Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel

Background and objectives: Clopidogrel is an important antiplatelet drug that is effective in preventing thrombotic events, especially for patients undergoing percutaneous coronary intervention. The therapeutic usefulness of clopidogrel has been limited by documented inter‐individual heterogeneity in platelet inhibition, which may be attributable to known clopidogrel pharmacokinetic variability. The objective of this study was to assess the influence of smoking cigarettes and abnormal body weight on the pharmacokinetics of clopidogrel. Methods: Seventy‐six healthy adult male volunteers were selected randomly. Each subject received a single 75 mg oral dose of clopidogrel after overnight fast. Clopidogrel carboxylate plasma levels were measured and non‐compartmental analysis was used to determine peak plasma concentration (C_max), time to peak plasma concentration (T_max), elimination half‐life (t_1/2e), and area under the curve (AUC_0→∞). Results: One‐third of volunteers were smokers (n = 27) and one‐half had abnormal body weight (n = 39). Smokers had lower AUC_0→∞ (smokers: 6·24 ± 2·32 μg/h/mL vs. non‐smokers: 8·93 ± 3·80 μg/h/mL, P < 0·001) and shorter half‐life (smokers: 5·46 ± 2·99 vs. non‐smokers: 8·43 ± 4·26, P = 0·001). Smoking behaviour had no influence on C_max (P = 0·3) and T_max (P = 0·7). There was no statistically significant difference in C_max, AUC_0→∞, T_max and t_1/2e between volunteers with abnormal body weight and normal body weight. However the difference in body weight of the two groups was relatively narrow (mean ± SE; 26·93 ± 0·16 vs. 23·11 ± 0·27). In general, the pharmacokinetic parameters were characterized by considerable inter‐individual differences (C_max = 3·09 ± 0·99 μg/mL, CV = 32%), (T_max =0·76 ± 0·24 h, CV = 31·6%), (AUC_0→∞ = 7·98 ± 3·58 μg/h/mL, CV = 44·8%), and (t_1/2e = 7·38 ± 4·10 h, CV = 55·6%). Conclusion: Smoking is a significant factor affecting the pharmacokinetics of clopidogrel, following administration of a single 75 mg dose in healthy young volunteers. The study supports smoking‐cessation recommendations. Further studies are required to evaluate the influence of smoking and body weight on the pharmacokinetics of the active metabolite of clopidogrel and on the clinical effects of any differences observed.     

Comparative pharmacokinetic evaluation of two formulations of bicalutamide 50-mg tablets: An open-label,randomized-sequence,single-dose,two-period crossover study in healthy Korean male volunteers

Background: Bicalutamide is an oral nonsteroidal antiandrogen drug used during hormone ablation therapy for prostate cancer. A new generic formulation of bicalutamide has been developed.Objectives: This study was conducted to meet Korean and US regulatory requirements for the marketing of the generic 50-mg tablet formulation of bicalutamide. To this end, the pharmacokinetic properties of the new (test) formulation were compared with those of the currently marketed (reference) formulation. Tolerability was also evaluated.Methods: An open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy Korean male volunteers. Subjects received either the test or reference formulation of bicalutamide 50-mg tablets in the first period and crossed over to the alternative formulation in the second period. Serial blood samples for pharmacokinetic analysis were taken over 672 hours after dosing. Plasma concentrations of bicalutamide were measured by HPLC-MS/MS. Pharmacokinetic parameters, including AUC_0–672h, were determined by noncompartmental analysis. Log-transformed C_max and AUC_0–672h for the 2 formulations were compared. Tolerability was monitored based on laboratory tests, ECGs, vital signs, and physical examinations.Results: Of the 34 subjects initially enrolled, 33 completed the study. The mean (SD) age, height, and weight of participants were 25.8 (4.1) years, 173.6 (5.7) cm, and 68.9 (7.8) kg, respectively. The median T_max was 36.0 hours for both formulations. The mean (SD) t_½, C_max, and AUC_0–672h for the reference formulation were 135.4 (28.6) hours, 933.2 (169.2) μg/L, and 215,680.1 (48,753.4) μg · h/L, respectively. Corresponding values for the test formulation were 134.3 (30.7) hours, 946.7 (179.9) μg/L, and 221,708.8 (54,935.1) μg · h/L. The 90% CIs for the mean ratios (test/reference) of log-transformed C_max and AUC_0–672h were 0.97 to 1.06 and 0.98 to 1.07, respectively. Twelve adverse events were reported for each formulation, none of which were considered drug related in the test-formulation group and 4 of which were considered drug related in the reference-formulation group (3 cases of headache, 1 case of erythematous rash).Conclusions: In this single-dose study in healthy Korean male subjects, the new formulation of bicalutamide 50-mg tablets met Korean and US regulatory criteria for assumption of bioequivalence with the currently marketed formulation. Both formulations were generally well tolerated, with no clinically relevant safety concerns.     

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.     

Pharmacokinetics of a Once-Daily extended-release formulation of pramipexole in healthy male volunteers: Three studies

Background: Pramipexole is a dopamine agonist used in the treatment of Parkinson's disease. The currently available immediate-release (IR) formulation is taken orally 3 times daily.Objectives: These studies were conducted to evaluate the pharmacokinetic properties of a variety of prototypes for a once-daily extended-release (ER) formulation of pramipexole and to further characterize the prototype whose pharmacokinetics best matched those of the IR formulation.Methods: Three Phase I studies were conducted, all in healthy adult men aged ≤50 years with a body mass index of 18.5 to 29.9 kg/m². In the first study, 7 prototypes of a once-daily ER formulation with various release properties, including rate and pH dependence, were compared with the IR formulation taken 3 times daily to identify the optimal pharmacokinetic resemblance based on predefined criteria derived from plasma AUC_0?24h, C_max, and C_min. In the second study, a level A in vitro/in vivo correlation (IVIVC) suitable for predicting an entire in vivo bioavailability time course based on in vitro dissolution was established and validated, and the single-dose pharmacokinetics of the optimal ER formulation identified in the first study were analyzed for food effect. In the third study, steady-state pharmacokinetics of the optimal ER formulation were assessed across a range of pramipexole doses (0.375–4.5 mg/d), including investigation of the food effect at steady state for the highest dose. Tolerability was assessed throughout all studies based on physical examinations, laboratory measurements, and adverse events (AEs).Results: The 3 studies included 18, 15, and 39 subjects, respectively. Among the ER prototypes tested at 0.75 mg once daily in study 1, a matrix tablet had the optimal pharmacokinetic resemblance to IR pramipexole 0.25 mg TID, with a geometric mean AUC_0?24h,ss of 17.4 ng·h/mL (vs 16.0 ng·h/mL for the IR formulation), C_max,ss of 0.967 ng/mL (vs 1.09 ng/mL), and C_min,ss of 0.455 ng/mL (vs 0.383 ng/mL). For single-dose ER 0.375 mg administered in the fasted state in study 2, in vivo bioavailability was predictable from in vitro dissolution data, with internal mean absolute percent prediction errors of 3.18% for AUC_0?30h and 4.87% for C_max, and external mean absolute prediction errors of 6.61% and 3.34%, respectively, satisfying current guidelines for a level A IVIVC. For single-dose ER 0.375 mg administered in the fed state, the upper bound of the 90% CI for fed:fasted values was 119.8 for AUC_0–30h (within the bioequivalence limits of 80%–125%) and 134.1 for C_max. At steady state in study 3 (subjects' 5th treatment day), dosing at 0.375 to 4.5 mg in the fasted state was associated with a linear, dose-proportional increase in pharmacokinetic parameters, including AUC_0–24h,ss and C_max,ss. At the highest fasted dose (4.5 mg), the geometric coefficient of variation for interindividual variability at steady state was 30.1% for AUC_0–24h,ss (vs 21.4% for IR pramipexole 1.5 mg TID) and 22.3% for C_max,ss(vs 19.0%). At steady state, the upper bounds of the 90% CIs for fed:fasted values with ER 4.5 mg were 122.1 for AUC_0–24h and 126.8 for C_max. No serious AEs occurred, and the dropout rate was low.Conclusions: In these studies in healthy male volunteers, an ER pramipexole formulation was identified that resembled the IR formulation in terms of both pharmacokinetics and tolerability. In patients with Parkinson's disease, once-daily use of an ER formulation may improve the convenience of treatment relative to the IR formulation taken 3 times daily and thus increase compliance.     

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.     

Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: A randomized,open-label,single-dose,fasting, two-period,two-sequence crossover comparison in healthy male South American volunteers

Background: Imatinib is a tyrosine kinase inhibitor that has been established as a highly effective therapy for chronic myelogenous leukemia and gastrointestinal stromal tumors. A new generic, once-daily 400-mg tablet of imatinib has been developed by a pharmaceutical company in Argentina, where the regulatory standard for marketing authorization of an imatinib generic is in vitro dissolution testing.Objective: The aim of this study was to assess the bioequivalence of a new generic film-coated test tablet formulation versus a film-coated reference tablet formulation of imatinib 400 mg. The local manufacturer seeks to validate the in vitro performance of this new formulation with a bioequivalence study.Methods: A randomized, open-label, single-dose, fasting, 2-period, 2-sequence crossover design with a 2-week washout period was used in this study. The study population consisted of healthy male South American (Uruguayan) volunteers, who were assigned in a 1:1 ratio to a randomized sequence (test-reference or reference-test). In each period, the test or reference formulation was administered after an overnight fast. During the 72-hour follow-up period, participants were monitored for vital signs and symptoms. Blood samples were collected at 15 time points, including baseline, until 72 hours. Physical examination and laboratory tests (blood, urine) were repeated 1 week after study completion. A noncompartmental model was used to determine the pharmacokinetic parameters of imatinib. The 90% CIs of the test/reference ratios for AUC_0-∞ and C_max were determined; the test and reference formulations were considered bioequivalent if the 90% CIs were between 0.80 and 1.25. Adverse events were assessed by a nurse who administered a questionnaire while the healthy volunteers were admitted in the unit.Results: The bioequivalence study was conducted in 30 Uruguayan male volunteers. Demographic characteristics (mean [SD]) included age, 27.8 (6.5) years; weight, 71.2 (9.8) kg; height, 1.71 (0.09) m; and body mass index, 24.3 (3.0) kg/m2. The mean (SD) of AUC_0-∞ was 38,179 (15,504) ng/mL · h^?1 for the test formulation and 40,554 (17,027) ng/mL · h^?1 for the reference formulation. The mean of Cmax for the test formulation was 2472 (933) ng/mL, and the mean Tmax was 3.28 (0.93) hours. The mean of Cmax for the reference formulation was 2566 (963) ng/mL, and the mean T_max was 3.63 (1.20) hours. The point estimates (90% CIs) for the test/reference ratios of the log-transformed AUC- and C_max mean values were 0.95 (0.87–1.03) and 0.97 (0.89–1.05), respectively, which met the regulatory criteria for bioequiv-alence. Thirty-four mild to moderate adverse events were reported (13 with the test formulation and 21 with the reference formulation), and no serious or unexpected adverse events were observed during the study. The adverse events included 16 cases of headache, 13 cases of nausea, 4 cases of vomiting, and 1 episode of diarrhea.Conclusions: The results of this study suggest that the test formulation of imatinib met the regulatory criteria for bioequivalence to the reference formulation in these healthy fasting male volunteers. Both formulations were generally well tolerated and appeared to have a similar adverse-event profile.     

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.     

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.     

Benzathine penicillin G: a model for long‐term pharmacokinetic comparison of parenteral long‐acting formulations

What is known and Objective:  Long‐acting intramuscular penicillin G injection is an important product for the management of some severe infections. However, testing the bioequivalence of such long‐acting formulations is difficult. Our aim was to undertake such a test using a generic formulation containing 1 200 000 IU of benzathine penicillin G powder and an innovator’s product (Retarpen^® 1·2 million units; Sandoz, Switzerland). Methods:  In an open, double‐blind, randomized, two‐periods, two‐group crossover study, 12 healthy male volunteers received both formulations of benzathine penicillin G on two different days with a 5‐month washout period between the doses and a sampling period of over 500 h. A simple, sensitive and rapid high‐performance liquid chromatography (HPLC)‐UV method was developed and validated for determination of penicillin G plasma concentrations and other pharmacokinetic (PK) parameters. Results and Discussion:  The analytical method used produced linear responses within a wide analyte concentration range with average within‐run and between‐run variations of below 15% with acceptable recovery, accuracy and sensitivity. The primary PK parameters we used were maximum plasma concentration (C_max), time to reach the maximal concentration (T_max) and the area under the plasma concentration vs. time curve from time zero to the last sampling time (AUC_0→t) using a standard non‐compartmental approach. Based on these parameters, the two formulations were bioequivalent. What is new and Conclusion:  We illustrate the bioequivalence testing of a very long‐acting product. The data indicate that the generic test formulation and the branded reference formulation were bioequivalent in fasting healthy Iranian male volunteers.     

A limited sampling strategy for estimating mycophenolic acid area under the curve in adult heart transplant patients treated with concomitant cyclosporine

Objective: Heart transplantation studies have shown a relationship between the mycophenolic acid area under the curve (AUC) 0–12 h (MPA AUC_0–12h) values and risk of acute rejection episodes and fewer side‐effects in patient receiving cyclosporine during the first year post‐transplant. However, measurement of full AUC is costly and time consuming and in this case it is an impractical approach to drug monitoring. Therefore, the authors describe a limited sampling strategy to estimate the MPA AUC_0–12h value in adult heart transplant recipients. Methods: Ninety MPA pharmacokinetic (PK) profiles were studied. The samples were collected immediately before and 0·5, 1, 1·5, 2, 2·5, 3, 4, 6, 9, 12 h after the morning dose of mycophenolate mofetil (MMF) following an overnight fast. PK profiles were determined at 6–8 weeks, 6, 12 months and more than 1 year after transplantation. Using stepwise multiple linear regression analysis a sampling strategy from 60 of PK profiles was obtained and next the bias and precision of the model were evaluated in another 30 PK profiles. Results: The three‐point model using C_0·5h, C_1h, C_2h was found to be superior to all other models tested (r² = 0·841). The regression equation for AUC estimation which gave the best fit to this model is: 9·69 + 0·63C_0·5 + 0·61C₁ + 2·20C₂. Using that model 63 of the 90 (70%) full AUC values were estimated within 15% of their actual value. For the best‐fit model, the mean prediction error was 3·2%, with 95% confidence intervals for prediction error to range from ?42·2% to 40·3%. All other models which use one, two or three time‐points over the first 2 h are poorer predictors of the full AUC than the model above. Conclusion: The proposed three time‐point equation to estimate AUC will be helpful in optimizing immunosuppressive therapy in heart transplantation.     

Bioavailability of three rufinamide oral suspensions compared with the marketed 400-mg tablet formulation: results from a randomized-sequence, open-label, four-period, four-sequence crossover study in healthy subjects

BackgroundRufinamide is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients aged ≥4 years.ObjectivesThe primary purpose of this study was to compare the relative bioavailability and other pharmacokinetics of rufinamide administered as a 400-mg tablet formulation (reference) with 10 mL of a newly developed 40-mg/mL suspension (test) manufactured using 3 different homogenization speeds in healthy subjects under fed conditions. The study also explored whether homogenization speed had any effect on rufinamide pharmacokinetics when administered as a suspension formulation.MethodsThis was a randomized, open-label, crossover, single-dose study in healthy, fed subjects aged 18 to 55 years (inclusive), conducted at a single center in the United Kingdom. Subjects were randomized to 1 of 4 treatment sequences, with each sequence consisting of 4 treatment periods. In each treatment period, subjects received a single dose of either the reference product (400-mg rufinamide tablet) or the test product (10 mL of rufinamide suspension [40 mg/mL] manufactured using 3 different homogenization speeds [1800, 2100, and 3000 revolutions per minute (rpm)]). Serial blood samples were collected for 72 hours after dosing for the measurement of rufinamide in plasma. Primary comparisons between test (suspension) and reference (tablet) formulations focused on AUC from 0 to 72 hours (AUC_0–72h) and C_max. The formulations were considered bioequivalent if the ratios of geometric least squares means and associated 90% CIs of AUC_0–72h and C_max were within the predetermined range of 80%–125%, according to the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) requirements. Tolerability was assessed by subject interviews, physical examinations, and laboratory tests.ResultsTwenty-four healthy subjects were randomized: 8 were male and 16 were female; 22 white, 1 black, and 1 Asian subjects were enrolled. Mean (SD) age was 29.8 (10.0) years. Mean weight was 68.2 (11.0) kg, and mean body mass index was 23.6 (3.0) kg/m². Twenty-one subjects completed the study; 2 subjects discontinued because of adverse events (both urinary tract infections considered unrelated to treatment) and 1 because of protocol deviation. The 72-hour pharmacokinetic data for the last complete treatment period before discontinuation were included in group means.The geometric least squares mean C_max value for the reference tablet formulation was 4840.24 ng/mL; and 4254.87, 4204.29, and 4418.44 ng/mL for the 1800-, 2100-, and 3000-rpm test suspensions, respectively. The ratios of the geometric least squares mean values (test/reference) for C_max were 0.88 (90% CI, 0.84–0.92), 0.87 (0.83–0.91) and 0.91 (0.88–0.95) for the 1800-, 2100-, and 3000-rpm suspensions, respectively, compared with the tablet formulation. The geometric least squares mean AUC_0–72h values were 75,960.48 ng · h/mL for the tablet formulation and 74,279.02, 73,746.03, and 73,701.17 ng · h/mL for the 1800-, 2100-, and 3000-rpm suspensions, respectively. The ratios of the geometric least squares mean values (test/reference) for AUC_0–72h were 0.98 (90% CI, 0.95–1.00), 0.97 (0.95–1.00) and 0.97 (0.95–0.99) for the 1800-, 2100-, and 3000-rpm suspensions, respectively, compared with the tablet formulation. The ratios and associated 90% CI limits (for test suspensions to the reference tablet) for AUC_0–72h and C_max were within the FDA and EMA criteria for assuming bioequivalence to the 400 mg tablet. Comparisons among the 3 rufinamide test suspensions also met the regulatory criteria for assuming bioequivalence to one another.Treatment-emergent adverse events (TEAEs) were experienced by 18.2% (4/22) of subjects treated with the 400-mg tablet, 21.7% (5/23) of subjects treated with the 1800-rpm suspension, 26.1% (6/23) of subjects treated with the 2100-rpm suspension, and 8.7% (2/23) of subjects treated with the 3000-rpm suspension. Overall, 54.2% (13/24) of subjects experienced a TEAE; all TEAEs were mild or moderate in severity, with headache being the most frequently reported (37.5% [9/24]). There were no serious adverse events or deaths.ConclusionThis single-dose study in a small population of fed, healthy subjects found no statistically significant differences in relative bioavailability among each of the 3 test suspensions and the currently marketed 400-mg tablet formulation of rufinamide, meeting FDA and EMA regulatory requirements for assuming bioequivalence.     

Pharmacology and tolerability of a single dose of exenatide in adolescent patients with type 2 diabetes mellitus being treated with metformin: A randomized,placebo-controlled,single-blind,dose-escalation,crossover study

Objective: This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single doses of exenatide in adolescent patients with type 2 diabetes mellitus (T2DM).Methods: This was a randomized, single-blind, dose-escalation, crossover study in adolescent (age 10–16 years) patients with T2DM who were being treated with diet and exercise or a stable dose of metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea for at least 3 months before screening. Eligible patients were allocated to receive single subcutaneous doses of exenatide 2.5 μg, exenatide 5 μg, and placebo, each followed by a standardized meal, on 3 separate days (maximum interval between first and third doses, 5 weeks). Exenatide 2.5 μg always preceded exenatide 5 μg in each treatment sequence. The primary end points were the pharmacokinetics and safety profile of exenatide; secondary end points included postprandial plasma glucose, serum insulin, and plasma glucagon concentrations.Results: The study enrolled 13 adolescent patients with T2DM (7 females, 6 males; mean [SD] age, 15 [1] years; body mass index, 32.5 [5.0] kg/m²; glycosylated hemoglobin, 8.2% [1.5%]). After administration of exenatide 5 μg, the geometric mean (SE) exenatide AUC_0?∞ and C_max were 339.5 (39.6) pg · h/mL and 85.1 (11.5) pg/mL, respectively (n = 12). The exenatide AUC appeared to be dose dependent, although exenatide was not quantifiable in all patients at the 2.5-μg dose; after administration of exenatide 2.5-μg, the geometric mean AUC_0?∞) was 159.2 (23.1) pg · h/mL (n = 6) and the geometric mean C_max was 56.3 (10.1) pg/mL (n = 9). Both exenatide doses were associated with significant reductions in postprandialplasma glucose excursions compared with placebo (P < 0.01); the incremental mean (SE) AUC_15–360min was ?3465.6 (1587.3) mg · min/dL for exenatide 2.5 pg, ?4422.2 (2434.4) mg · min/dL for exenatide 5 μg, and 3457.4 (1615.5) mg · min/dL for placebo. The 2 exenatide doses were also associated with significant reductions in postprandial plasma glucagon concentrations compared with placebo (P < 0.01); the respective incremental mean values for AUC_15–180min were 125.5 (658.4), ?1403.8 (632.1), and 1843.1 (540.6) pg · min/mL. There were no significant differences in serum insulin concentrations between exenatide and placebo. Exenatide was generally well tolerated, with no hypoglycemic events recorded during the study.Conclusions: In these adolescent patients with T2DM, administration of single 2.5- and 5-μg doses of exenatide were associated with dose-dependent increases in plasma exenatide concentrations and improved postprandial glucose concentrations compared with placebo. Both doses appeared to be well tolerated. ClinicalTrials.gov Identifier: NCT00254254.     

Reduction of the acute bioavailability of metformin by the α-glucosidase inhibitor acarbose in normal man

In a double-blind cross-over study, we investigated a possible influence of the α-glucosidase inhibitor acarbose on the bioavailability of the biguanide compound metformin. Each of the six healthy young male volunteers was randomly allocated during two consecutive 7 day periods to either acarbose (days 1–3: 3 times 50mg day^?1; days 4–7: 3 times 100 mg day^?1) or placebo. At day 7 and 14 of the study, the overnight-fasted subjects ingested 1000mg metformin with the first bite of a standardized breakfast (500kcal; 60 g carbohydrates) and together with either placebo or 100 mg acarbose. Acarbose significantly (P < 0·05) reduced the meal-induced increase in blood glucose and plasma insulin levels. Acarbose induced a significant (P < 0·05) reduction in early (90, 120, 180min) serum levels, peak concentrations (Cmax: 1·22 ± 0·14 vs. 1·87 ± 0·60 mgl^?1) and area under the curve of metformin (AUC 0–540min: 423±55 vs. 652±55 mg minl^?1), but did not diminish its 24 h urinary excretion. In conclusion, acarbose significantly reduces the acute bioavailability of metformin in normal subjects.     

Pharmacokinetics and bioequivalence evaluation of two formulations of 10-mg amlodipine besylate: An open-label,single-dose,randomized, two-way crossover study in healthy chinese male volunteers

Background: Amlodipine is a third-generation dihydropyridine calcium antagonist for the treatment of angina and hypertension. The relative bioavailability of a newly developed dispersible tablet as compared with an established branded formulation has not been reported in a Chinese population.Objective: The aim of this study was to assess and compare the pharmacokinetic properties, bioavailabili-ty, and bioequivalence of a newly developed dispersi-ble tablet formulation of amlodipine besylate with those of an established branded formulation in healthy Chinese adult male volunteers.Methods: An open-label, single-dose, randomized, 2-way crossover study was conducted in fasted healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 2 tablets (5 mg each) of the test or reference formulation, followed by a 2-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Serum samples were collected over 120 hours. Amlodipine concentrations in the serum were analyzed by liquid chromatography tandem mass spectrometry with positive ion electrospray ionization using the multiple reaction monitoring mode. The visible detection of the method was in the range of 0.2 to 32.0 ng/mL, and the lower limit of quantification for amlodipine was 0.2 ng/mL. The amlodipine serum concentration-time curves were used to obtain pharmacokinetic parameters including AUC_0?t, AUC_0?∞), and C_max. The criteria for bioequivalence were 90% CIs of 80% to 125% for AUC and 70% to 143% for C_max, according to guidelines of the State Food and Drug Administration of the People's Republic of China. Tolerability was based on the recording of adverse events (AEs), monitoring vital signs, electrocardiograms, and clinical laboratory tests at baseline and completion of the study.Results: A total of 20 healthy Chinese male volunteers (mean [SD] age, 21.4 [2.6] years [range, 1926 years]; weight, 61.3 [5.4] kg [range, 54.0–75.0 kg]; and height, 171.2 [3.6] cm [range, 162.0–177.0 cm) were included in the study. The mean (SD) C_max, T_max, AUC_0?t, and AUC_0?∞) values after administration of the test and reference formulations, respectively, were as follows: 5.46 (1.13) versus 5.88 (1.24) ng/mL, 7.70 (2.08) versus 9.20 (4.18) hours, 284.56 (77.59) versus 311.34 (75.97) ng/mL/h, and 331.37 (111.03) versus 358.74 (101.10) ng/mL/h. The mean (SD) t_1/2 was 38.52 (10.51) hours for the test formulation and 38.75 (7.07) hours for the reference formulation. On analysis of variance, no period or sequence effects were observed for any pharmacokinetic property; however, a significant formulation effect was observed for C_max, AUC_0?t, and AUC_0?∞). The relative bioavaila-bility of the test formulation was 90.9% by mean AUC_0?t and 91.2% by mean AUC_0?∞. The 90% CIs for the ratios of C_max, AUC_0?t, and AUC_0?∞ were 88.4% to 97.5%, 86.4% to 95.7%, and 85.8% to 97.0%, respectively, meeting the predetermined criteria for bioequivalence. One subject (5%) reported 2 AEs. The AEs were mild, possibly associated with study drug, and resolved spontaneously by the next evaluation. No serious AEs were reported.Conclusions: In this small study in healthy Chinese adult male volunteers, a single 10-mg dose of the dispersible tablet formulation (test) of amlodipine besy-late met the regulatory criteria for bioequivalence to the established tablet formulation (reference) based on the rate and extent of absorption. Both formulations were well tolerated.     

Single-dose bioequivalence assessment of two formulations of polysaccharide iron complex capsules in healthy adult male Chinese volunteers: A sequence-randomized, double-blind, two-way crossover study

Background: Iron deficiency anemia (IDA) is a common nutritional disease worldwide. Iron supplementation is an efficient method for treating patients with IDA. Polysaccharide iron complex is an oral iron supplement that is associated with generally good tolerability and good bioavailability.Objective: The aim of this study was to evaluate the bioequivalence of 2 branded formulations of polysaccharide iron complex in healthy adult male Chinese volunteers by determining the pharmacokinetic parameters after single-dose oral admi ni strati on.Methods:This sequence-randomized, double-blind, 2-way crossover study was carried out in the Affiliated Hospital, Institute of Medical Sciences of Qingdao University, Qingdao, China. Healthy adult male Chinese volunteers were enrolled and evenly randomized to receive 1 of 2 formulations on day 1. Subjects received an oral dose of 150 mg (1 capsule) of polysaccharide iron complex with 150 mL of warm water in the morning. Capsules were of similar size, shape, and color to ensure blinding. Four hours after administration, the subjects were given standardized meals. After a 1-week washout period, the subjects were crossed over to receive the other formulation in a similar manner. The serum iron concentration 12 hours after study drug administration was determined using atomic-absorption spectrometry. The pharmacokinetic parameters C_max, T_max, AUC_0−t, and AUC_0−∞ were obtained and analyzed using the Schuir mann 2 one-sided t test. The 2 formulations were considered bioequi valent if the test/reference ratios of Cmax, AUC_0−t, and their 90% CIs were within the range of 70% to 143% for C_max and within 80% to 125% for AUC_0−t. Tolerability was monitored by inquiring whether the subjects had experienced adverse events (AEs), with a focus on gastrointestinal AEs, during the clinic visits during the 24-hour period after drag administration and subsequently via telephone throughout the study.Results: Thirty adult male Chinese volunteers were assessed for inclusion. Twenty healthy male volunteers (10 in each group) (mean [SD] age, 21.5 [2.9] years [range, 19-23 years]; weight, 66.2 [5-8] kg [range, 56-80 kg]; height, 172.5 [5.1] cm [range, 162-180 cm]) were enrolled and completed the study. The pharmacokinetic parameters of the test and reference formulations were as follows: AUC_O−t, 6.58 (2.09) and 6.58 (1.91) μg/mL · h⁻¹; C_max, 1.10 (0.28) and 1.07 (0.25) μg/mL; T_max, 3.93 (0.37) and 3-93 (0.37) hours; t_½, 8.33 (0.36) and 8.38 (0.41) hours; and AUC_0−∞, 6.93 (2.23) and 6.95 (2.13) μg/mL · h⁻¹, respectively. There were no statistically significant differences in AUC_0−∞ or T_max by formulation, period, or subject between the test and reference formulations. Similarly, there were no statistically significant differences in C_max by period; however, a significant difference was found in C_max by formulation (P = 0.012). No clinically significant AEs were reported with either formulation.Conclusions: In these healthy adult male Chinese volunteers, the test formulation of polysaccharide iron complex was found to be bioequivalent to the reference formulation according to the Chinese regulatory definition. A significant difference by formulation was found in Cmax. The sample size was smaller than that recommended by the US Food and Drug Administration for a bioequivalence study, and additional studies with larger sample sizes are needed.     

Bioequivalence of Two Intravenous Formulations of Antithrombin III: A Two-Way Crossover Study in Healthy Korean Subjects

Background

Treatment with antithrombin (AT)-III is indicated for patients with sepsis or hereditary AT deficiency.

Objective

The purpose of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of 2 AT-III formulations in healthy Korean volunteers to satisfy the regulatory requirements for bioequivalence for marketing purposes.

Methods

A single-center, single-dose, open-label, randomized, 2-period, 2-sequence crossover study was conducted in healthy Korean volunteers. Blood samples for the drug analysis were collected for up to 216 hours after drug administration. Participants received either the test or reference formulation of AT-III 100 U/kg IV for 20 minutes in the first period and the alternative formulation in the second period. Both the AT-III activity and antigen (Ag) were measured for the analysis of pharmacokinetic properties, and the prothrombin time and the activated partial thromboplastin time were assessed for the analysis of pharmacodynamic properties. Because AT-III is an endogenous compound, the analysis used data corrected from baseline values. The tolerability of the 2 formulations was also assessed based on physical examinations including vital sign measurements, laboratory tests, and 12-lead ECG.

Results

Of the 20 subjects enrolled (mean [SD] age, height, and weight, 25.3 [2.3] years, 175.3 [4.5] cm, and 67.4 [6.3] kg, respectively), 19 completed both treatment periods; 1 subject withdrew consent for personal reasons. The observed mean (SD) C_max, AUC_last, and AUC_0–∞ of AT-III activity were, respectively, 279.24% (35.92), 14,364.10 (2325.25) %·h, and 17,526.38 (3150.81) %·h with the test formulation and 249.75% (31.96), 12,962.95 (1897.52) %·h, and 15,957.67 (3189.21) %·h with the reference formulation. The observed mean (SD) C_max, AUC_last, and AUC_0–∞ of AT-III Ag were 62.58 (5.66) mg/dL, 3051.94 (401.87) mg/dL·h, and 3639.80 (726.01) mg/dL·h, respectively, with the test formulation and 58.63 (5.27) mg/dL, 2805.08 (272.38) mg/dL·h, and 3340.00 (428.46) mg/dL·h with the reference formulation. The geometric mean ratios (90% CI) of the log-transformed data for AT-III activity between the 2 formulations were 1.11494 (1.08994–1.14053) for C_max, 1.11305 (1.05435–1.17503) for AUC_last, and 1.11527 (1.03754–1.19889) for AUC_0–∞; corresponding values for AT-III Ag were 1.08802 (1.06258–1.11405), 1.10905 (1.05804–1.16242), and 1.11460 (1.02058–1.21726). During the study period, 8 adverse events were reported, and all were transient, mild, and resolved completely during the treatment period.

Conclusion

The results of the present study showed that these 2 AT-III formulations met the regulatory criteria for pharmacokinetic bioequivalence with respect to AT-III activity and Ag in these healthy Korean subjects. ClinicalTrials.gov identifier: NCT00846274.     

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.     

Serum sialic acid changes in type 2 diabetic patients on metformin or rosiglitazone treatment

What is known and objective: Serum sialic acid is a recently investigated potential risk‐marker for cardiovascular complications. There is a known association between sialic acid and cardiovascular complications in diabetes mellitus. We aimed to investigate the effect of antidiabetic drugs on the serum concentration of sialic acid. Methods: We investigated the effect of metformin and rosiglitazone on the concentration of sialic acid in 120 type 2 diabetic patients, divided into a group (n = 60) receiving metformin and a group (n = 60) receiving rosiglitazone treatment. Results: Serum sialic acid was significantly higher in patients on rosiglitazone (66·90 ±8·80 mg/dL vs. 57·6 ± 8·46 mg/dL, P <0·01) and metformin (61·95 ± 10·49 mg/dL vs. 57·6 ±8·46mg/dL, P < 0·04) when compared with control subjects. In addition, rosiglitazone‐treated patients showed a significant increase in cardiovascular risk factors, notably total cholesterol (246·45 ± 20·2 mg/dL vs. 170·6 ± 15·1 mg/dL, P =0·01), triglyceride (178 ± 9·20 mg/dL vs. 149·35 ±6·31 mg/dL, P < 0·04) and glycohemoglobin (HbA1‐c) concentration (8·17 ± 1·43% vs. 4·38 ±0·96%, P < 0·02) compared with normal control subjects. The patients on metformin also showed significantly higher levels of serum glucose (133·7 ± 9·63 mg/dL vs. 88·35 ± 6·31 mg/dL, P <0·04) and glycohemoglobin (HbA1‐c) (8·23 ±1·75% vs. 4·38 ± 0·96%, P < 0·02) when compared with control subjects. Comparison of the two groups of patients revealed a significantly higher serum sialic acid (66·90 ± 8·80 mg/dL vs. 61·95 ±10·49 mg/dL, P < 0·05), total cholesterol (246·45 ±20·2 mg/dL vs. 192 ± 14·23 mg/dL, P <0·02) and triglyceride (178 ± 9·20 mg/dL vs. 158 ± 14·51mg/dL, P < 0·05) concentrations in the rosiglitazone‐treated patients. What is new and conclusions: This study suggests significantly higher levels of serum sialic acid and other cardiovascular risk factors in rosiglitazone‐treated patients than in metformin‐treated patients. The lower sialic acid concentration may explain a better metformin antidiabetic effect than with rosiglitazone.     

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.     

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.