Pharmacokinetics and safety of transdermal and oral granisetron in healthy Chinese subjects: An open-label, randomized, crossover study
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AIMS: To examine the pharmacokinetics and safety of granisetron during transdermal delivery and oral administration to healthy Chinese male subjects. MATERIALS AND METHODS: A single 34.3 mg/52 cm2 transdermal delivery patch of granisetron and the 1-mg tablet of granisetron were dosed to subjects in an open-label, randomized, crossover study. Two dosing schemes were established: scheme 1, in which the 5-day oral administration phase of the tablet (the OA phase) (twice daily every 12 hours) was conducted, followed by the 6-day transdermal delivery phase of the patch (the TD phase); and scheme 2, in which these two phases were conducted in reverse order. Plasma concentrations of granisetron were measured according to high-performance liquid chromatography, and the following pharmacokinetic parameters were determined: Cavg [AUC0-24,ss (day 5)/24 for OA and AUC24-144/120 for TD], Cmax, tmax, AUC, and T1/2. RESULTS: All of the subjects completed the TD phase, and 1 subject withdrew from the study due to increased alanine aminotransferase. The Cavg values for OA and TD were 2.95 ± 1.60 ng/mL and 2.83 ± 1.43 ng/mL, respectively. The Cmax values at steady state for OA and TD were 5.98 ± 2.27 ng/mL and 3.91 ± 2.23 ng/mL, respectively. The incidences of adverse events (AEs) possibly or definitely related to OA and TD were 45.83% and 37.5%, respectively. No serious AEs were found in the two dosing schemes. CONCLUSION: The Cavg values determined through TD and OA were equivalent, indicating similar drug exposures. Therefore, the granisetron patch may be an alternative formulation for oral granisetron in Chinese individuals.
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Influence of hepatic dysfunction on the pharmacokinetics and safety of fimasartan.

This study was designed to assess the pharmacokinetics (PK) and safety of fimasartan, an angiotensin II type 1 receptor blocker, in hepatic impairment patients as compared with healthy subjects. An open-label, single-dose, parallel study was conducted in 6 healthy male volunteers and 12 subjects with hepatic impairment. Healthy subjects were matched with hepatic dysfunction patients on the basis of age, gender, and body weight. After a single 120-mg oral administration of fimasartan, PK parameters and safety were analyzed between the hepatic dysfunction groups and healthy group. Compared with the healthy subjects, the geometric mean ratio and 90% confidence intervals for the maximum plasma concentration and the mean area under the plasma concentration-time curve from 0 to infinity (AUC)inf were 0.77 (0.24-2.47) and 1.11 (0.50-2.46), respectively, for the mild hepatic impairment and 6.55 (3.56-12.03) and 5.17 (4.19-6.37), respectively, for moderate hepatic impairment. However, there was no significant difference in time to peak plasma concentration (t(max)) and elimination half-life, and there were no serious or severe adverse events in all subjects. Subjects with mild hepatic impairment exhibited similar bioavailability compared with healthy subjects, whereas subjects with moderate hepatic impairment seemed to exhibit a higher level of systemic exposure to fimasartan than healthy subjects. In addition, all subjects were tolerable with fimasartan.

The UGT1A3*2 polymorphism affects atorvastatin lactonization and lipid-lowering effect in healthy volunteers.

OBJECTIVE: We investigated whether the UGT1A3 polymorphisms play an important role in interindividual variations in atorvastatin lactonization and lipid-lowering effect. METHODS: Twenty-three healthy volunteers were administered atorvastatin 20 mg once daily for 14 days. Serum levels of lipids were measured before and 7, 13, 14, 15, 21, and 28 days after the initial dosing. Blood samples for pharmacokinetic analysis were collected up to 48 h after the last dose. RESULTS: The UGT1A3*2 and UGT1A1*28 polymorphism had a perfect linkage in the participants. Lactone formation was significantly higher in the UGT1A3*2 carriers. The areas under the curve of atorvastatin lactone and 2-hydroxyatorvastatin lactone were 72 and 160% higher in individuals with UGT1A3*2/*2 than UGT1A3*1/*1, respectively. The maximum percent decreases in the total and the low-density lipoprotein cholesterol from baseline in UGT1A3*2 carriers were 29 and 18% less than the UGT1A3*2 noncarriers, respectively. CONCLUSION: The UGT1A3*2 polymorphism is correlated with increased atorvastatin lactonization and may affect its lipid-lowering effect.

Modeling of the LDL cholesterol-lowering effect of atorvastatin in Korean dyslipidemic patients and non-patient volunteers.

OBJECTIVE: The aim of this study was to develop a longitudinal pharmacodynamic model describing the time-courses of low-density lipoprotein cholesterol (LDL) profiles during and after atorvastatin treatment in Korean dyslipidemic patients and non-patient volunteers. METHODS: 15 dyslipidemic patients and 11 non-patient volunteers with no prior therapy participated in a parallel, 2-step dose escalation study. Subjects received atorvastatin doses ranging from 10 to 80 mg for 42 days (dyslipidemic patients) or 10 mg for 21 days (non-patient volunteers). Plasma samples were collected before and during the treatment period and up to 2 weeks after the last administration. A population pharmacodynamic model was built using the NONMEM software package. An indirect response model consisting of production in hepatocyte and elimination from plasma stimulated by atorvastatin described the LDL time-course. RESULTS: The typical population value of the estimated dose producing 50% of maximal stimulation on LDL elimination (SD50) for dyslipidemic patients was 11.9 mg, which was about 6 times higher than that of non-patient volunteers (2.0 mg). CONCLUSION: A longitudinal population pharmacodynamic model for the LDL-lowering effect of atorvastatin in both dyslipidemic patients and non-patient volunteers was developed. This could help guide optimal therapies according to the target population.

Effect of Rifampicin on the Pharmacokinetics of Evogliptin in Healthy Volunteers.

Purpose: Evogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase 4 (DPP-4) inhibitor for treating type 2 diabetes mellitus. This study investigates the effect of rifampicin on evogliptin pharmacokinetics. Patients and Methods: An open-label, crossover, one-sequence study was conducted on 12 healthy subjects. Reference baseline pharmacokinetic samples were collected on day 1 after the subjects were administered a single dose of 5 mg evogliptin. After a washout period, the subjects were administered 600 mg rifampicin once daily for 10 days, from days 8 to 17, for full induction of hepatic enzyme activity. On day 17, single doses of evogliptin (5 mg) were administered along with rifampicin (600 mg). The test pharmacokinetic samples were collected with a sampling schedule identical to that used for the reference. Results: Maximum concentration (Cmax) and area under the plasma drug concentration-time curve (AUC0-96h) of evogliptin with and without co-administration of rifampicin were compared. Reference and test Cmax and AUC0-96h values of evogliptin were 4.70 ng/mL vs 4.86 ng/mL and 153.97 ng∙h/mL vs 58.83 ng∙h/mL, respectively. All adverse events were mild in intensity and considered unrelated to evogliptin administration. Conclusion: Rifampicin decreased the AUC0-96h of evogliptin by 61.8% without significantly affecting Cmax. The mechanism underlying the decrease in AUC0-96h is thought to be the induction of cytochrome P450 (CYP), especially 3A, by rifampicin. The adverse events, none of which were serious, were not significantly altered by the concomitant administration of evogliptin and rifampicin. Nevertheless, it would be prudent that evogliptin dosing should be carefully considered when co-administered with CYP3A inducers.

Effects of Hepatic Impairment on the Pharmacokinetic Profile and Safety of Lobeglitazone.

In this open-label, single-dose, parallel-group study, we compared the pharmacokinetic profile and safety of lobeglitazone, a thiazolidinedione acting as an agonist for peroxisome proliferator-activated receptors, in patients with hepatic impairment (HI) and healthy matched controls for age, sex, and body weight. After a single oral dose of lobeglitazone (0.5 mg), the lobeglitazone (parent drug) and M7 (major metabolite) plasma concentrations and pharmacokinetic parameters were analyzed and compared between the HI patient groups and healthy matched control groups. The geometric mean ratio (GMR; 90% confidence interval [CI]) for maximum concentration (Cmax ) and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf ) of lobeglitazone was 1.06 (0.90-1.24) and 1.07 (0.82-1.40), respectively, for mild HI vs control A. The GMR (90%CI) of Cmax and AUCinf was 0.70 (0.56-0.88) and 1.00 (0.72-1.37), respectively, for moderate HI vs control B. For M7, the GMR (90%CI) of Cmax and AUCinf was 1.09 (0.75-1.57) and 1.18 (0.71-1.97), respectively, for mild HI vs control A and 1.50 (0.95-2.38) and 1.79 (1.06-3.04), respectively, for moderate HI vs control B. Notable adverse events or tolerability issues were not observed. Lobeglitazone may be safely used in patients with mild or moderate HI without dose adjustment.

Awareness and attitude of the public toward personalized medicine in Korea.

OBJECTIVES: As personalized medicine (PM) is expected to greatly improve health outcomes, efforts have recently been made for its clinical implementation in Korea. We aimed to evaluate public awareness and attitude regarding PM. METHODS: We performed a self-administered questionnaire survey to 703 adults, who participated in the survey on a voluntary basis. The primary outcome measures included public knowledge, attitude, and acceptance of PM. We conducted multinomial multivariate logistic analysis for outcome variables with three response categories and performed multivariate logistic regression analyses for dichotomous outcome variables. RESULTS: Only 28% of participants had knowledge that genetic factors can contribute to inter-individual variations in drug response and the definition of PM (199 out of 702). Higher family income was correlated with greater knowledge concerning PM (OR = 3.76, p = 0.034). A majority of respondents preferred integrated pharmacogenomic testing over drug-specific testing and agreed to inclusion of pharmacogenomic testing in the national health examination (64% and 77%, respectively), but only 51% were willing to pay for it. DISCUSSION: Our results identify the urgent need for public education as well as the potential health disparities in access to PM. This study helps to frame policies for implementing PM in clinical practice.

Correction: Awareness and attitude of the public toward personalized medicine in Korea.

[This corrects the article DOI: 10.1371/journal.pone.0192856.].

Pharmacokinetic interactions between glimepiride and rosuvastatin in healthy Korean subjects: does the SLCO1B1 or CYP2C9 genetic polymorphism affect these drug interactions?

To improve cardiovascular outcomes, dyslipidemia in patients with diabetes needs to be treated. Thus, these patients are likely to take glimepiride and rosuvastatin concomitantly. Therefore, this study aimed to evaluate the pharmacokinetic (PK) interactions between these two drugs in healthy males and to explore the effect of SLCO1B1 and CYP2C9 polymorphisms on their interactions in two randomized, open-label crossover studies. Glimepiride was studied in part 1 and rosuvastatin in part 2. Twenty-four participants were randomly assigned to each part. All subjects (n=24) completed part 1, and 22 subjects completed part 2. A total of 38 subjects among the participants of the PK interaction studies were enrolled in the genotype study to analyze their SLCO1B1 and CYP2C9 polymorphisms retrospectively (n=22 in part 1, n=16 in part 2). Comparison of the PK and safety of each drug alone with those of the drugs in combination showed that both glimepiride and rosuvastatin did not interact with each other and had tolerable safety profiles in all subjects. However, with regard to glimepiride PK, the SLCO1B1 521TC group had a significantly higher maximum plasma concentration (Cmax,ss) and area under the plasma concentration-time curve during the dose interval at steady state (AUCτ,ss) for glimepiride in combination with rosuvastatin than those for glimepiride alone. However, other significant effects of the SLCO1B1 or CYP2C9 polymorphism on the interaction between the two drugs were not observed. In conclusion, there were no significant PK interactions between the two drugs; however, the exposure to glimepiride could be affected by rosuvastatin in the presence of the SLCO1B1 polymorphism.

Comparison of pharmacokinetics and safety of fixed-dose combination of SKI306X and aceclofenac versus separate tablets in healthy subjects.

JOINS (SKI306X) is an herbal anti-arthritic medicine that is widely used with aceclofenac for treating osteoarthritis in Korea. A fixed-dose combination (FDC) tablet containing SKI306X and aceclofenac was developed to improve patient compliance. This study aimed to compare the pharmacokinetics (PK) and safety of the FDC tablet with those of co-administered SKI306X and aceclofenac in healthy subjects. In this randomized, open-label, two-way crossover, single-dose study, the FDC tablet (SKI306X 300 mg/aceclofenac 100 mg) (test) was given or co-administration of 300 mg of SKI306X and 100 mg of aceclofenac (reference) was performed followed by a 7-day wash-out period. Blood samples were collected before and after drug administration to evaluate aceclofenac PK parameters, and safety was assessed throughout the study. A total of 54 healthy male subjects were enrolled in and completed the study. Tmax and t1/2 of aceclofenac of the FDC tablet were similar to those of aceclofenac co-administered with SKI306X (Tmax: test 2.96 h and reference 2.14 h; t1/2: test 3.46 h and reference 4.04 h). The geometric mean ratios (90% confidence intervals) of Cmax and AUClast (T/R) were 0.85 (0.81 to 0.91) and 1.03 (1.01 to 1.06) respectively; these results were within the predefined range (0.8 to 1.25). There was only one drug-related adverse event (dizziness) occurred after administration of the FDC tablet; however, it was mild in severity and resolved without any complications. The FDC tablet was well tolerated and exhibited an absorption rate and extent comparable to those of SKI306X and aceclofenac administered simultaneously.

Pharmacokinetics, pharmacodynamics and safety of CKD-519, a CETP inhibitor, in healthy subjects.

CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of dyslipidemia to raise high-density lipoprotein cholesterol. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of CKD-519 in healthy adult subjects. A randomized, double-blinded, placebo-controlled, single ascending dose study was performed. Eight healthy subjects were enrolled in each CKD-519 dose group (25, 50, 100, 200, or 400 mg) and randomized to CKD-519 (n=6) or matching placebo (n=2). CKD-519 reached the maximum plasma concentration (Cmax) at 5-6 h post-dose, and had a long terminal half-life ranging between 40-70 h. The area under the plasma concentration-time curve (AUC) and Cmax increased with the dose, however, Cmax and AUC normalized by dose decreased with each incremental dose. CETP activity decreased with dose, and the maximum decrease (63%-83%) was observed at 6-8 h post-dose. A sigmoid Emax model best described the relationship between CKD-519 plasma concentrations and CETP activity with an EC50 of 17.3 ng/mL. Overall, 11 adverse events (AEs) were observed. All AEs were mild or moderate in intensity, and resolved without any complications. There were no clinically significant effects on blood pressure. In conclusion, single doses of CKD-519 up to 400 mg were well tolerated and showed potent inhibition of CETP activity.

First-in-human study with new recombinant agalsidase beta (ISU303) in healthy subjects.

ISU303 is a new recombinant agalsidase beta (Agal) enzyme replacement therapy under investigation for Fabry disease, caused by a deficiency in α-galactosidase A activity that leads to fatty deposits in tissues. We evaluated the pharmacokinetic (PK) parameters, safety and tolerability of ISU303 in healthy adult volunteers. The study was a dose block-randomized, double-blinded, placebo-controlled, single-dosing, and dose escalation phase 1 clinical trial. A total of 18 healthy subjects were enrolled (0.3 mg/kg, n = 6; 1.0 mg/kg, n = 6; placebo, n = 6). Blood samples for PK analysis were collected according to planned time. The PK parameters in each 0.3 and 1.0 mg/kg Agal group were as follows: Cmax (mU/mL) 43.19 ± 5.9 and 195.86 ± 32.3; AUClast (h·mU/mL) 207.91 ± 25.1 and 939.96 ± 158.3; t1/2 (hours) 1.13 ± 0.3 and 1.46 ± 0.2; Cl (mL/min/kg) 1.79 ± 0.2 and 1.34 ± 0.2, respectively. There were seven adverse events (AE) overall. All AEs were resolved without any complications. None were related to the study drug. There were no immunogenicity or any significant infusion-related reactions. The new Agal product exhibited a dose-dependent PK and was well tolerated with no significant AEs in healthy adult volunteers.

Impact of ABCC2, ABCG2 and SLCO1B1 polymorphisms on the pharmacokinetics of pitavastatin in humans.

Pitavastatin, a 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitor is distributed to the liver, a target organ of action and excreted mainly into the bile. To investigate the impact of influx (OATP1B1) and efflux (MRP2, BCRP) transporter alleles on its disposition, the pharmacokinetic (PK) parameters were compared among the following groups: SLCO1B1 (*15 carrier and non-carrier), ABCC2 (G1249A, C3972T, C-24T, G1549A, and G1774T), and ABCG2 (C421A) single nucleotide polymorphisms in 45 healthy Korean volunteers. Pitavastatin AUC(last) was higher in individuals carrying the SLCO1B1*15 allele than those not carrying it (144.1 ± 55.3 vs. 84.7 ± 25.7 h·ng/mL [mean ± SD], p = 0.002). The AUC(last) varied significantly according to the ABCC2 C-24T allele (103.4 ± 42.2, 80.2 ± 23.8, and 39.0 h·ng/mL in CC, CT and TT, respectively; p = 0.027). Other SNPs of ABCC2 and ABCG2 were not significant. The effect of these transporters and body weight on the AUC(last) and C(max) were tested, and only SLCO1B1 and ABCC2 C-24T genotypes were significant factors by analysis of covariance. These variants accounted for almost 50% of the variation in AUC(last) and C(max) of pitavastatin. Therefore, ABCC2 C-24T was significantly associated with pitavastatin human PK when the known effect of SLCO1B1*15 was also considered.

Effect of HMGCR variant alleles on low-density lipoprotein cholesterol-lowering response to atorvastatin in healthy Korean subjects.

The investigators quantified the relationship between the genetic polymorphism of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) and the low-density lipoprotein cholesterol (LDL-C)-lowering effects of atorvastatin in a prospective clinical study. Twenty-four healthy participants were grouped into HMGCR rs3846662 GG (n = 13) and AA (n = 11) genotypes and given atorvastatin (20 mg/d) for 14 days. Serum levels of LDL-C, high-density lipoprotein cholesterol, total cholesterol, triglycerides, and creatinine kinase (CK) were measured before (day 1) and 7, 13, 14, 15, 16, 21, and 28 days after dosing initiation. Blood samples for pharmacokinetics were taken on days 14 through 16. The levels of LDL-C in the GG group were significantly higher than in the AA group at all observation times, with mean differences of 18% to 33% (P < .05). The area under the LDL-C-time curve and the minimum value of LDL-C in the GG group were 24% and 23% higher than in the AA group, respectively (P < .01). There was no significant difference in other lipids, CK, and pharmacokinetic parameters. The HMGCR rs3846662 GG genotype was quantitatively documented to be a significant determinant for higher LDL-C level in basal state and possibly in response to atorvastatin.