokinetic parameters were within the commonly accepted bioequivalence range of 0.8 to 1.25, indicating that the extent of bioavailability of S-amlodipine was not affected by telmisartan. The intensity of all AEs was considered to be mild, and there were no significant differences in the prevalences of AEs between the 2 formulations. CONCLUSIONS Following multiple-dose coadministration of high doses of telmisartan and S-amlodipine, the steady-state pharmacokinetic properties of telmisartan were not significantly affected, and telmisartan had no significant effect on the pharmacokinetic properties of S-amlodipine at steady state in these selected groups of healthy volunteers. Both formulations were generally well-tolerated.

Effects of food on the pharmacokinetics of gemigliptin/metformin sustained-release 50/1,000 mg (25/500 mg x 2 tablets) fixeddose combination tablet in healthy male volunteers.

OBJECTIVES For patient convenience, a gemigliptin/metformin sustainedrelease fixed-dose combination (FDC) tablet was developed. This study was conducted to investigate the effects of food on the pharmacokinetic (PK) profile of the FDC tablets. MATERIALS AND METHODS This was an open-label, randomized, single dose, 2-period, 2-sequence crossover study in 24 healthy male volunteers. The FDC tablets (25/500 mg × 2 tablets) were administered in high-fat fed and fasted states on separate occasions, and each subject was randomly allocated to each sequence with a 7-day washout period. PK blood samplings were conducted from predose to 48 hours after dosing. Tolerability assessments were performed throughout the study. RESULTS Nine adverse events (AEs) of mild intensity were reported from 8 subjects after study drug administration, and the AE frequency was similar between treatments. No serious AEs were reported. The PK parameters of gemigliptin and metformin were compared between fasting and fed states. For gemigliptin, the geometric mean ratios (GMRs) (fed : fasted state) of the Cmax and AUClast were 0.886 (90% confidence interval (CI) 0.781 - 1.006) and 1.021 (90% CI 0.949 - 1.099), respectively. For metformin, the GMRs of the Cmax and AUClast were 0.811 (90% CI 0.712 - 0.923) and 1.144 (90% CI 1.013 - 1.291), respectively. A prolonged tmax for metformin was observed. These results are similar to the effects of food on each component. CONCLUSION The FDC tablet may have a similar PK profile as that of individual drugs and is generally tolerable when administered with food. These results indicate that the FDC tablet can be administered in the same dosing regimen as each component, especially that of metformin sustained-release.

Effects of Ketoconazole on the Pharmacokinetic Properties of CG100649, A Novel NSAID: A Randomized, Open-Label Crossover Study in Healthy Korean Male Volunteers

BACKGROUND CG100649, a novel selective cyclooxygenase-2 inhibitor that also inhibits carbonic anhydrase I/II, is expected to reduce the cardiovascular risk typical of other NSAIDs. Concurrent medications may influence the activities of the cytochrome P450 (CYP) 3A enzyme through which CG100649 is metabolized. OBJECTIVES This study was designed to evaluate the influence of ketoconazole, a known strong inhibitor of CYP3A, on the pharmacokinetic properties of CG100649. METHODS This randomized, open-label, 2 × 2 crossover study was conducted in healthy Korean male volunteers. Each subject received the following 2 treatments in a randomly allocated sequence, separated by a washout period of 42 days: single oral dose of CG100649 6 mg, and concurrent dosing of CG100649 6 mg and ketoconazole 400 mg followed by ketoconazole 400 mg/d over 4 days. Blood samples for pharmacokinetic analysis were collected at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 240, 384, and 480 hours after dosing of CG100649 in each sequence. Tolerability assessments were performed throughout the study. RESULTS Thirty subjects participated, and 26 subjects completed the study. Seventeen adverse events (AEs) were reported in 10 subjects, and all AEs were recovered without any sequelae. No serious AEs were reported. Six subjects receiving the single dose of CG100649 had 9 AEs, and 7 subjects receiving the combination of ketoconazole and CG100649 had 8 AEs. The Cmax of CG100649 with CG100649 only and with concurrent administration of CG100649 + ketoconazole were similar (10.7 and 11.0 ng/mL, respectively). The CG100649 AUClast with concurrent ketoconazole was 1.29-fold greater than that with CG100649 only (2074.0 and 2685.8 ng · h/mL) and demonstrated a statistically significant difference (P < 0.05). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or AEs between treatments. CONCLUSION Although the AUC of CG100649 increased by 29% with the concurrent medication of ketoconazole, it is considered that concurrent administration of CG100649 with ketoconazole would not change the safety profile of CG100649.

Single dose pharmacokinetics of the novel transdermal donepezil patch in healthy volunteers

Background Donepezil is an acetylcholinesterase inhibitor indicated for Alzheimer’s disease. The aim of this randomized, single-blind, placebo-controlled, single-dose, dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics of the donepezil patch in healthy male subjects. Methods Each healthy male subject received a single transdermal donepezil patch (72 hours patch-on periods) of 43.75 mg/12.5 cm2, 87.5 mg/25 cm2, or 175 mg/50 cm2. Serial blood samples were collected up to 312 hours after patch application. The plasma concentrations of donepezil were determined by using a validated liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability of the patches and performance of the patches (adhesion, skin irritation, residual donepezil content in the patch) were assessed throughout the study. Results The study was completed by 36 healthy subjects. After patch application, the maximal plasma donepezil concentration (Cmax) and the area under the curve (AUC) increased in a dose-proportional manner. Median time to Cmax was ~74–76 hours (~2–4 hours after patch removal), and mean t1/2β was ~63.77–93.07 hours. The average donepezil residue in the patch after 72 hours was ~73.9%–86.7% of the loading dose. There were neither serious adverse events nor adverse events that lead to discontinuation. Skin adhesion of the patch was good in 97.2% of the subjects. All skin irritations after patch removal were mild and were resolved during the study period. Conclusion The donepezil patch appeared to be generally well tolerated and adhesive. Pharmacokinetic analysis of the donepezil patch demonstrated linear kinetics.

Pharmacokinetic comparison of sustained- and immediate-release formulations of cilostazol after multiple oral doses in fed healthy male Korean volunteers

Background A new extended-release form of cilostazol has recently been developed. This study was conducted to compare the pharmacokinetic characteristics of sustained-release (SR) and immediate-release (IR) formulations of cilostazol after multiple oral doses in healthy male Korean volunteers. Methods This was an open-label, randomized, multiple-dose, crossover study conducted in 30 healthy Korean subjects. In each treatment period, subjects received oral doses of 200 mg SR formulation every 24 hours or 100 mg IR formulation every 12 hours for 5 consecutive days in a fed state, with a washout period of 9 days. The plasma concentrations of cilostazol and its metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method. The area under the plasma concentration–time curve within a dosing interval (AUCT), the measured peak plasma concentration at steady state (Cmax,ss), and the time to reach Cmax,ss (tmax,ss) were analyzed using a noncompartmental method. Results A total of 24 healthy male subjects completed the study. The mean (standard deviation [SD]) AUCT (96–120 hours) values for SR and IR were 27,378.0 (10,301.6) ng·h/mL and 27,860.3 (7,152.3) ng·h/mL, respectively. The mean (SD) Cmax,ss values were 2,741.4 (836.0) ng/mL and 2,051.0 (433.2) ng/mL, respectively. The median tmax,ss values were 8.0 hours and 4.0 hours, respectively. The geometric mean ratios (90% confidence intervals) of the SR to IR formulations were 0.937 (0.863–1.017), 0.960 (0.883–1.043), and 0.935 (0.859–1.017) for AUCT and 0.644 (0.590–0.703), 0.586 (0.536–0.642), and 0.636 (0.577–0.702) for dose-normalized Cmax,ss of cilostazol, OPC-13015 (3,4-dehydro-cilostazol), and OPC-13213 (4′-trans-hydroxyl-cilostazol), respectively. All formulations were well tolerated. Conclusion At steady state, the AUCT of cilostazol SR 200 mg is comparable to that of cilostazol IR 100 mg twice a day in healthy male Korean subjects. Both formulations are well tolerated.