Kyung-Mi Park

Pharmacokinetic comparison of controlled-release and immediate-release oral formulations of simvastatin in healthy Korean subjects: A randomized, open-label, parallel-group, single- and multiple-dose study

BACKGROUNDnA controlled-release (CR) formulation of simvastatin was recently developed in Korea. The formulation is expected to yield a lower C(max) and similar AUC values compared with the immediate-release (IR) formulation.nnnOBJECTIVEnThe goal of this study was to compare the pharmacokinetics of the new CR formulation and an IR formulation of simvastatin after single- and multiple-dose administration in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency.nnnMETHODSnThis was a randomized, open-label, parallelgroup, 2-part study. Eligible subjects were healthy male or female volunteers between the ages of 19 and 55 years and within 20% of their ideal weight. In part I, each subject received a single dose of the CR or IR formulation of simvastatin 40 mg orally (20 mg x 2 tablets) after fasting. In part II, each subject received the same dose of the CR or IR formulation for 8 consecutive days. Blood samples were obtained for 48 hours after the dose in part I and after the first and the last dose in part II. Pharmacokinetic parameters were determined for both simvastatin (the inactive prodrug) and simvastatin acid (the active moiety). An adverse event (AE) was defined as any unfavorable sign (including an abnormal laboratory finding) or symptom, regardless of whether it had a causal relationship with the study medication. Serious AEs were defined as any events that are considered life threatening, require hospitalization or prolongation of existing hospitalization, cause persistent or significant disability or incapacity, or result in congenital abnormality, birth defect, or death. AEs were determined based on patient interviews and physical examinations.nnnRESULTSnTwenty-four healthy subjects (17 men, 7 women; mean [SD] age, 29 [7] years; age range, 22-50 years) were enrolled in part I, and 29 subjects (17 men, 12 women; mean age, 33 [9] years; age range, 19-55 years) were enrolled in part II. For simvastatin acid, C(max) was significantly smaller (1.68 vs 3.62 ng/mL; P < 0.013) and T(max) and apparent t((1/2)) significantly longer (10.33 vs 4.04 hours [P < 0.001] and 11.41 vs 4.16 hours [P < 0.011]) for the CR formulation compared with the IR formulation, respectively, after the single-dose administration. After the multiple-dose administration, for simvastatin acid, the C(max) for the CR formulation was significantly smaller (3.40 vs 5.16 ng/mL; P < 0.037), while the values for T(max) and apparent t((1/2)) were significantly longer (8.40 vs 4.57 hours and 13.09 vs 4.52 hours; both, P < 0.001) compared with the IR formulation. There was no significant difference between the CR and the IR formulations for AUC(0-last) and AUC(0-infinity)) during either the single- or multiple-dose testing. Both CR and IR formulations were well tolerated in all subjects, and no serious AEs or adverse drug reactions were found. No subjects reported any AEs during part I of the study. During part II, 6 subjects (3 from each formulation group) reported headache, 1 reported lumbago before the dose, and 1 subject had a hordeolum while receiving the CR formulation.nnnCONCLUSIONSnThe C(max) of the simvastatin CR formulation was found to be significantly smaller while the AUC of the active moiety did not differ significantly from that of the IR formulation in these healthy Korean subjects. The simvastatin CR and IR formulations were well tolerated, with no serious AEs observed. To evaluate the characteristics of the CR formulation, its clinical efficacy must be examined in patient populations.

Tolerability and pharmacokinetics of a new P-glycoprotein inhibitor, HM30181, in healthy Korean male volunteers: single- and multiple-dose randomized, placebo-controlled studies.

BACKGROUNDnHM30181 is an oral P-glycoprotein (P-gp) inhibitor developed to enhance the oral bioavailability of P-gp substrate drugs.nnnOBJECTIVEnThe objective of this study was to investigate the tolerability and pharmacokinetic properties of HM30181 after single and multiple oral administrations to healthy Korean male volunteers. The study was performed to meet regulatory criteria for marketing the test product in South Korea.nnnMETHODSnA dose-block-randomized, double-blind, placebo-controlled, dose-escalation study was performed in 180-, 360-, 600-, and 900-mg single-dose groups and 60-, 180-, and 360-mg multiple-dose groups with 10 subjects (8 active; 2 placebo) per group. In the single-dose study, blood and urine samples were collected for up to 120 hours after drug administration. In the multiple-dose study, subjects received the study drug or placebo orally once daily for 5 days. Blood samples were collected up to 624 hours after the last dose, and up to 24 hours after the first dose to evaluate the accumulation index. Urine samples were collected up to 120 hours after the last dose. Pharmacokinetic analysis was performed using noncompartmental methods. Adverse events were collected by the spontaneous reporting of the subjects or when subjects were asked general health-related questions.nnnRESULTSnThirty and 70 healthy male volunteers completed the single- and multiple-dose studies, respectively. Mean (SD) age and body weight of subjects in the single administration group were 24.0 (1.8) years and 68.8 (7.4) kg, respectively, and those of the multiple administration group were 24.5 (2.6) years and 67.6 (7.7) kg, respectively. The plasma concentrations peaked at 14 to 42 hours and declined with t(½) of 75.7 to 169.3 hours after single administration, and peaked at 5.5 to 8.0 hours and declined with t(½) of 153.5 to 215.2 hours after multiple administrations. C(max) and area under the concentration curve within dosing intervals (AUC(τ)) increased dose dependently after single administration; however, dose-dependent increases in C(max) and AUC(τ) were not observed after multiple administrations. The fraction of drug excreted unchanged in urine was minimal, with values <0.01% in all dose groups. HM30181 accumulated after multiple administrations with an accumulation index of 4.0 to 7.4. All adverse events reported were mild in intensity; there were no serious adverse events reported. The most frequently reported adverse event was gastrointestinal disorder.nnnCONCLUSIONSnHM30181 was well tolerated after oral administration within the dose range evaluated, with the exception of the repeated administration of 360 mg, for which gastrointestinal disorders were frequently reported. The systemic exposure of HM30181 was relatively low, and dose proportional properties of HM30181 were not observed.

The Pharmacokinetics and Safety of a Fixed-Dose Combination of Acetylsalicylic Acid and Clopidogrel Compared With the Concurrent Administration of Acetylsalicylic Acid and Clopidogrel in Healthy Subjects: A Randomized, Open-Label, 2-Sequence, 2-Period, Single-Dose Crossover Study

BACKGROUNDnDual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is used for the treatment of acute coronary syndrome. A combined formulation of ASA and clopidogrel has been developed to provide dosing convenience and improve adherence.nnnOBJECTIVEnThis study was designed to compare the pharmacokinetic properties and safety profile of a fixed-dose combination formulation of ASA and clopidogrel with concurrent administration of each agent in healthy male Korean volunteers.nnnMETHODSnThis single-dose, randomized, open-label, 2-period crossover study was conducted in 64 healthy Korean volunteers. Equal numbers of eligible participants were randomly assigned to receive either the fixed-dose combination of ASA 100 mg and clopidogrel 75 mg or the free combination of each agent followed by a 7-day washout period and then administration of the alternate formulation. Serial blood samples were collected immediately before and after dosing for 24 hours. The safety profile was evaluated by using adverse events (AEs), which were assessed by physical examination, vital signs, ECGs, clinical laboratory tests, and interviews. The 2 formulations were considered to be bioequivalent if the 90% CIs for the log-transformed C(max) and AUC(0-last) values were within the predetermined range of 0.8 to 1.25.nnnRESULTSnSixty-four volunteers (mean [SD] age, 27.51 [8.15] years; weight, 68.55 [7.86] kg; height, 173.80 [5.94] cm) were enrolled, and 63 completed the study. For ASA, the 90% CIs for the geometric mean ratios of C(max) and AUC(0-last) were 0.9483 to 1.1717 and 0.9946 to 1.1020, respectively. For salicylic acid, the 90% CIs were 0.9614 to 1.0396 for C(max) and 0.9778 to 1.0163 for AUC(0-last). For clopidogrel, the 90% CIs were 0.9809 to 1.2562 for C(max) and 0.9674 to 1.2073 for AUC(0-last). Six of the 20 AEs reported were drug related: decreased hemoglobin levels (n = 2), fever (n = 1), and headache (n = 1) with the test formulation and increased alanine aminotransferase levels (n = 1) and dyspepsia (n = 1) with the reference formulation. All of the drug-related AEs were transient and mild in severity.nnnCONCLUSIONSnThe fixed-dose combination of ASA and clopidogrel 100 mg/75 mg did not meet the regulatory criteria for bioequivalence as defined by the Korea Food and Drug Administration. Both formulations were well tolerated in these healthy male Korean subjects. ClinicalTrials.gov Identifier: NCT01448330.

Pharmacokinetic interactions between eperisone hydrochloride and aceclofenac: a randomized, open-label, crossover study of healthy Korean men.

BACKGROUNDnEperisone hydrochloride, a centrally acting muscle relaxant, is a calcium antagonist that causes vasodilation and antispastic actions. Aceclofenac, an anti-inflammatory analgesic and antipyretic drug, has similar efficacy and improved gastrointestinal tolerance compared with other nonsteroidal anti-inflammatory drugs, such as diclofenac. Although eperisone hydrochloride and aceclofenac are frequently coadministered, no published studies have reported on the pharmacokinetic interactions between these 2 drugs.nnnOBJECTIVEnThe aim of this study was to investigate any pharmacokinetic interactions between eperisone hydrochloride and aceclofenac in healthy Korean men.nnnMETHODSnThis was a randomized, open-label, crossover study. Each participant was randomly assigned to 1 of 6 treatment sequences and received eperisone hydrochloride (3 doses of 50 mg each), aceclofenac (2 doses of 100 mg each), or both as a single dose with a 7-day washout period between each dose. Blood samples were collected ≤ 24 hours after dosing, and plasma eperisone hydrochloride and aceclofenac concentrations were determined using validated LC/MS-MS. Pharmacokinetic analyses were conducted using noncompartmental methods. A safety profile was determined using the measurement of vital signs, ECG, and clinical laboratory tests.nnnRESULTSnA total 24 of men were enrolled, and all completed the study. The geometric mean ratios (90% CIs) of the Cmax and AUC0-∞ values for eperisone were 1.18 (0.828-1.673) and 1.12 (0.836-1.507), respectively. The geometric mean ratios (90% CIs) of the Cmax and AUC0-∞ for aceclofenac were 0.93 (0.847-1.022) and 1.01 (0.979-1.036), respectively. A total of 7 adverse events were reported in 7 men. All adverse events were mild, and no significant differences were found between treatment groups.nnnCONCLUSIONnNo clinically significant pharmacokinetic differences exist between 150 mg eperisone hydrochloride and 200 mg aceclofenac when administrated as a monotherapy or in combination.

Pharmacokinetic and Pharmacodynamic Properties of a New Long-Acting Granulocyte Colony-Stimulating Factor (HM10460A) in Healthy Volunteers

BackgroundHM10460A is a newly developed recombinant human granulocyte colony-stimulating factor with long-lasting characteristics. This factor is expected to be used for chemotherapy-related neutropenic conditions.ObjectiveThe aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of HM10460A following subcutaneous administration to healthy Korean subjects.MethodsA randomized, double-blind, placebo-controlled, escalating single-dose study was conducted in 40 healthy Korean subjects. The subjects were allocated to single-dose groups of 5, 15, 45, 135 or 350xa0μg/kg, or placebo. Serial blood samples for pharmacokinetic/pharmacodynamic analyses were collected up to 22xa0days, and urine samples for pharmacokinetic analysis were collected up to 3xa0days after subcutaneous administration of HM10460A. The serum and urine concentrations were analyzed by enzyme-linked immunosorbent assay.ResultsMost of the serum concentrations in the 5 and 15xa0μg/kg dosing groups were below the lower limit of quantification (LLOQ). The median times to the peak concentration (Tmax) of HM10460A in the 45, 135, and 350xa0μg/kg dosing groups were 8.0, 14.0, and 24.0xa0h, respectively. The meanxa0±xa0standard deviation values of the dose-normalized maximum concentration (Cmax) and dose-normalized area under the concentration-time curve (AUClast) for the 45, 135, and 350xa0μg/kg dosing groups were 14.13xa0±xa06.37, 66.19xa0±xa038.71, and 34.65xa0±xa019.69xa0μg/L/mg, respectively, and 265.0xa0±xa0124.1, 2144xa0±xa01232, and 1386xa0±xa0701.2xa0μgxa0h/L/mg, respectively. The concentrations of HM10460A in the urine were below the LLOQ in all of the subjects. In all of the dosing groups, the area under the effect-time curve (AUEClast) of both the absolute neutrophil count (ANC) and the CD34+ cell count increased as the dose increased.ConclusionHM10460A showed dose-dependent pharmacokinetic characteristics, and the systemic exposure of HM10460A was positively correlated with the ANC and CD34+ cell counts.

Pharmacokinetic comparison of controlled- and immediate-release formulations of dexibuprofen after single and multiple oral doses in fasting healthy male Korean volunteers.

BACKGROUNDnDexibuprofen is a pure S(+)-enantiomer product of racemic ibuprofen. A new extended-release form of dexibuprofen has recently been developed.nnnOBJECTIVEnWe aimed to compare pharmacokinetic characteristics of controlled-release (CR) and immediate-release (IR) formulations of dexibuprofen after single and multiple oral doses in fasting healthy male Korean volunteers.nnnMETHODSnBoth single- and multiple-dose studies used an open-label, randomized, 2-way, crossover design. In the single-dose study, 24 subjects were administered a 600-mg CR or 300-mg IR formulation. In the multiple-dose study, 24 subjects were administered a 600-mg CR formulation q12h or 300-mg IR formulation q6h. Pharmacokinetic parameters of dexibuprofen were determined by noncompartmental analysis.nnnRESULTSnAll formulations used in the single- and multiple-dose studies were well tolerated, and there were no severe adverse events. In the single-dose study, the mean (SD) AUC(0-t) was 155.60 (40.94) μg/h/mL for the CR formulation and 161.11 (37.50) μg/h/mL for the IR formulation; the mean (SD) C(max) values were 22.71 (6.64) and 23.77 (4.91) μg/mL, respectively; and the median T(max) values were 2.01 hours and 2.00 hours, respectively. The geometric mean ratios (90% CI) of the CR to IR formulations were 0.96 (0.92-1.00) for AUC(0-t) and 1.00 (0.87-1.14) for C(max). In the multiple-dose study, the mean (SD) AUC(0-τ) values for CR and IR were 129.70 (23.72) μg/h/mL and 150.04 (27.09) μg/h/mL, respectively; the mean (SD) C(max,ss) values were 24.51 (5.12) and 21.69 (5.21) μg/mL, respectively; and the median T(max.ss) values were 2.51 hours and 5.25 hours, respectively. The geometric mean ratios (90% CI) of the CR to IR formulations were 0.86 (0.81-0.91) for AUC(0-τ) and 1.13 (1.03-1.24) for C(max).nnnCONCLUSIONSnThe pharmacokinetic parameters of single and multiple administrations of dexibuprofen did not differ for the IR and CR formulations in this small, selected group of healthy male Korean subjects. Both formulations were well tolerated.