Confidence Intervals For Cmax Research Articles

Bioequivalence study between two formulations of betamethasone dipropionate and betamethasone disodium phosphate injectable suspension in healthy adults

Objective: To evaluate bioequivalence between two formulations of 5,0 mg/mL betamethasone dipropionate + 2,0 mg/mL betamethasone disodium phosphate injectable suspension in healthy adults under fasting condition. Methods: The study was an open label, randomized, single dose, 2x2 crossover study in 36 healthy adult subjects under fasting conditions. Betamethasone concentrations in human plasma were determined using a validated liquid chromatography coupled to a tandem mass spectrometer detector method. Results: Statistical analysis has determined confidence intervals, power of the test and p-value for sequence effect to the pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞. The geometric mean ratio (90%CI) of the test drug/reference drug for betamethasone were 87.74% to 92.23% for Cmax, 93.95% to 98.91% for AUC0-t and 94.36% to 99.95% for AUC0-∞. Power of the test was 100% for all parameters and p-value for sequence effect were 33.39% for Cmax, 19.98% AUC0-t, and 24.32% for AUC0-∞. Conclusion: Reference and test formulations are statistically bioequivalent and, therefore, interchangeable, according to the local and international criteria, since confidence intervals for Cmax and AUC0-t ratios were within 80% and 125%, according to Anvisa resolution RE nº 1170/2006.

BIOEQUIVALENCE STUDY BETWEEN TWO FORMULATIONS OF TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN COATED TABLETS IN HEALTHY MALE AND FEMALE SUBJECTS UNDER FASTING CONDITIONS

Objective:To evaluate bioequivalence between a new formulation of Tramadol Hydrochloride/Acetaminophen and Ultracet® coated tablets in healthy subjects under fasting conditions. Methods:The present study was conducted as an open-label, monocentric, randomized, 2 x 2 crossover study on 40 healthy subjects in a state of fasting. The objective of the study was to compare the pharmacokinetic profiles of two formulations of tramadol hydrochloride and acetaminophen-coated tablets. The concentrations of the analytes in human plasma were measured using a validated UPLC-MS/MS method. Results:The geometric mean of the test/reference ratio, confidence intervals, and power of the test for the pharmacokinetic parametersCmax and AUC0-t, were determined by statistical analysis, in accordance with the Anvisas guidelines. The geometric mean ratio (90% CI) of the test drug/reference drug for acetaminophen was found to be 82.69% to 100.00% for Cmax and 95.36% to 100.34% for AUC0-t. The results for tramadol hydrochloride were 89.01% to 99.25% for Cmax and 94.86% to 100.71% for AUC0-t. The power of the test was greater than 98%. Conclusion:Both formulations demonstrated bioequivalent profiles, indicating that they are interchangeable in accordance with the Brazilian criteria. This is evidenced by the fact that the confidence intervals for Cmax and AUC0-t ratios were within 80% and 125%, respectively, as stipulated in Anvisa resolution RE nº 1170/2006.

A single-dose, randomized, open-label, four-period, crossover equivalence trial comparing the clinical similarity of the proposed biosimilar rupatadine fumarate to reference Wystamm® in healthy Chinese subjects.

The aim of this study was to evaluate the bioequivalence of two formulations of rupatadine (10-mg tablets) under fasting and fed conditions in healthy Chinese subjects. A total of 72 subjects were randomly assigned to the fasting cohort (n = 36) and fed cohort (n = 36). Each cohort includes four single-dose observation periods and 7-day washout intervals. Blood samples were collected at several timepoints for up to 72h post-dose. The plasma concentration of rupatadine and the major active metabolites (desloratadine and 3-hydroxydesloratadine) were analyzed by a validated HPLC-MS/MS method. The non-compartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation of the reference formulation, a reference-scaled average bioequivalence or average bioequivalence method was used to evaluate the bioequivalence of the two formulations. For the fasting status, the reference-scaled average bioequivalence method was used to evaluate the bioequivalence of the maximum observed rupatadine concentration (Cmax; subject standard deviation > 0.294), while the average bioequivalence method was used to evaluate the bioequivalence of the area under the rupatadine concentration-time curve from time 0 to the last detectable concentration (AUC0-t) and from time 0 to infinity (AUC0-∞). The geometric mean ratio (GMR) of the test/reference for Cmax was 95.91%, and the upper bound of the 95% confidence interval was 95.91%. For AUC0-t and AUC0-∞ comparisons, the GMR and 90% confidence interval (CI) were 98.76% (93.88%-103.90%) and 98.71% (93.93%-103.75%), respectively. For the fed status, the subject standard deviation values of Cmax, AUC0-t, and AUC0-∞ were all <0.294; therefore, the average bioequivalence method was used. The GMR and 90% CI for Cmax, AUC0-t, and AUC0-∞ were 101.19% (91.64%-111.74%), 98.80% (94.47%-103.33%), and 98.63% (94.42%-103.03%), respectively. The two-sided 90% CI of the GMR for primary pharmacokinetic endpoints of desloratadine and 3-hydroxydesloratadine was also within 80%-125% for each cohort. These results met the bioequivalence criteria for highly variable drugs. All adverse events (AEs) were mild and transient. The test drug rupatadine fumarate showed a similar safety profile to the reference drug Wystamm® (J. Uriach y Compañía, S.A., Spain), and its pharmacokinetic bioequivalence was confirmed in healthy Chinese subjects based on fasting and postprandial status. http://www.chinadrugtrials.org.cn/index.html, identifier CTR20213217.

In Vitro In Vivo Extrapolation and Bioequivalence Prediction for Immediate-Release Capsules of Cefadroxil Based on a Physiologically-Based Pharmacokinetic ACAT Model.

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic concept, which helps to judge the effects of biopharmceutical properties of drug product such as in vitro dissolution on its pharmacokinetic and in vivo performance. With the application of virtual bioequivalence (VBE) study, the drug product development using model-based approach can help in evaluating the possibility of extending BCS-based biowaiver. Therefore, the current study was intended to develop PBPK model as well as in vitro in vivo extrapolation (IVIVE) for BCS class III drug i.e. cefadroxil.A PBPK model was created in GastroPlus™ 9.8.3 utilizing clinical data of immediate-release cefadroxil formulations. By the examination of simulated and observed plasma drug concentration profiles, the predictability of the proposed model was assessed for the prediction errors. Furthermore, mechanistic deconvolution was used to create IVIVE, and the plasma drug concentration profiles and pharmacokinetic parameters were predicted for different virtual formulations with variable cefadroxil in vitro release. Virtual bioequivalence study was also executed to assess the bioequivalence of the generic verses the reference drug product (Duricef®).The developed PBPK model satisfactorily predicted Cmax and AUC0-t after cefadroxil single and multiple oral dose administrations, with all individual prediction errors within the limits except in a few cases. Second order polynomial correlation function obtained accurately predict in vivo drug release and plasma concentration profile of cefadroxil test and reference (Duricef®) formulation. The VBE study also proved test formulation bioequivalent to reference formulation and the statistical analysis on pharmacokinetic parameters reported 90% confidence interval for Cmax and AUC0-t in the FDA acceptable limits.The analysis found that a validated and verified PBPK model with a mechanistic background is as a suitable approach to accelerate generic drug development.

Bioequivalence of zolpidem hemitartrate: new formulations of 5 mg SL, 10 mg and 12.5 mg XR and comparison of their bioavailabilities

Objective: To evaluate pharmaceutical bioequivalence between two formulations of 5 mg zolpidem hemitartrate sublingual and, 10 and 12.5 mg extended-release formulations tablets in healthy subjects under fasting and fed conditions. Methods: An open label, monocentric, randomized, 2 x 2 crossover study in 40 healthy adults under fasting conditions comparing two formulations of zolpidem 5mg sublingual tablets. Analyte concentrations in human plasma were determined using a validated liquid chromatography with a tandem mass spectrometer detector method (LC-MS/MS). The same design was utilized to evaluate the other formulations.&#x0D; Results: Statistical analysis has determined geometric mean of test / reference ratio, confidence intervals, and power of the test to the pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞. The geometric mean ratio (90%CI) of the test drug/reference drug for zolpidem 5mg were 99.89 to 113.57% for Cmax, 97.15% to 108.40% for AUC0-t, and 97.22% to 108.13% for AUC0-∞. Power of the test was 99.35% for Cmax and 100% AUC0-t, and AUC0-∞. Conclusion: Both test and reference are bioequivalent for all formulations and, therefore, they are interchangeable, according to the Brazilian criteria (Anvisa resolution RE nº 1170/2006), since confidence intervals for Cmax and AUC0-t ratios were within 80% and 125%.

Methylphenidate Multiphasic Release Tablet: Bioequivalence Assessment between Two Formulations Administered under Fasting and Fed Conditions.

Methylphenidate hydrochloride is used to treat children, adolescents, and adults with attention deficit/hyperactivity disorder (ADHD). Multiphasic release formulation has been used to control drug levels, mainly during children's school period. This study aimed to evaluate the bioequivalence between two methylphenidate hydrochloride extended-release tablets to meet regulatory requirements for registration in Brazil. Two independent studies (under fasting and fed conditions) designed as open-label, randomized, single-dose, two-period, two-way crossover trials were conducted in healthy subjects of both genders. Subjects were enrolled and randomly received a single dose of the test formulation methylphenidate hydrochloride 54 mg extended-release tablet (Consiv®, Adium S.A., São Paulo, Brazil) or the reference formulation (Concerta®, Janssen-Cilag Farmacêutica Ltd., São Paulo, Brazil), in each period, with a 7-day washout interval. Serial blood samples were collected up to 24 h post dose and methylphenidate plasma concentrations were obtained using a validated LC-MS/MS method. A total of 96 healthy subjects were enrolled in the fasting study, of which 80 completed the study. For the fed study, 52 healthy subjects were enrolled, and 46 subjects completed it. In both studies, 90% confidence intervals for Cmax, AUC0-t, AUC0-inf, and partial AUCs were within the acceptable limits of 80.00 to 125.00%. Thus, according to regulatory requirements, the test formulation (Consiv®) was considered to be bioequivalent to the reference formulation (Concerta®) in both conditions (fasting and fed) and, therefore, it can be considered interchangeable in clinical practice. Both formulations were safe and well tolerated in single-dose administration.

Pharmacokinetic and Pharmacodynamic Comparison of Fluticasone Propionate/Formoterol Fumarate Administered via a Pressurized Metered-Dose Inhaler and a Novel Breath-Actuated Inhaler in Healthy Volunteers.

Introduction: Fluticasone propionate/formoterol fumarate (fluticasone/formoterol) exposures, following administration of Flutiform® K-haler®, a breath-actuated inhaler (BAI), were compared with the Flutiform pressurized metered-dose inhaler (pMDI) with/without spacer in two healthy volunteer studies. In addition, formoterol-induced systemic pharmacodynamic (PD) effects were examined in the second study. Methods: Study 1: single-dose, three-period, crossover pharmacokinetic (PK) study with oral charcoal administration. Fluticasone/formoterol 250/10 μg was administered via BAI, pMDI, or pMDI with spacer (pMDI+S). Pulmonary exposure for BAI was deemed no less than for pMDI (primary comparator) if the lower limit of 94.12% confidence intervals (CIs) for BAI:pMDI maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUCt) ratios was ≥80%. Study 2: two-stage adaptive design, both stages being single-dose, crossover without charcoal administration. The PK stage compared fluticasone/formoterol 250/10 μg via BAI, pMDI, or pMDI+S. The primary comparisons were as follows: BAI versus pMDI+S for fluticasone and BAI versus pMDI for formoterol. Systemic safety with BAI was deemed no worse than primary comparator if the upper limit of 94.12% CIs for Cmax and AUCt ratios was ≤125%. PD assessment was to be conducted if BAI safety was not confirmed in the PK stage. Based on PK results, only formoterol PD effects were evaluated. The PD stage compared fluticasone/formoterol 1500/60 μg via BAI, pMDI, or pMDI+S; fluticasone/formoterol 500/20 μg pMDI; and formoterol 60 μg pMDI. The primary endpoint was maximum reduction in serum potassium within 4 hours postdose. Equivalence was defined as 95% CIs for BAI versus pMDI+S and pMDI ratios within 0.5-2.0. Results: Study 1: lower limit of 94.12% CIs for BAI:pMDI ratios >80%. Study 2, PK stage: upper limit of 94.12% CIs for fluticasone (BAI:pMDI+S) ratios <125%; upper limit of 94.12% CIs for formoterol (BAI:pMDI) ratios >125% (for Cmax, not AUCt). Study 2, PD stage: 95% CIs for serum potassium ratios 0.7-1.3 (BAI:pMDI+S) and 0.4-1.5 (BAI:pMDI). Conclusions: Fluticasone/formoterol BAI performance was within the range observed for the pMDI with/without a spacer. Sponsor: Mundipharma Research Ltd. EudraCT 2012-003728-19 (Study 1) and 2013-000045-39 (Study 2).

A Pharmacokinetic Drug-Drug Interactions Study between Entecavir and Hydronidone, a Potential Novel Antifibrotic Small Molecule, in Healthy Male Volunteers.

Hepatic fibrosis is an inevitable process of hepatic sclerosis, malignancy, and insufficiency, and hydronidone is an innovative antifibrosis drug. This study focus on the pharmacokinetic interaction of hydronidone and entecavir in healthy Chinese male subjects. An open-label, three-period, multiple-dosage, self-controlled clinical trial was executed in 12 healthy male subjects. In period 1, the subjects took hydronidone 60mg, q8h, for 7days. In period 2, they were given entecavir 0.5mg once daily for 9days. Then, hydronidone and entecavir were given in combination for 6days (days 20-26). Blood samples were taken up to 24h post-dosing, while pre-dose blood samples were drawn on days 7, 19, and 26. The area under the curve (AUC)0-t_ss of entecavir slightly increased from 15.56 ± 2.67 to 16.17 ± 2.77ngh/ml with coadministration with hydronidone, while the other pharmacokinetic parameters of hydronidone and entecavir were comparable between monotherapy and combination therapy. The geometric mean ratios (GMRs) [90% confidence intervals (CIs)] of Cmax_ss, AUC0-t_ss, and AUC0-∞_ss of entecavir after coadministration compared with entecavir alone were 107.21% (97.04-118.45%), 103.85% (100.94-106.83%), and 110.81% (97.19-126.33%), respectively. And the GMRs and 90% CIs of Cmax,ss, AUC0-t_ss, and AUC0-∞_ss for combination therapy compared with the hydronidone monotherapy group were 102.72% (84.21-125.29%), 106.52% (97.06-116.90%), and 108.86% (96.42-122.89%), respectively. There was no drug-drug interaction between hydronidone and entecavir in healthy male volunteers. However, multiple doses of hydronidone have a risk with increasing exposure to entecavir in vivo, which needs to be further clarified. ChiCTR2200059683 (retrospectively registered).

Bioequivalence study of two Esomeprazole40 mg MUPS tablets in healthy adult Bangladeshi human subjects

Background: The primary objective of this study is to investigate the bioequivalence of two formulations (test&amp; reference) of Esomeprazole 40 mg MUPS Tablet in healthy, adult human subjects. Method: In this study, a single dose, two-sequence, two-way crossover randomized design was used to investigate the bioequivalence under fasting conditions. 14 healthy volunteers received the two formulations over the course of two treatment days, each followed by a seven-day washout period. Following the administration of a single dose of 40 mg of each formulation, blood samples were taken at predetermined time points and subjected to a validated LC-MS/MS method for Esomeprazole concentration analysis. The plasma concentration-time profiles of both formulations were used to determine the pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞. Result: Pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ did not show any statistically significant differences. The 90 % confidence intervals of Cmax, AUC0-t, and AUC0-∞ for Esomeprazole was found 89.35% (82.27-97.03%), 107.61% (99.78-116.05%), and 107.72 (99.87-116.20%) respectively which is within predetermined bioequivalence acceptance limits of 80 - 125 %. Conclusion: In terms of absorption rate and extent, the test product of Beximcopharmaceuticals has met the regulatory requirements for bioequivalence with the reference product Nexium MUPS.

Pharmacokinetics, Bioequivalence, and Safety Studies of a Generic Selective Tyrosine Kinase Inhibitor Nilotinib Capsule Versus a Branded Product in Healthy Chinese Volunteers.

Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved in the United States and Europe as a treatment for patients with newly diagnosed chronic myeloid leukemia (CML)-chronic phase (CP) and patients with CML-CP or chronic myeloid leukemia-accelerated phase (CML-AP) who are resistant or intolerant to imatinib (a first-generation TKI). This study compared the bioequivalence and safety of the test nilotinib capsule and reference nilotinib capsule (Tasigna, Novartis) in healthy Chinese volunteers under fasting conditions for marketing authorization in China. The results of the study are reported for the first time. This was a single-dose, randomized, open-label, two-period, and cross-over study. Thirty healthy volunteers were randomly assigned to receive a single dose of a 200-mg test or reference capsule under fasting conditions in each period with a 10-day washout. Plasma samples were analyzed with liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated with WinNonlin software. The geometric mean ratio and the corresponding 90% confidence intervals of Cmax , AUC0-t , and AUC0-∞ for nilotinib between the two fixed-dose combination formulations were within the bioequivalence acceptance range of 80%-125%, therefore the generic and branded formulations were bioequivalent in healthy Chinese volunteers.

Effect of hepatic impairment on the pharmacokinetics of ripretinib.

e16031 Background: Ripretinib is a tyrosine kinase inhibitor indicated for the treatment of patients with advanced gastrointestinal stromal tumor who have received prior treatment with ≥3 kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are CYP3A substrates and coadministration with itraconazole (CYP3A inhibitor) increased exposure to each analyte by ̃100%. Therefore, we studied ripretinib in subjects with varying degrees of hepatic impairment (HI). Methods: Subjects with mild, moderate, and severe HI based on Child-Pugh, and matched healthy subjects received a single oral dose of ripretinib (50 mg, fasting) with 8 days of PK sampling. Concentrations of ripretinib and DP-5439 in plasma were measured by a liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay. PK parameters were calculated using Phoenix WinNonlin, and the geometric least squares mean ratios and corresponding 90% confidence intervals of Cmax, AUC0-t, and AUC0-∞ (total and unbound) were calculated. Unbound concentrations were assessed at Tmax and 24 hours postdose. Results: Eight subjects with mild HI, 8 with moderate HI, 4 with severe HI, and 13 healthy matches were enrolled. As shown in the table, total ripretinib and DP-5439 PK was comparable for mild HI vs. healthy matches. For moderate HI, total ripretinib AUC was ̃100% higher (Cmax was comparable), whereas DP-5439 AUC was marginally higher (Cmax was 32% lower). For severe HI, total ripretinib AUC0-t was ̃160% higher and Cmax was ̃24% lower, whereas DP-5439 AUCs were ̃50% lower and Cmax was 78% lower. Unbound fraction was &lt; 0.6% for ripretinib and 0.2-1.4% for DP-5439, with no clear trend with HI severity. The safety profile in HI subjects was similar to healthy matches; common adverse events (in ≥2 subjects) included increased lipase or amylase, diarrhea, and headache. Conclusions: Consistent with current labeling, mild HI had no impact on total PK. In this study, moderate and severe HI increased ripretinib AUC ̃100% and 163%, respectively. PK exposure to DP-5439 and combined ripretinib + DP-5439 was impacted to a lesser extent. Dose recommendations in moderate and severe HI are currently under development.[Table: see text]

Bioequivalence Study of Two Formulations of Telmisartan 40 mg Tablets in Healthy Adult Bangladeshi Subjects under Fasting Conditions

Background: Telmisartan is a highly variable drug which is used to treat hypertension. This study compared to compare the bioavailability of two 40 mg Telmisartan tablets in adult and healthy Bangladeshi subjects. Materials and Method: This study was open label, randomized, laboratory blind, single dose, three periods, two treatments, three-sequence, partial-replicate, crossover and comparative oral bioavailability study. In this study, 18 Bangladeshi subjects were enrolled and 17 subjects were completed. Serial blood samples were collected up to 96 hours following drug administration. By using Liquid Chromatography Mass Spectrometry (LC-MS/MS) method, plasma concentrations of Telmisartan were determined. Results: The two formulations of Telmisartan were considered bioequivalent if 90% Confidence Interval (CI) fall within the range of 80.00% - 125.00% for AUC parameters and reference-scaled-average bioequivalence of 69.84% - 143.19% for Cmax. The 90% Confidence Interval for Cmax, AUC0-t & AUC0-∞ was found 84.88% - 107.79%, 89.76% - 109.55%, and 91.20% - 114.52%, respectively. Conclusion: According to rate and extent of absorption with the single dose of Reference Product (R): Micardis® 40 mg Tablet, under fasting conditions, a single dose of Telmisartan 40 mg Tablet is bioequivalent.

P-205: PORT (OP-109): Phase 2, randomised, Pharmacokinetic (PK), cross-over study of peripheral vs central intravenous administration of Melflufen in patients with Relapsed/Refractory Multiple Myeloma (RRMM)

P-205: PORT (OP-109): Phase 2, randomised, Pharmacokinetic (PK), cross-over study of peripheral vs central intravenous administration of Melflufen in patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Pharmacokinetics and Bioequivalence of a Generic Fixed-Dose Combination Tablet of Metformin Hydrochloride/Vildagliptin Versus a Branded Product in Healthy Chinese Subjects Under Fed and Fasting Conditions.

The purpose of this study was to compare the bioequivalence and safety of test and reference preparations of fixed-dose combination tablets of metformin hydrochloride/vildagliptin 850 mg/50 mg in healthy volunteers under fasting and fed conditions for marketing authorization in China. A single-dose, randomized, open-label, 2-way crossover study was conducted. Blood samples were collected up to 36 hours after dosing in each period with a 7-day washout. Pharmacokinetic parameters, including maximum plasma concentration (Cmax ), time to reach Cmax , area under the plasma concentration-time curve (AUC) from time 0 to the last time point of the measurable concentration, AUC from time 0 to infinity, terminal elimination half-life, and apparent clearance, were calculated using noncompartmental methods and compared between the 2 formulations. Safety profiles were assessed, including significant findings of vital signs, electrocardiogram, laboratory tests, physical examination, and adverse events. A total of 30 healthy subjects (19 men, 11 women) were randomized, and 29 subjects were treated under fasting conditions. Likewise, 30 subjects (24 men, 6 women) were randomized and treated under fed conditions. The geometric mean ratio and corresponding 90% confidence intervals of Cmax , AUC from time 0 to the last time point of the measurable concentration , and AUC from time 0 to infinity for both metformin hydrochloride and vildagliptin between the 2 fixed-dose combination formulations were within the bioequivalence acceptance range of 80% to 125% under fasting or fed conditions. Therefore, the generic and branded formulations were bioequivalent and well tolerated in healthy Chinese subjects.

Evaluation of tramadol human pharmacokinetics and safety after co-administration of magnesium ions in randomized, single- and multiple-dose studies

BackgroundMagnesium ions (Mg2+) increase and prolong opioid analgesia in chronic and acute pain. The nature of this synergistic analgesic interaction has not yet been explained. Our aim was to investigate whether Mg2+ alter tramadol pharmacokinetics. Our secondary goal was to assess the safety of the combination.MethodsTramadol was administered to healthy Caucasian subjects with and without Mg2+ as (1) single 100-mg and (2) multiple 50-mg oral doses. Mg2+ was administered orally at doses of 150 mg and 75 mg per tramadol dosing in a single- and multiple-dose study, respectively. Both studies were randomized, open label, laboratory-blinded, two-period, two-treatment, crossover trials. The plasma concentrations of tramadol and its active metabolite, O-desmethyltramadol, were measured.ResultsA total of 25 and 26 subjects completed the single- and multiple-dose study, respectively. Both primary and secondary pharmacokinetic parameters were similar. The 90% confidence intervals for Cmax and AUC0-t geometric mean ratios for tramadol were 91.95–102.40% and 93.22–102.76%. The 90% confidence intervals for Cmax,ss and AUC0-τ geometric mean ratios for tramadol were 93.85–103.31% and 99.04–105.27%. The 90% confidence intervals for primary pharmacokinetic parameters were within the acceptance range. ANOVA did not show any statistically significant contribution of the formulation factor (p > 0.05) in either study. Adverse events and clinical safety were similar in the presence and absence of Mg2+.ConclusionsThe absence of Mg2+ interaction with tramadol pharmacokinetics and safety suggests that this combination may be used in the clinical practice for the pharmacotherapy of pain.Graphic abstract

Pharmacokinetic Interaction Among Ezetimibe, Rosuvastatin, and Telmisartan.

To evaluate the pharmacokinetic interactions among rosuvastatin, ezetimibe, and telmisartan, a randomized, open-label, 3-period, 6-sequence crossover study was conducted in healthy subjects. Subjects received one of the following treatments once daily for 7 days in each period with a 1-week washout: a fixed-dose combination of ezetimibe/rosuvastatin 10/20 mg, telmisartan 80 mg, combination therapy of ezetimibe/rosuvastatin 10/20 mg, or telmisartan 80 mg. Blood samples were collected up to 24 hours postdose at steady state. Geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) of the combination therapy to monotherapy for the maximum plasma concentration (Cmax,ss ), and the area under the time-concentration curve within a dosing interval at steady state (AUCtau,ss ) were estimated. Among the 36 randomized subjects, 31 subjects completed the study. The GMRs and 90%CIs of Cmax,ss and AUCtau,ss of total ezetimibe were not significantly altered. The Cmax,ss of free ezetimibe was increased (GMR, 1.85; 90%CI, 1.56-2.19) but not for the AUCtau,ss (GMR, 1.16; 90%CI, 1.06-1.26). Similarly, the Cmax,ss of rosuvastatin was increased (GMR, 2.13; 90%CI, 1.88-2.43) without a change in the AUCtau,ss (GMR, 1.09; 90%CI, 1.03-1.15). The Cmax,ss (GMR, 1.16; 90%CI, 1.01-1.32) and AUCtau,ss (GMR, 1.26; 90%CI, 1.17-1.37) of telmisartan were slightly increased. Considering the therapeutic range of the components, the interaction would have limited clinical impact.

Comparative pharmacokinetics of a montelukast/levocetirizine fixed-dose combination chewable tablet versus individual administration of montelukast and levocetirizine after a single oral administration in healthy Korean male subjects .

Asthma patients often have co-existing symptoms of allergic rhinitis and are often prescribed with both asthma and rhinitis treatments such as montelukast and levocetirizine. The objective of this study was to compare the pharmacokinetic profiles of a montelukast/levocetirizine fixed-dose combination chewable tablet with individual administration of montelukast and levocetirizine in healthy subjects. A randomized, open-label, single-dose crossover study was conducted in healthy male subjects. One of the following treatments was administered in each period: co-administration of 1 chewable tablet of montelukast 5 mg and 1 tablet of levocetirizine 5 mg or administration of 1 chewable tablet of montelukast/levocetirizine 5/5 mg fixed-dose combination. Serial blood samples were collected up to 48 hours post dose. Plasma drug concentrations were measured by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from dosing to the last measurable concentration (AUClast), were determined by non-compartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% confidence intervals (CIs) of Cmax and AUClast were calculated to evaluate pharmacokinetic equivalence. A total of 22 subjects were included in pharmacokinetic analysis. The GLSM ratios and 90% CIs of Cmax and AUClast were 1.0054 (0.9535-1.0601) and 1.0628 (1.0013-1.1281) for montelukast and 1.0105 (0.9488-1.0764) and 1.0396 (0.9935-1.0879) for levocetirizine, respectively. The pharmacokinetic parameters of montelukast and levocetirizine when administered as separate tablets or as a fixed-dose combination were compared, and the parameters met the pharmacokinetic equivalence criteria. (ClinicalTrials.gov Identifier: NCT03371849).

Pharmacokinetic and bioequivalence study of new S-1 capsule in Chinese cancer patients

S-1 is a multicomponent capsule containing tegafur, gimeracil, and oteracil potassium that has shown anticancer activity against numerous tumor types. However, S-1 capsules from different manufacturing companies have shown variations in pharmacokinetics and safety. Therefore, this multicenter, single-dose, randomized-sequence, open-label, two-way, self-crossover study was conducted to evaluate the bioequivalence of a newly developed generic S-1 (New Times Pharmaceutical Co., Ltd., Shandong, China) and the original brand-name S-1 capsule (Taiho Pharmaceutical Co., Ltd., Japan). Furthermore, the safety profiles of both products were compared. A total of 70 patients with 18 types cancer including breast, lung, gastric, and colorectal recruited at 5 hospitals who were randomly and alternatively administered 50 mg of the reference and test S-1 with a 7-day interval. Plasma concentrations of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), oteracil potassium, and 5-fluorouracil were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters, including maximum drug concentration (Cmax), time to achieve Cmax (Tmax), half-life (t1/2, area under the concentration-time curve from 0–time t (AUC0–t), and AUC from 0–infinity (AUC0–∞) were determined using non-compartmental analysis with DAS2.0 software. Bioequivalence of the reference and test S-1 was evaluated according to 90% confidence intervals (CIs) for ratios of AUC and Cmax of S-1. Adverse events were evaluated by monitoring symptoms, physical and laboratory examinations, electrocardiogram, and subject interviews. No significant difference was observed in plasma concentrations and pharmacokinetic profiles of tegafur, CDHP, oteracil potassium, or 5-fluorouracil (p > 0.05) among cancer patients treated with the reference or test S-1 formulation. The 90% CIs of Cmax, AUC0–t, and AUC0–∞ ratios were within the 80%–125% limit. The generic S-1 caused eight mild adverse events including liver dysfunction, diarrhea, nausea, fatigue, abnormal blood electrolytes, hyperglycemia, and dermal toxicity. Similarly, 18 mild adverse events were observed including dysarteriotony, diarrhea, nausea, fatigue, fever, hematotoxicity, abnormal blood electrolytes, hyperglycemia, dermal toxicity, and joint pain. There were no differences in the adverse event incidence between the two formulations. In conclusion, the newly developed generic S-1 showed similar pharmacokinetics to those of an original brand-name S-1 in cancer patients, thereby indicating bioequivalence. Furthermore, both treatments were well tolerated, suggesting that the cost-effective generic S-1 should be considered as a feasible option when treating patients.

Evaluation of the pharmacokinetics and food effects of a novel formulation tamsulosin 0.4 mg capsule compared with a 0.2 mg capsule in healthy male volunteers.

Tamsulosin, an alpha-1 adrenoreceptor antagonist, has been used as a primary option for medical treatment of benign prostate hyperplasia. An open-label, single-dose, randomized, three-treatment, three-period, three sequence crossover study was conducted to evaluate the pharmacokinetics (PKs) of 0.2 and 0.4 mg tamsulosin hydrochloride (HCl) in the fed versus the fasted state. Subjects were randomly assigned to three sequences and received one of the following treatments at each period: tamsulosin HCl 0.2 or 0.4 mg in the fed state with a high-fat meal, or tamsulosin HCl 0.4 mg in the fasted state. Blood samples for the PK analysis were collected at pre-dose and up to 48 h post-dose. The PK parameters were calculated by a non-compartmental method. The geometric mean ratio (GMR) and its 90% confidence intervals (CIs) of the plasma maximum concentration (Cmax) and area under concentration curve from time zero to last measurable concentration (AUClast) were calculated. Twenty-two subjects completed the study. The systemic exposure of tamsulosin 0.4 mg decreased approximately 9% in the fed state compared to the fasted state, and the time to reach peak concentration was slightly delayed in the fed state. The dose normalized GMR and its 90% CIs of Cmax and AUClast for 0.2 and 0.4 mg tamsulosin in the fed state were within 0.8 and 1.25 range. Systemic exposure of tamsulosin was decreased in the fed condition compared to the fasted condition. Linear PK profiles were observed between 0.2 and 0.4 mg tamsulosin in the fed state.Trial RegistrationClinicalTrials.gov Identifier: NCT02529800

Pharmacokinetic comparison of two bazedoxifene acetate 20 mg tablet formulations in healthy Korean male volunteers.

Bazedoxifene, used as bazedoxifene acetate, is a selective estrogen receptor modulator that selectively affects the uterus, breast tissue, bone metabolism, and lipid metabolism by antagonizing or enhancing estrogens in the estrogen receptor in the tissue. This study was conducted as an open, randomized, two-period, two-treatment, crossover design to compare the pharmacokinetic (PK) characteristics and tolerability of two bazedoxifene tablets when administered to 50 healthy Korean male volunteers. Enrolled subjects were randomly allocated to 2 sequences of a single oral administration of a test drug and a reference drug, or vice versa with a 14-day washout period between the two doses. Serial blood samples were collected over 96 h for PK analysis. Plasma concentration of bazedoxifene was assayed using liquid chromatography-tandem spectrometry mass. Forty-five participants completed the study with no clinically relevant safety issues. The peak concentrations (Cmax, mean ± strandard deviation) of reference drug and test drug were 3.191 ± 1.080 and 3.231 ± 1.346 ng/mL, respectively, and the areas under the plasma concentration‐time curve from 0 to the last measurable concentration (AUClast) were 44.697 ± 21.168 ng∙h/mL and 45.902 ± 23.130 ng∙h/mL, respectively. The geometric mean ratios of test drug to reference drug and their 90% confidence intervals for Cmax and AUClast were 0.9913 (0.8828–1.1132) and 1.0106 (0.9345–1.0929), respectively. The incidence of adverse events between the two formulations was similar. The present study showed that PK and tolerability of two bazedoxifene tablet formulations were comparable when administered to healthy Korean male volunteers.Trial RegistrationClinical Research Information Service Identifier: KCT0003978