Influence of CYP2D6*10 on the pharmacokinetics of metoprolol in healthy Korean volunteers

Background and objective: Genetic polymorphism of CYP2D6 leads to differences in pharmacokinetics of CYP2D6 substrates. The CYP2D6*10 allele is clinically important in Koreans because of its high frequency in Asians. We investigated whether the pharmacokinetics of metoprolol was altered by the presence of the CYP2D6*10 allele in Korean subjects. Methods: One hundred and seven volunteers were recruited and grouped as CYP2D6*1/*1, CYP2D6*1/*10 and CYP2D6*10/*10 according to their genotypes. Metoprolol tartrate 100 mg (Betaloc^®) was administered orally once to each subject in these three groups (n = 6, 7 and 5, respectively). The pharmacokinetic parameters of metoprolol and its metabolite, α‐hydroxymetoprolol, and the metabolic ratio for the three groups were estimated and compared. Results and discussion: The area under the plasma concentration–time curve (AUC_0→∞), the maximum plasma concentration (C_max) and the elimination half‐life (T_1/2) of metoprolol and α‐hydroxymetoprolol for the CYP2D6*10/*10 group were all significantly different from those of the CYP2D6*1/*1 group (P < 0·05). The AUC_0→∞s of metoprolol were 443·7 ± 168·1, 995·6 ± 321·4 and 2545·3 ± 632·0 ng·h/mL, and the AUC_0→∞s of α‐hydroxymetoprolol were 1232·0 ± 311·2, 1344·0 ± 288·1 and 877·4 ± 103·4 ng·h/mL for groups CYP2D6*1/*1, *1/*10 and *10/*10, respectively. The corresponding T_1/2 values of metoprolol were 2·7 ± 0·5, 3·2 ± 1·3 and 5·0 ± 1·1 h, while those of α‐hydroxymetoprolol were 5·4±1·5, 6·0 ± 1·4 and 10·5 ± 4·2 h, respectively. The metabolic ratios of the three groups were significantly different (P < 0·05). Conclusion: The CYP2D6*10 allele altered the pharmacokinetics of metoprolol in Korean subjects and is likely to affect other drugs metabolized by the CYP2D6 enzyme, similarly.     

Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers

What is known and objective: Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mainly metabolized by human cytochrome P450 CYP2D6 and partly by CYP3A4 to 9‐hydroxyrisperidone. Ketoconazole is used as a CYP3A4 inhibitor probe for studying drug–drug interactions. We aim to investigate the effect of ketoconazole on the pharmacokinetics of risperidone in healthy male volunteers. Methods: An open‐label, randomized, two‐phase crossover design with a 2‐week washout period was performed in 10 healthy male volunteers. The volunteers received a single oral dose of 2 mg of risperidone alone or in combination with 200 mg of ketoconazole, once daily for 3 days. Serial blood samples were collected at specific periods after ingestion of risperidone for a period of 96 h. Plasma concentrations of risperidone and 9‐hydroxyrisperidone were determined using a validated HPLC–tandem mass spectrometry method. Results and discussion: After pretreatment with ketoconazole, the clearance of risperidone decreased significantly by 34·81 ± 15·10% and the T_1/2 of risperidone increased significantly by 28·03 ± 40·60%. The AUC_0–96 and AUC_0–∞ of risperidone increased significantly by 66·61 ± 43·03% and 66·54 ± 39·76%, respectively. The Vd/f of risperidone increased significantly by 39·79 ± 53·59%. However, the C_max and T_max of risperidone were not significantly changed, indicating that ketoconazole had minimal effect on the absorption of risperidone. The C_max, T_max and T_1/2 of 9‐hydroxyrisperidone did not decrease significantly. However, the Cl/f of 9‐hydroxyrisperidone increased significantly by 135·07 ± 124·68%, and the Vd/f of 9‐hydroxyrisperidone decreased significantly by 29·47 ± 54·64%. These changes led to a corresponding significant decrease in the AUC_0–96 and AUC_0–∞ of 9‐hydroxyrisperidone by 47·76 ± 22·39% and 48·49 ± 20·03%, respectively. Ketoconazole significantly inhibited the metabolism of risperidone through the inhibition of hepatic CYP3A4. Our results suggest that besides CYP2D6, CYP3A4 contributes significantly to the metabolism of risperidone. What is new and Conclusion: The pharmacokinetics of risperidone was affected by the concomitant administration of ketoconazole. If a CYP3A4 inhibitor is used concomitantly with risperidone, it is necessary for the clinicians to monitor their patients for signs of adverse drug reactions.     

Pharmacokinetics of single‐dose rosiglitazone in chronic ambulatory peritoneal dialysis patients

Background: End‐stage renal disease (ESRD) is associated with marked alterations in the pharmacokinetics of many drugs, not only from reduction in renal clearance but also from changes in metabolic activity, bioavailability, volume of distribution and plasma protein binding. Objective: To study the pharmacokinetics of a single 8‐mg oral dose of rosiglitazone in patients with ESRD and requiring long‐term chronic ambulatory peritoneal dialysis (CAPD). Method: The medication was administered just before the first exchange of peritoneal dialysis fluid on the day that blood and peritoneal dialysate collection was performed. Results: In our CAPD patients the mean (±SD) T_max and T_1/2 of rosiglitazone were 1·20 ± 0·26 and 21·38 ± 21·96 h respectively. These values were different to those reported for healthy volunteers reported in previous studies. The mean area under the concentration–time curve (AUC_(0–∞)) and an average maximum observed plasma concentration (C_max) of rosiglitazone in our CAPD patients were 4203·56 ± 2916·97 ng h/mL and 409·67 ± 148·89 ng/mL respectively. These appear no different from those reported in healthy volunteers . Conclusion: The apparently significant difference in T_1/2 of rosiglitazone in CAPD patients compared with healthy volunteers suggest that dose adjustment may be necessary in order to avoid toxicity.     

OATP1B1 388A>G polymorphism and pharmacokinetics of pitavastatin in Chinese healthy volunteers

Purpose: To investigate the contribution of the most frequent single nucleotide polymorphism (SNPs) of the organic anion transporting polypeptide 1B1 (OATP1B1) 388A>G to the pharmacokinetics of pitavastatin in Chinese healthy volunteers. Methods: Eighteen healthy volunteers participated in this study. Group 1 consisted of nine subjects who were of 388AA wild‐type OATP1B1 genotype. Group 2 consisted of seven subjects with the 388GA genotype and two 388GG homozygotes. Two milligram of pitavastatin was administered orally to the volunteers. The plasma concentration of pitavastatin was measured for up to 48 h by liquid chromatography–mass spectrometry (LC–MS). Results: The pharmacokinetic parameters of pitavastatin were significantly different between the two genotyped groups. The concentration (C_max) value was higher in the 388GA + 388GG group than that in the 388AA group (39·22 ± 8·45 vs. 22·90 ± 4·03 ng/mL, P = 0·006). The area under the curve to the last measurable concentration (AUC_0–48) and area under the curve extrapolated to infinity (AUC_0–∞) of pitavastatin were lower in the 388AA group than in the 388GA + 388GG group (100·42 ± 21·19 vs. 182·19 ± 86·46 ng h/mL, P = 0·024; 108·12 ± 24·94 vs. 199·64 ± 98·70ng h/mL, P = 0·026) respectively. The oral clearance (Cl/F) was lower in the 388GA + 388GG group than that in the 388AA group (12·46 ± 4·79 vs. 19·21 ± 3·74/h, P = 0·012). The elimination of half‐life (t_1/2) and peak concentration times (T_max) values showed no difference between these groups. Conclusions: The OATP 388A>G polymorphism causes significant alterations in the pharmacokinetics of pitavastatin in healthy Chinese volunteers and this may well be clinically significant.     

Pharmacokinetics and safety of bromotetrandrine (BrTet, W198) after single-dose intravenous administration in healthy Chinese volunteers

Objective: To investigate the safety and pharmacokinetics of bromotetrandrine (BrTet, W198), a novel inhibitor of P‐glycoprotein (P‐gp), after single‐dose i.v. infusion in healthy Chinese volunteers. Methods: We conducted a randomized, dose‐escalating, phase I clinical study for that purpose. Thirty healthy subjects received BrTet at the doses of 10, 20 or 30 mg/m² by i.v. infusion. Plasma and urine concentrations of bromotetrandrine were determined by using a liquid chromatography–tandem mass spectrometric (LC/MS/MS) method. AUC was calculated by the trapezoidal rule extrapolation method. C_max, T_max, t_1/2α, t_1/2β, Cl and V_d were compiled from the plasma concentration–time data. Results: Bromotetrandrine was generally well tolerated at all doses. No serious or severe adverse events were found in the study. The pharmacokinetic parameters of BrTet after single i.v. infusion doses of BrTet 10, 20 and 30 mg/m² were as follows: T_max were 1·5 h in three groups, C_max were 24·79, 39·59 and 64·31 μg/L, t_1/2α were 0·37, 0·29 and 0·30 h, t_1/2β were 62·88, 56·45 and 52·20 h. AUC_0–194h were 345·83, 688·15 and 1096·28 μg h/L, Cl were 23·68, 25·69 and 25·66 L h/m², V_d were 157·73,156·96 and 140·73 L/m². In urine, the total eliminate rate of originate compound was 0·61 ± 0·19%. Conclusions: This study suggested that bromotetrandrine was well tolerated in healthy volunteers within the dose range evaluated. The pharmacokinetics parameters of bromotetrandrine indicated that the compound was rapidly distributed and accumulated in the tissues, and slowly cleared from plasma, which supported the use of BrTet for a once or twice dosing per chemotherapy cycle.     

Pharmacogenetic determinants for interindividual difference of tacrolimus pharmacokinetics 1 year after renal transplantation

What is known and objective: Tacrolimus, a widely used immunosuppressive agent in organ transplantation, has a narrow therapeutic window. It has been suggested that its interaction with lansoprazole could be dependent on polymorphisms of CYP3A5 and CYP2C19. The objective of this study was to investigate how, 1 year after renal transplantation, CYP3A5 and CYP2C19 polymorphisms, biochemical parameters and coadministration with lansoprazole, influenced tacrolimus pharmacokinetics. Methods: The pharmacokinetics of tacrolimus was studied 1 year after renal transplantation, in 75 recipients who were all receiving continuation treatment with 12‐hourly oral tacrolimus, and 30 mg lansoprazole daily (Group 1; n = 20) or, 10 mg rabeprazole daily or no proton pump inhibitor (Group 2; n = 55). Results: There were no significant differences in the dose‐adjusted area under the plasma concentration–time curve (AUC_0–12) and maximum plasma concentration (C_max) of tacrolimus between CYP2C19 genotype groups, but there were significant differences between CYP3A5 genotypes groups (*1/*1 + *1/*3 vs. *3/*3 = 45·2 ± 20·0 vs. 71·0 ± 34·1 ng·h/mL/mg, P < 0·0001 and 6·3 ± 2·6 vs. 9·3 ± 7·0 ng/mL/mg, P = 0·0017, respectively) and between co‐administration with and without lansoprazole (74·5 ± 34·0 vs. 52·4 ± 27·4 ng·h/mL/mg, P = 0·0054 and 10·9 ± 8·8 vs. 6·7 ± 3·0 ng/mL/mg, P = 0·0024, respectively). In a multiple regression analysis, the dose‐adjusted AUC_0–12 and C_max of tacrolimus were associated with CYP3A5*3/*3 and co‐administration with lansoprazole. What is new and conclusion: CYP2C19 does not seem to contribute to the interaction between tacrolimus and lansoprazole. The long‐term combination of tacrolimus and lansoprazole requires careful monitoring of patients with the CYP3A5*3/*3 genotype.     

Determination of glycyrrhetic acid in human plasma by HPLC-MS method and investigation of its pharmacokinetics

Objective: To develop a high performance liquid chromatography mass spectrometry (HPLC‐MS) method for the determination of the glycyrrhetic acid (GA) in human plasma and for the investigation of its pharmacokinetics after the oral administration of 150 mg diammonium glycyrrhizinate test and reference capsule formulations. Methods: The GA in plasma was extracted with ethyl acetate, separated on a C₁₈ column with a mobile phase of methanol (5 mmol/L ammonium acetate)–water (85 : 15, V/V) and analysed using a MS detector. Ursolic acid (UA) was used as internal standard. The target ions were m/z 469·5 for GA and m/z 455·6 for UA, the fragment voltages were 200 V and 100 V for GA and UA respectively. Results: The calibration curve was linear over the range of 0·5–200 ng/mL (r = 0·9974). The limit of quantification for GA in plasma was 0·5 ng/mL, the recovery was 76·0–80·0%, and the inter‐ and intra‐day relative standard deviations (RSD) were <12%. The pharmacokinetic parameters of GA after a single dose of 150 mg diammonium glycyrrhizinate test and reference were as follows: the half life (t_1/2) 9·65 ± 3·54 h and 9·46 ± 2·85 h, the time to peak concentration (T_max) 10·95 ± 1·32 h and 11·00 ± 1·30 h, the peak concentration (C_max) 95·57 ± 43·06 ng/mL and 103·89 ± 49·24 ng/mL; the area under time‐concentration curve (AUC_0–48 and AUC_0–∞) 1281·84 ± 527·11 ng·h/mL and 1367·74 ± 563·27 ng·h/mL, 1314·32 ± 566·40 ng·h/mL and 1396·97 ± 630·06 ng·h/mL. The relative bioavailability of diammonium glycyrrhizinate capsule was 98·88 ± 12·98%. Conclusion: The assay was sensitive, accurate and convenient, and can be used for the determination of GA in human plasma. Comparison of the bioavailability and pharmacokinetic profile of GA indicated that the test and reference capsules were bioequivalent.     

Pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers

What is known and Objective: Ivabradine is a novel heart rate‐lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Our objective was to evaluate a possible pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers. Methods: The study consisted of two periods: Period 1 (Reference), when each volunteer received a single dose of 10 mg ivabradine and Period 2 (Test), when each volunteer received a single dose of 10 mg ivabradine and 400 mg carbamazepine. Between the two periods, the subjects were treated for 15 days with a single daily dose of 400 mg carbamazepine. Plasma concentrations of ivabradine were determined during a 12‐h period following drug administration, using a high‐throughput liquid chromatography with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment period were calculated using non‐compartmental and compartmental analysis to determine if there were statistically significant differences. Results and Discussion: In the two periods of treatments, the mean peak plasma concentrations (C_max) were 16·25 ng/mL (ivabradine alone) and 3·69 ng/mL (ivabradine after pretreatment with carbamazepine). The time taken to reach C_max, t_max, were 0·97 and 1·14 h, respectively, and the total areas under the curve (AUC_0‐∞) were 52·49 and 10·33 ng h/mL, respectively. These differences were statistically significant for C_max and AUC_0‐∞ when ivabradine was administered with carbamazepine, whereas they were not for t_max, half‐life and mean residence time. What is new and Conclusion: TCarbamazepine interacts with ivabradine in healthy volunteers, and lowers its bioavailability by about 80%. This magnitude of effect is likley to be clinically significant.     

A single-dose,three-period,six-sequence crossover study comparing the bioavailability of solution,suspension, and enteric-coated tablets of magnesium valproate in healthy Mexican volunteers under fasting conditions

Background: Valproic acid has been associated with a highly variable intersubject absorptive phase; therefore, magnesium salt (magnesium valproate [MgV]) was developed to diminish variation during enteric absorption.Objectives: The aims of this study were to assess the pharmacokinetics of single oral doses of MgV 500-mg solution, suspension, and enteric-coated tablets in a healthy Mexican population, and to compare formulation-related differences.Methods: This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy Mexican volunteers aged 18 to 45 years. In each period, subjects received single oral doses of 500-mg MgV solution, suspension, and enteric-coated tablet formulations, with a 7-day washout period between each dosing period. Serial blood samples were collected at 0 hour (prior to MgV administration) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 24, 48, and 72 hours after dosing. Valproate was measured by a new method of ultraperformance liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters of interest were C_max, T_max, AUC_0–72, AUC_0?∞, t½, V_d/F, CL/F, and mean residence time (MRT). Formulation-related differences were assayed in accordance with the Mexican regulatory bioequivalence criteria. Log-transformed values of C_max and AUC were used to construct a classic 90% CI. Bioequivalence was established if the 90% CI for the mean test:reference ratio of log-transformed C_max and AUC were within the range of 0.80 to 1.25. Tolerability was assessed based on subject interview, vital sign monitoring, and clinical assessment.Results: A total of 24 healthy volunteers (12 women and 12 men; mean [SD] age, 28.79 [6.5] years; height, 164 [9.8] cm; weight, 65.42 [8.95] kg; and body mass index, 24.28 [2.11] kg/m²) were included. For the MgV solution, the mean (SD) pharmacokinetic parameters of C_max, T_max, AUC_0–72, AUC_0–∞, t½, V_d/F, CL/F, and MRT were 59.75 (8.24) μg/mL, 0.542 (0.14) hours, 1099.67 (241.70) μg · h/mL, 1156.30 (264.01) μg · h/mL, 16.19 (2.36) hours, 9633.68 (1892.70) mL, 418.35 (92.01) mL/h, and 18.36 (1.44) hours, respectively. For the MgV suspension, the mean (SD) pharmacokinetic parameters of C_max, T_max, AUC_0–72, AUC_0?∞, t½, V_d/F, CL/F, and MRT were 55.04 (7.72) μg/mL, 0.773 (0.51) hour, 1057.76 (223.37) μg · h/mL, 1111.09 (245.07) μg · h/mL, 16.32 (2.20) hours, 1069.05 (1775.64) mL, 435.43 (99.59) mL/h,\ and 18.41 (1.43) hours, respectively. For the MgV entericcoated tablets, the mean (SD) pharmacokinetic parameters of C_max, T_max, AUC_0–72, AUC_0?∞, t½, V_d/F, CL/F, and MRT were 54.88 (6.73) μg/mL, 2.79 (0.89) hours, 1100.79 (216.70) μg · h/mL, 1163.61 (238.36) μg · h/mL, 16.48 (2.10) hours, 9675.15 (1659.36) mL, 412.36 (85.24) mL/h, and 19.95 (1.53) hours, respectively. The 90% CIs for the tablets:solution ratio were 82.15 to 95.44, 94.60 to 105.39, and 95.43 to 105.95 for C_max, AUC_0–72, and AUC_0?∞, respectively. The 90% CIs for the suspension:solution ratio were 84.79 to 98.50, 88.89 to 99.02, and 89.15 to 98.97, respectively. The 90% CIs for the tablets:suspension ratio were 89.90 to 104.43, 100.84 to 112.34, and 101.60 to 112.80, respectively.Conclusion: This single-dose study found that the 3 formulations (solution, suspension, and enteric-coated tablets) of MgV met the regulatory criteria for bioequivalence in these healthy, fasting, Mexican volunteers.     

Pharmacokinetics of midazolam tablet in different Chinese ethnic groups

What is known and Objectives: Subjects of different ethnic groups may respond differently to drugs. The present study was conducted to compare the oral pharmacokinetics of midazolam among healthy volunteers from five different ethnic groups in China: Han, Mongolian, Uygur, Hui and Korean. Methods: Healthy volunteers (10 Hans, 10 Mongolians, 10 Uygurs, 10 Huis and 9 Koreans) of Chinese nationality received a single oral tablet dose of 15 mg midazolam in an open label, parallel‐group study. Blood samples were collected at intervals and analysed for midazolam by high performance liquid chromatography (HPLC). Ethnic differences in pharmacokinetic parameters of midazolam using non‐compartmental methods and anova and Kruskal–Wallis rank test. Results and Discussion: Midazolam maximum concentration (C_max) was significantly lower in Mongolians than that in Hans, Uygurs, Huis and Koreans (74·9 ± 33·7, 103·1 ± 26·4, 124·8 ± 50·0, 130·0 ± 38·3 and 189·0 ± 82·1 μg/L, respectively). C_max for the Koreans were significantly greater, compared with Hans and Mongolians. The time to attain C_max (t_max) for Hans was significantly longer as compared with Koreans and Uygurs (1·5 ± 0·7, 0·8 ± 0·5, 0·6 ± 0·7 h, respectively). Midazolam terminal half‐life (t_1/2z) were 3·0 ± 0·8, 2·2 ± 0·7, 1·9 ± 0·7, 3·5 ± 1·9, 3·8 ± 2·3 h for Hans, Mongolians, Uygurs, Huis and Koreans, respectively. The differences in half‐life were significant between Koreans and Mongolians, Koreans and Uygurs, Uygurs and Huis, respectively. There were no differences between young males and females for all pharmacokinetic parameters. Double peaks in the concentration–time profiles were observed in some subjects. What is new and Conclusion: There were some significant differences in midazolam pharmacokinetics between the five Chinese ethnic groups. However, the wide intra‐ethnic variability observed in PK parameters makes predictions of midazolam kinetics, using ethnicity as predictor, unreliable.     

Pharmacodynamic comparison of two formulations of Acarbose 100-mg tablets

What is known and Objective: Acarbose, an α‐glycosidase inhibitor, is used to treat diabetic patients. Pharmacokinetic evaluation of acarbose is difficult because <2% is absorbed systemically. The current investigation evaluated the bioequivalence of two formulations of acarbose through pharmacodynamic comparison. Methods: This investigation consisted of a pilot study and a main study. The pilot study had an open, single‐dose, single‐sequence design. Subjects received placebo and then two tablets of reference formulation (Glucobay^® 100 mg tablet; Bayer Healthcare) on two consecutive days with sucrose. The main study was an open, randomized, two‐period, two‐sequence crossover study. Subjects randomly received placebo and two tablets of either test formulation (generic acarbose 100‐mg tablet) or reference formulation with sucrose on two consecutive days in the first period. In the second period, placebo and alternative formulation were administered. Serial blood samples for pharmacodynamic assessment were taken after each administration. The maximum serum glucose concentration (G_max) and the area under the serum glucose concentration–time profile (AUC_gluc) were determined and compared. Results and Discussion: Five subjects completed the pilot study. The AUC_gluc from dosing until 1 h post‐dose (AUC_{gluc,1 h}) was significantly different between the placebo and acarbose. A total of 33 subjects completed the main study. The mean differences in G_max (ΔG_max) and AUC_{gluc,1 h} (ΔAUC_{gluc,1 h}) for the reference formulation compared with placebo were 22·0 ± 18·3 mg/dL and 928·2 ± 756·0 mg min/dL, respectively. The corresponding values for the test formulation were 23·3 ± 21·2 mg/dL and 923·0 ± 991·4 0 mg min/dL, respectively. The geometric mean ratios (GMRs) of the test formulation to the reference formulation for ΔG_max and ΔAUC_{gluc,1 h} were 1·06 and 1·00, respectively, and the 90% confidence intervals (CIs) corresponding values were 0·79–1·39 and 0·64–1·36, respectively. What is new and Conclusion: The 90% CIs of GMRs for the pharmacodynamic parameters chosen for bioequivalence evaluation of two formulations of acarbose did not meet the commonly accepted regulatory criteria for bioequivalence (0·80–1·25).     

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

Background

Dual 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.

Objective

This 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.

Methods

This 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.

Results

Sixty-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.

Conclusions

The 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     

Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized,Double-blind,Parallel-group Study

PurposeThe objective of this study was to assess pharmacokinetic (PK) and safety profiles of 2 fixed-dose combinations in development for the treatment of chronic obstructive pulmonary disease (COPD): budesonide/glycopyrronium/formoterol fumarate dihydrate metered-dose inhaler (BGF MDI; triple combination) and glycopyrronium/formoterol fumarate dihydrate (GFF MDI; dual combination). The PK and safety profiles of BGF MDI and GFF MDI were assessed for the first time in healthy Chinese adults after single and repeated (7-day) dosing.MethodsThis Phase I, randomized, double-blind, parallel-group study was conducted at a single site in Shanghai, China. Male or female Chinese subjects, 18–45 years of age and in good general health, were randomized 1:1:1 to receive BGF MDI 320/14.4/10 μg, BGF MDI 160/14.4/10 μg, or GFF MDI 14.4/10 μg. PK parameters were assessed after a single dose (day 1) and at steady state (day 8), and included AUC_0–12, C_max, and T_max. Tolerability was assessed using physical examination findings, adverse events reporting, 12-lead ECG, vital signs, and clinical laboratory values.FindingsNinety-six subjects (mean age, 25.6 years; 83.3% male) were randomized and received treatment. All randomized subjects were included in the safety and PK populations. After single and repeated dosing, budesonide AUC_0–12 and C_max were increased dose proportionally from BGF MDI 160/14.4/10 μg to BGF MDI 320/14.4/10 μg, respectively (single dose: AUC_0–12, 811.8 vs 1748 h · pg/mL; C_max, 224.3 vs 459.3 pg/mL; repeated dosing: AUC_0–12, 1250 vs 2510 h · pg/mL; C_max, 315.4 vs 626.4 pg/mL). After single and repeated dosing, glycopyrronium AUC_0–12 and C_max were similar across all treatments (single dose: AUC_0–12, 27.20–29.40 h · pg/mL; C_max, 4.884–5.674 pg/mL; repeated dosing: AUC_0–12, 69.49–77.08 h · pg/mL; C_max, 11.30–13.12 pg/mL) and formoterol (single dose: AUC_0–12, 46.49–53.58 h · pg/mL; C_max 9.651–10.62 pg/mL; repeated dosing: AUC_0–12, 81.94–85.32 h · pg/mL; C_max, 16.13–17.71 pg/mL), suggesting that the addition of budesonide did not appreciably alter the PK properties of GFF MDI. All treatment-emergent adverse events were mild in severity and rates were similar across groups (range, 50.0%–56.3%). There were no new or unexpected findings on tolerability.ImplicationsOverall, all treatments were well tolerated and PK parameters were generally comparable to those previously reported in Western and Japanese healthy subjects, suggesting that the doses of BGF MDI and GFF MDI in development globally for COPD are also appropriate for Chinese patients with COPD. ClinicalTrials.gov identifier: NCT03075267.     

Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers

Background and objective: CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. Methods: Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography–tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post‐dose. Results and discussion: There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC_0–∞ and C_max in group C were significantly higher [83·94 ± 40·41 vs. 16·39 ± 5·10 μg·h/mL (P = 0·000) and 1·50 ± 0·85 vs. 0·45 ± 0·18 μg/mL (P = 0·000)], and the oral clearance was significantly lower [1·17 ± 0·63 vs. 5·38 ± 1·86 L/h (P = 0·000)]. The half‐life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33·47 ± 12·39 vs. 19·34 ± 10·45 h), but the difference was not significant (P = 0·052). The increase in serum glucose level at 11 h after dosing (ΔC_glu11) in group C was significantly higher than that of group A (?1·08 ± 0·42 vs. 0·22 ± 1·01 mmol/L, P = 0·022). The corresponding insulin levels showed no difference between the two groups. Conclusion: CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result.     

Pharmacokinetics of duloxetine hydrochloride enteric-coated tablets in healthy Chinese volunteers: A randomized,open-label,single- and multiple-dose study

Background: Duloxetine hydrochloride is a balanced selective serotonin and norepinephrine reuptake inhibitor. Despite being widely used for the treatment of major depressive disorder in China, little information is available on the pharmacokinetic (PK) properties of duloxetine in Chinese subjects.Objectives: This study was designed to determine the concentration of duloxetine in human plasma and to compare the PK properties of duloxetine after administration of single and multiple doses of duloxetine in healthy Chinese volunteers.Methods: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining the concentration of duloxetine in human plasma was developed and applied to this single-center, open-label, single- and multiple-dose PK study. Subjects were randomized to receive a single dose of 30, 60, or 90 mg of duloxetine. Those who received the 30-mg dose continued on to the multiple-dose phase and received 30 mg twice daily for 7 days. In the single-dose phase, sequential blood samples were collected from 0 to 60 hours after drug administration. In the multiple-dose phase, samples were obtained before drug administration on days 4, 5, 6, and 7 to determine the Cssmin of duloxetine; on day 7, samples were collected from 0 to 60 hours after drug administration. The PK parameters that were calculated included C_max, T_max, t_1/2, AUC_0?t AUC_0?∞, CL, V_d, C_ssmax, C_ssmin, C_ssav, AUC_ss, AUC_ss(0?t), and C_max:C_min ratio. All values were expressed as mean (SD). Tolerability was assessed throughout the study.Results: The LC-MS/MS method was developed and validated. The standard calibration curve was linear in the concentration range from 0.89 to 106.8 ng/mL; the correlation coefficient was >0.995. The methodo-logic recovery and extraction recovery ranged from 87.22% to 113.75% and 72.81% to 89.96%, respectively. Both the intraday and interday relative SDs were <11%. Thirty Chinese subjects (3 groups of 10 subjects [5 men, 5 women] each) were enrolled in the single-dose phase of the PK study. The mean (SD) age of the subjects was 23.2 (1.8) years (range, 21–25 years); their mean (SD) weight was 61.0 (7.7) kg (range, 52–80 kg) and height was 169.0 (7.1) cm (range, 155–180 cm). The main PK parameters for duloxetine after administration of a single oral dose of 30, 60, and 90 mg were as follows: C_max = 22.46 (15.15), 44.40 (17.18), and 60.78 (27.84) ng/mL, respectively; AUC_0–60 = 328.64 (203.64), 696.04 (337.82), and 1219.33 (598.29) ng/mL · h^?1; AUC_0?∞) = 359.68 (201.01), 733.82 (343.40), and 1280.51 (644.81) ng/mL · h^?1; T_max = 6.83 (1.99), 6.10 (1.29), and 6.60 (1.58) hours; t1/2 = 12.95 (3.64), 12.81 (2.31), and 11.66 (2.06) hours; CL = 107.90 (53.05), 98.41 (41.98), and 109.58 (52.74) L/hour; and V_d = 2518.88 (1707.71), 1879.74 (999.09), and 1858.47 (1203.69) L. The 10 subjects who received the 30-mg dose in the single-dose phase continued on to the multiple-dose phase and received 30 mg of duloxetine twice daily for 7 days. Mean (SD) values for the main PK parameters for duloxetine after administration of multiple doses were as follows: C_ssmax = 47.33 (16.95) ng/mL; C_ssmm = 27.92 (9.46) ng/mL; AUC_ss(0?t) = 407.25 (125.94) ng/mL · h^?1; C_ssav = 33.94 (13.00) ng/mL; T_max = 6.36 (0.92) hours; t_1/2 = 11.19 (1.98) hours; CL = 83.12 (28.75) L/hour; and V_d = 1359.01 (590.06) L.Conclusions: In these healthy Chinese subjects, AUC and Cmax increased proportionally with the dose, whereas t_1/2 was independent of the dose. Linear PK properties were found at doses of 30 to 90 mg. No statistically significant differences were observed between the PK parameters for the subjects in the multiple-dose phase (t_1/2, CL, V_d) and those for subjects in the single-dose phase. The AUC and C_max were greater after administration of multiple doses than after administration of a single dose, suggesting du-loxetine accumulation with multiple-dose administration of 30 mg.     

Bioequivalence and tolerability of two clopidogrel salt preparations,besylate and bisulfate: A randomized,open-label,crossover study in healthy Korean male subjects

Background: Clopidogrel, a potent antiplatelet agent, reduces the risk for thrombotic events in patients with atherothrombotic diseases. Clopidogrel is marketed primarily as a bisulfate salt. A different salt preparation of clopidogrel, clopidogrel besylate, has been developed and might provide an additional treatment option for patients.Objective: The aim of this study was to compare the pharmacokinetic, pharmacodynamic, and tolerability profiles of clopidogrel besylate with those of clopidogrel bisulfate to determine bioequivalence for the purposes of marketing approval.Methods: A randomized, open-label, 2-period, single- and multiple-dose, comparative crossover study was conducted in healthy Korean male subjects. The subjects received either clopidogrel bisulfate or clopidogrel besylate as a single 300-mg oral loading dose (day 1) followed by a 75-mg/d (once daily) maintenance dose on days 2 to 6. After a 15-day washout period, subjects were administered the alternative salt preparation according to the same protocol. The plasma concentrations of clopidogrel and its primary metabolite (SR26334) were assessed using high-performance liquid chromatography/tandem mass spectrometry after administration of the loading dose. The platelet aggregation response to 10-μmol/L adenosine diphos-phate was measured using turbidometric aggregometry during the single- and multiple-dosing periods and at steady state (day 6). Tolerability was monitored using physical examination, including vital sign measurements, and laboratory analysis.Results: Forty-four subjects were enrolled and completed the study (mean [SD] age, 24.3 [2.7] years; weight, 70.0 [8.2] kg). The mean values for C_max, T_max, and AUC_0?t with clopidogrel (parent drug) of clopidogrel besylate (5.2 ng/mL, 0.9 hour, and 10.1 ng/mL/h, respectively) were similar to those with clopidogrel bisulfate (5.4 ng/mL, 0.9 hour, and 10.3 ng/mL/h). The mean values for Cmax, AUC_0?t, and AUC_0?∞ with the SR26334 of clopidogrel besylate (10.9 μg/mL, 38.8 μg/mL/h, and 43.0 μg/mL/h, respectively) were not significantly different from those with the SR26334 of clopidogrel bisulfate (11.9 μg/mL, 40.6 μg/mL/h, and 43.8 μg/mL/h). The mean values for maximal antiplatelet effect (Emax) and area under the time-effect curve (AUEC) with the 2 clopidogrel salt preparations were as follows: clopidogrel besylate, 58.8 h · % and 4299.1 h · % inhibition, respectively; and clopidogrel bisulfate, 61.7 h · % and 4406.9 h · % inhibition; these differences were not statistically significant. The 90% CIs for the ratios of the log-transformed C_max, AUC, E_max, and AUEC values were within the predetermined bioequivalence range of 80% to 125%. Three adverse events (6.8%) were reported during the study and included abdominal discomfort (1 subject [2.3%] in the group that received clopidogrel bisulfate), easy fatigability (1 subject [2.3%] immediately before administration of loading dose of clopidogrel besylate), and thrombocytopenia (1 subject [2.3%] in the group receiving the clopidogrel bisulfate). All adverse events were transient and mild.Conclusions: In these healthy Korean male subjects, the differences in the pharmacokinetic and pharmacodynamic properties between the 2 clopidogrel salt preparations did not reach statistical significance and met the regulatory requirements for bioequivalence. Both preparations were well tolerated.     

Comparative pharmacokinetics of Panadol Extend and immediate-release paracetamol in a simulated overdose model

Background: Panadol Extend is a modified‐release paracetamol formulation in which each 665 mg tablet contains 69% slow‐release and 31% immediate‐release paracetamol. There are no data on Panadol Extend pharmacokinetics in overdose. It is unknown whether the paracetamol treatment nomogram can be used to make decisions regarding the toxicity of this product in overdose. Objective: To compare the pharmacokinetics of Panadol Extend and immediate‐release paracetamol (APAP‐IR) in simulated overdose model in healthy volunteers. Methods: Cross‐over study using a dose of 90 mg/kg ideal body weight of Panadol Extend or APAP‐IR in seven healthy volunteers. Serum paracetamol concentrations were measured over 12 h. Maximal paracetamol concentration (Cmax), time to Cmax (Tmax), area under the curve (AUC) and elimination half‐life (t_1/2) were compared. Results: Mean paracetamol dose was 73 mg/kg actual body weight. Panadol Extend produced lower Cmax (0.208 mmol/L ± 0.02 vs 0.48 mmol/L ± 0.02, P = 0.0001) and AUC_{0?12 h} when compared with APAP‐IR. Tmax was delayed with Panadol Extend (2.83 h ± 0.26 vs 0.94 h ± 0.17, P = 0.0001). Absorption was complete in all subjects by 4 h post ingestion in both study arms. Elimination t_1/2 was 1.69 ± 0.09 h for APAP‐IR and 1.65 ± 0.13 h for Panadol Extend (not significant). Conclusions: Reductions in Panadol Extend Cmax and AUC_{0?12 h} might be related to elimination occurring during the absorption phase. In this model of Panadol Extend moderate overdose, Tmax was significantly delayed. In larger overdoses, time to peak paracetamol levels might be further delayed, because of continuing absorption from the formulation. Therefore, the paracetamol treatment nomogram might not reliably predict hepatotoxicity from Panadol Extend if paracetamol levels are measured too early.     

Effect of soybean administration on the pharmacokinetics of carbamazepine and omeprazole in rats

Influence of soybean administration on the bioavailability of carbamazepine and omeprazole was studied after single dose administration of soybean (10 g/kg p.o.) or after chronic administration of soybean (50% w/w mixed with normal feed) for 15 days in rats. Carbamazepine was administered orally at a dose of 10 mg/kg and omeprazole at a dose of 20 mg/kg. Soybean decreased the bioavailability of carbamazepine after both single dose and chronic administration. It produced a significant decrease in C_max, T_max, AUC_0–t of carbamazepine after single dose administration and increased the plasma clearance and V_d along with decrease in C_max, T_max, AUC_0–t and AUC_{0– ∞} after chronic administration. On the contrary, soybean administration increased the bioavailability of omeprazole by producing an increase in C_max, AUC_0–t and AUC_{0– ∞} and a decrease in V_d after single dose administration and a decrease in plasma clearance along with increase in C_max, AUC_0–t and AUC_{0– ∞} after chronic administration. The half‐life of omeprazole was also increased after both acute and chronic administration of soybean. It was concluded that soybean decreases the bioavailability of carbamazepine and increases the bioavailability of omeprazole after both single dose and chronic administration.     

Lack of significant food effect on the pharmacokinetics of ticagrelor in healthy volunteers

What is known and Objective: Ticagrelor is the first reversibly binding oral P2Y₁₂ receptor antagonist and has been approved in the European Union and the USA for the reduction of clinical thrombotic events in patients with acute coronary syndromes. This study aimed to assess the effect of food on ticagrelor pharmacokinetics. Methods: The study was an open‐label, randomized, 2‐period crossover single‐centre trial; 26 healthy volunteers received a single 270 mg (3 × 90 mg tablets) ticagrelor dose orally following: (i) a 10‐h overnight fast; and (ii) after a standard high‐fat, high‐calorie breakfast. Ticagrelor and AR‐C124910XX (a major pharmacologically active metabolite) plasma concentrations were quantified for pharmacokinetic analysis. Results: Ticagrelor median time to maximum concentration (t_max; 2·5 h vs. 1·5 h) was slightly delayed in the fed vs. fasting state. Maximum concentration of ticagrelor (C_max) was comparable between the two states with 95% confidence intervals (CI) of the geometric least‐squares (GLS) mean ratio (0·85–1·03) being within no‐effect limits (0·80–1·25). Ticagrelor exposure was slightly higher with food intake; area under the plasma concentration–time curve from zero to infinity (AUC) was 21% higher compared with fasting state (95% CI of GLS mean ratio = 1·13–1·30). For AR‐C124910XX, AUC (95% CI of GLS mean ratio = 0·93–1·07) was unaffected by food consumption. Median t_max of the metabolite was slightly longer in the fed than fasting state (3·5 h vs. 1·5 h). Mean C_max for AR‐C124910XX was slightly lower (22%) with food intake vs. fasting (95% CI of GLS mean ratio 0·69–0·88). What is new and Conclusion: Food effects on ticagrelor AUC and AR‐C124910XX C_max were small and are considered to be of minimal clinical significance. Thus, ticagrelor can be administered with or without food.     

A pharmacokinetic comparison of single doses of once-daily cyclobenzaprine extended-release 15 mg and 30 mg: A randomized,double-blind,two-period crossover study in healthy volunteers

Objective: The purpose of this study was to compare the pharmacokinetics and tolerability of single oral doses of cyclobenzaprine extended-release (CER) 15- and 30-mg capsules.Methods: This was a randomized, double-blind, 2-period crossover study in healthy adults aged 18 to 40 years. Subjects were assigned to receive a single dose of either CER 15 mg or 30 mg on days 1 and 15, separated by a 14-day washout. Study comparisons included the plasma cyclobenzaprine AUC to 168 hours after dosing (AUC_0–168), AUC_0–∞, and C_max. Plasma cyclobenzaprine T_max, terminal elimination t_1/2, and adverse events (AEs) were also assessed.Results: Sixteen subjects (9 women, 7 men) were randomized to receive cyclobenzaprine 15 mg or 30 mg; 13 (81.3%) were white and 3 (18.8%) were black. Mean age and weight were 30.2 years and 70.7 kg, respectively. The shapes of the pharmacokinetic profiles for CER 15 and 30 mg were parallel. Mean observed values for dose-dependent pharmacokinetic parameters of CER 15 and 30 mg were as follows: AUC_0–168, 318.3 and 736.6 ng · h/mL, respectively; AUC_0–∞), 354.1 and 779.9 ng · h/mL; and C_max, 8.3 and 19.9 ng/mL. Dose-independent parameters were comparable across doses. Median observed Tmax was 6.0 hours for both CER doses; mean t_1/2 was 33.4 hours for CER 15 mg and 32.0 hours for CER 30 mg. The bioavailability of the 2 doses, as indicated by the least squares mean AUC_0–∞, was 330.3 ng · h/mL for CER 15 mg and 755.1 ng · h/mL for CER 30 mg. During the CER 15-mg treatment sequence, 5 subjects experienced 5 AEs (headache, dizziness, musculoskeletal pain, dermatitis, and glossodynia); during the CER 30-mg treatment sequence, 2 subjects experienced 2 AEs (somnolence and dysmenorrhea). All AEs were mild in intensity. No serious AEs occurred during the study.Conclusions: Once-daily CER 15 and 30 mg exhibited similarly shaped pharmacokinetic profiles. AUC_0–168, AUC_0–∞), and C_max values for the 30-mg dose were approximately double those for the 15-mg dose, a result consistent with previously reported data on the dose proportionality of cyclobenzaprine immediate release.