scholarly journals Effect of high-fat diet on the pharmacokinetics and safety of flumatinib in healthy Chinese subjects

2020 ◽  
Vol 86 (3) ◽  
pp. 339-346
Author(s):  
Yun Kuang ◽  
Hui-ling Song ◽  
Guo-ping Yang ◽  
Qi Pei ◽  
Xiao-yan Yang ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Least Square ◽  
Pharmacokinetic Parameters ◽  
High Fat ◽  
Open Label ◽  
Clinical Trial Registration ◽  
Healthy Chinese ◽  
Chinese Subjects

Abstract Purpose To evaluate the effect of a high-fat diet on the pharmacokinetics and safety of flumatinib mesylate tablets in healthy Chinese subjects. Methods This study was a randomized, open-label, single-dose, two-period crossover trial in which subjects were randomly assigned to take 400 mg of flumatinib mesylate after a high-fat diet or a fasted state. After a 14-day washout period, the two groups were administered flumatinib mesylate under opposite conditions. Blood samples were collected at baseline 0 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h, respectively. Plasma concentrations of flumatinib and its metabolites (M1 and M3) were analyzed using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated using the non-compartmental module of the Phoenix WinNonlin Version 7.0 software. BE module of WinNonLin was used for statistical analysis of AUC0–t, AUC0–∞ and Cmax in plasma. Results Twelve healthy subjects, half male and half female, were enrolled. One subject withdrew due to a treatment-emergent adverse event. Eleven subjects were administered drugs on fasting and 12 were administered drugs after a high-fat diet. On high-fat diet/fasting, the least square geometric mean (LSGM) ratios of flumatinib, M1, M3, and their 90% confidence interval (CI) were as follows: for flumatinib, Cmax, AUC0–t and AUC0–∞ were 281.65% (225.80–351.31%), 167.43% (143.92–194.79%), and 166.87% (143.47–194.09%); for M1, Cmax, AUC0–t, and AUC0–∞ were 188.59% (145.29–244.79), 163.94% (149.11–180.24%), and 164.48% (150.36–179.94%); for M3, Cmax, AUC0–t, and AUC0–∞ were 63.47% (54.02–74.57%), 85.23% (74.72–97.22%), and 96.73% (86.63–108.02%). Conclusion Among the subjects, oral administration of 400 mg of flumatinib was safe and well tolerated. High-fat diet significantly increases the exposure to flumatinib, therefore, fasting may be recommended. Clinical trial registration The study was registered at chictr.org Identifier: ChiCTR-IIR-17013179.

scholarly journals Pharmacokinetics and Bioequivalence of Rasagiline Tablets in Chinese Healthy Subjects Under Fasting and Fed Conditions: An Open, Randomized, Single-Dose, Double-Cycle, Two-Sequence, Crossover Trial

2020 ◽  
Vol 11 ◽  
Author(s):  
Yinjuan Li ◽  
Lu Qi ◽  
Haihong Bai ◽  
Ying Liu ◽  
Rongxia Fan ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Subjects ◽  
Geometric Mean ◽  
Pharmacokinetic Parameters ◽  
Serious Adverse Events ◽  
Good Tolerability ◽  
Clinical Trial Registration ◽  
Reference Drug ◽  
Healthy Chinese ◽  
Chinese Subjects

Objective: This study evaluated the pharmacokinetics, safety, and bioequivalence (BE) of two formulations of rasagiline tablets in healthy Chinese subjects under fasting and fed conditions.Methods: An open, randomized, single-dose, double-cycle, two-sequence, self-crossover pharmacokinetic study in healthy Chinese subjects under fasting and high-fat postprandial conditions was performed. A total of 108 healthy subjects (36 in the fasting group and 72 in the postprandial group) were recruited. In each cycle of the study under both conditions, subjects received a single oral dose of 1 mg of a test or reference preparation of rasagiline tablets (1 mg each). A washout period of 3 days was observed. Blood samples were obtained up to 10 h post-intake. Primary endpoints were the BE of major pharmacokinetic parameters (AUC0–t and AUC0–∞) and the maximum observed serum concentration (Cmax). Secondary endpoints were safety parameters.Results: The 90% confidence interval (CI) of the geometric mean ratio (GMR) of the test drug vs. the reference drug for rasagiline was 94.16–105.35% for the AUC0–t under fasting conditions and 99.88–107.07% under postprandial conditions. The 90% CIs for the AUC0–∞ were 93.55–105.01% and 99.59–107.05% under fasting and postprandial conditions, respectively. The 90% CIs for the Cmax were 88.26–108.46% and 89.54–118.23% under fasting and postprandial conditions, respectively. The 90% CIs for the test/reference AUC ratio and Cmax ratio were within the acceptable range (0.80–1.25) for BE. In this BE study, there were no serious adverse events (AEs).Conclusion: BE between the test and the reference products was established in both fasting and postprandial conditions. The two formulations of rasagiline showed good tolerability and a similar safety profile.Clinical Trial Registration:chinaDrugtrials.org.cn, identifier CTR20181466.

scholarly journals Bioequivalence of levamlodipine besylate tablets in healthy Chinese subjects: A single-dose and two-period crossover randomized study

2020 ◽  
Author(s):  
Li Xin ◽  
Chenjing Wang ◽  
Ting Li ◽  
Yanping Liu ◽  
Shuqin Liu ◽  
...  
Keyword(s):  
Single Dose ◽  
Randomized Study ◽  
Plasma Concentrations ◽  
Bioequivalence Study ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Liquid Chromatography Tandem Mass ◽  
The Mean ◽  
Healthy Chinese ◽  
Chinese Subjects

Abstract Background: Levamlodipine, a calcium channel blocker, has been show act as a cardiovascular drug. To compare the pharmacokinetic parameters between levamlodipine (test formulation) at a single dose of 5 mg and amlodipine (reference formulation) at a single dose of 10 mg, the bioequivalence study was carried out.Methods: A single-dose randomized, open-label, two-period crossover study was designed in healthy Chinese subjects. 48 subjects were divided into fasted and fed groups equally. The subjects randomly received the test or reference formulations at the rate of 1:1. Following a 21-day washout period, the alternative formulations were received. The blood samples were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, 36, 48, 72, 96, 120, 144, 168 hours later. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine the plasma concentrations of levamlodipine. Adverse events were recorded.Results: The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ under both fasted and fed conditions were within the prespecified bioequivalence limits between 80~125%. Under fasted conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.70±0.49) ng/mL, AUC0-t was (141.32±36.24) ng×h/mL and AUC0-∞ was (157.14±45.65) ng×h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.83±0.52) ng/mL, AUC0-t was (153.62±33.96) ng×h/mL and AUC0-∞ was (173.05±41.78) ng×h/mL after a single dose of 10 mg amlodipine. Under fed conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.73±0.55) ng/mL, AUC0-t was (166.93±49.96) ng×h/mL and AUC0-∞ was (190.99±70.89) ng×h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.87±0.81) ng/mL AUC0-t was (165.46±43.58) ng×h/mL and AUC0-∞ was (189.51±64.70) ng×h/mL after a single dose of 10 mg amlodipine. Serious adverse event was not observed.Conclusion: The trial confirmed that levamlodipine at a single dose of 5 mg and amlodipine at a single dose of 10 mg were bioequivalent under both fasted condition and fed condition.Trial registration: Cinicaltrials, NCT04411875. Registered 3 June 2020 - Retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0009W1Q&selectaction=Edit&uid=U00050YQ&ts=3&cx=-6iqkm8

scholarly journals Bioequivalence of levamlodipine besylate tablets in healthy Chinese subjects: A single-dose and two-period crossover randomized study

2020 ◽  
Author(s):  
Li Xin ◽  
Chenjing Wang ◽  
Ting Li ◽  
Yanping Liu ◽  
Shuqin Liu ◽  
...  
Keyword(s):  
Single Dose ◽  
Randomized Study ◽  
Plasma Concentrations ◽  
Bioequivalence Study ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Liquid Chromatography Tandem Mass ◽  
The Mean ◽  
Healthy Chinese ◽  
Chinese Subjects

Abstract Background: Levamlodipine, a calcium channel blocker, has been show act as a cardiovascular drug. To compare the pharmacokinetic parameters between levamlodipine (test formulation) at a single dose of 5 mg and amlodipine (reference formulation) at a single dose of 10 mg, the bioequivalence study was carried out.Methods: A single-dose randomized, open-label, two-period crossover study was designed in healthy Chinese subjects. 48 subjects were divided into fasted and fed groups equally. The subjects randomly received the test or reference formulations at the rate of 1:1. Following a 21-day washout period, the alternative formulations were received. The blood samples were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, 36, 48, 72, 96, 120, 144, 168 hours later. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine the plasma concentrations of levamlodipine. Adverse events were recorded.Results: The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ under both fasted and fed conditions were within the prespecified bioequivalence limits between 80~125%. Under fasted conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.70±0.49) ng/mL, AUC0-t was (141.32±36.24) ng×h/mL and AUC0-∞ was (157.14±45.65) ng×h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.83±0.52) ng/mL, AUC0-t was (153.62±33.96) ng×h/mL and AUC0-∞ was (173.05±41.78) ng×h/mL after a single dose of 10 mg amlodipine. Under fed conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.73±0.55) ng/mL, AUC0-t was (166.93±49.96) ng×h/mL and AUC0-∞ was (190.99±70.89) ng×h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.87±0.81) ng/mL AUC0-t was (165.46±43.58) ng×h/mL and AUC0-∞ was (189.51±64.70) ng×h/mL after a single dose of 10 mg amlodipine. Serious adverse event was not observed.Conclusion: The trial confirmed that levamlodipine at a single dose of 5 mg and amlodipine at a single dose of 10 mg were bioequivalent under both fasted condition and fed condition.Trial registration: Cinicaltrials, NCT04411875. Registered 3 June 2020 - Retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0009W1Q&selectaction=Edit&uid=U00050YQ&ts=3&cx=-6iqkm8

scholarly journals Bioequivalence of levamlodipine besylate tablets in healthy Chinese subjects: a single-dose and two-period crossover randomized study

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Xin Li ◽  
Chenjing Wang ◽  
Ting Li ◽  
Yanping Liu ◽  
Shuqin Liu ◽  
...  
Keyword(s):  
Single Dose ◽  
Randomized Study ◽  
Plasma Concentrations ◽  
Bioequivalence Study ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Liquid Chromatography Tandem Mass ◽  
The Mean ◽  
Healthy Chinese ◽  
Chinese Subjects

Abstract Background Levamlodipine, a calcium channel blocker, has been show act as a cardiovascular drug. To compare the pharmacokinetic parameters between levamlodipine (test formulation) at a single dose of 5 mg and amlodipine (reference formulation) at a single dose of 10 mg, the bioequivalence study was carried out. Methods A single-dose randomized, open-label, two-period crossover study was designed in healthy Chinese subjects. 48 subjects were divided into fasted and fed groups equally. The subjects randomly received the test or reference formulations at the rate of 1:1. Following a 21-day washout period, the alternative formulations were received. The blood samples were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, 36, 48, 72, 96, 120, 144, 168 h later. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine the plasma concentrations of levamlodipine. Adverse events were recorded. Results The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ under both fasted and fed conditions were within the prespecified bioequivalence limits between 80 ~ 125%. Under fasted conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.70 ± 0.49) ng/mL, AUC0-t was (141.32 ± 36.24) ng × h/mL and AUC0-∞ was (157.14 ± 45.65) ng × h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.83 ± 0.52) ng/mL, AUC0-t was (153.62 ± 33.96) ng × h/mL and AUC0-∞ was (173.05 ± 41.78) ng × h/mL after a single dose of 10 mg amlodipine. Under fed conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.73 ± 0.55) ng/mL, AUC0-t was (166.93 ± 49.96) ng × h/mL and AUC0-∞ was (190.99 ± 70.89) ng × h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.87 ± 0.81) ng/mL AUC0-t was (165.46 ± 43.58) ng × h/mL and AUC0-∞ was (189.51 ± 64.70) ng × h/mL after a single dose of 10 mg amlodipine. Serious adverse event was not observed. Conclusion The trial confirmed that levamlodipine at a single dose of 5 mg and amlodipine at a single dose of 10 mg were bioequivalent under both fasted condition and fed condition. Trial registration Cinicaltrials, NCT04411875. Registered 3 June 2020 - Retrospectively registered

scholarly journals Effects of high-fat diet and CYP2B6 mutants on the pharmacokinetics of bupropion and hydroxybupropion among healthy chinese subjects

2021 ◽  
Author(s):  
Hui Ma ◽  
Xiao Ying Yang ◽  
Wen Ping Zhang ◽  
Yu Xin Zhang ◽  
Shi Jie Wei ◽  
...  
Keyword(s):  
High Fat Diet ◽  
High Performance ◽  
Apparent Volume ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
High Fat ◽  
Time Curve ◽  
Feeding Group ◽  
Healthy Chinese ◽  
Chinese Subjects

Aims To provide evidence for the clinically rational administration of bupropion (BUP), the effects of high-fat diet and CYP2B6 mutants on BUP and hydroxybupropion (HBUP) among 44 healthy Chinese subjects. Methods The concentrations of BUP and HBUP in plasma were determined with a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis. Genotypes were ascertained after amplified by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Results The maximum plasma concentration (Cmax) and time to Cmax (tmax) of BUP as well as the concentration–time curve (AUC(0→96)) and Cmax of HBUP all increased by 1.18-, 1.41-, 1.38-, and 1.33-fold in the feeding group relative to the fasting group, respectively. Interestingly, the Cmax and terminal half-life (t1/2) of BUP increased by 1.33- and 1.39-fold among those subjects carrying the CYP2B6*1/*1 genotype in the feeding group relative to those in the fasting group. Similarly, the apparent volume of distribution (Vd) and clearance (CL) of HBUP increased by 1.38- and 1.59-fold, respectively, while the Cmax and AUC(0→96) of HBUP decreased by 1.44- and 1.49-fold among those subjects carrying the CYP2B6*1/*1 genotype in the feeding group relative to those in the fasting group. Concliusion These data suggest that high-fat diet and CYP2B6 mutants can influence the pharmacokinetic parameters of BUP and HBUP, thereby offering clear evidence for the rational administration of BUP among Chinese subjects in clinical settings.

scholarly journals Pharmacokinetics of Liposomal Amphotericin B for Injection in Chinese Healthy Subjects Based on a Bioequivalence Study

2021 ◽  
Author(s):  
Xueyuan Zhang ◽  
Huanhuan Qi ◽  
Manman Wang ◽  
Yuhuan Ji ◽  
Chunlei Li ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Bioequivalence Study ◽  
Liposomal Amphotericin B ◽  
Pharmacokinetic Parameters ◽  
Healthy Population ◽  
Open Label ◽  
Liposomal Form

Abstract Purpose: The aim of this study was to evaluate the pharmacokinetic characteristics and safety of Liposomal Amphotericin B for injection in healthy Chinese volunteers based on a pilot bioequivalence clinical trial between a generic formulation and Ambisome ® Methods: This randomized, two sequence, open label, single dose,two period crossover study was conducted in healthy volunteers at the dose of 2mg kg Blood samples were collected at pre defined time points up to 674 h after the start of the 2 h infusion. Plasma concentrations of total, unencapsulated and encapsulated amphotericin B were determined. Pharmacokinetic parameters were calculated using non compartmental model . The formulations were considered bioequivalent if the 90% confidence interval ls (CIs) of the geometric mean ratio of C max and AUC of both products for free and encapsulated amphotericin B were within80.00 1 25.00 for L n transformed data. Results and conclusion: All the 12subjects completed the two period study , no subjects withdrew the study. The plasma pharmacokinetic profile of liposomal amphotericin B based on free, encapsulated and total amphotericin B demonstrated the characteristics of a three compartment al model. The majority drug in the circulating system after IV infusion of liposomal amphotericin B is remained liposomal form . Pharmacokinetic behaviors in Chinese population w ere consistent with that in western healthy population based on total and unbound amphotericin B concentrations in plasma. The generic liposomal amphotericin B for injection is bioequivalent to Ambisome ® in terms of the Pharmacokinetic parameters for free, encapsulated and total amphotericin B. Trial registration number at National Medical Products Administration CTR20200885 . Date of registration: May 22 , 20 2 0.

scholarly journals Bioequivalence of levamlodipine besylate tablets in healthy Chinese subjects: A single-dose and two-period crossover randomized study

2020 ◽  
Author(s):  
Li Xin ◽  
Chenjing Wang ◽  
Ting Li ◽  
Yanping Liu ◽  
Shuqin Liu ◽  
...  
Keyword(s):  
Single Dose ◽  
Randomized Study ◽  
Pharmacokinetic Parameters ◽  
Reference Formulation ◽  
High Fat ◽  
Fasting Condition ◽  
Test Formulation ◽  
Healthy Chinese ◽  
Chinese Subjects ◽  
Fat Meal

Abstract Background: Levamlodipine, a calcium channel blocker, is used in treatment of hypertension. To compare the pharmacokinetic parameters between levamlodipine test formulation at a single dose of 5 mg and amlodipine reference formulation at a single dose of 10 mg, the bioequivalence study was carried out.Methods: A single-dose randomized, open-label, two-period crossover study was designed in healthy Chinese subjects. 48 subjects were divided into fasting and high-fat meal group equally. The subjects randomly received the test or reference formulations at the rate of 1:1. Following a 21-day washout period, the alternative formulations were received. The blood samples were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, 36, 48, 72, 96, 120, 144, 168 hours later. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine levamlodipine in the plasma samples.Results: Within equivalence limits between 80 ~ 125%, the test formulation and the reference formulation were bioequivalent, with the 90% confidence intervals (CIs) for the ratio of geometric means of Cmax, AUC0-t, and AUC0-∞. The data were shown as Cmax (89.59% ~ 101.61%), AUC0-t (87.83% ~ 94.87%) and AUC0-∞ (86.28% ~ 93.49%) under fasting condition, Cmax (90.93% ~ 102.37%), AUC0–t (95.75% ~ 104.93%) and AUC0–∞ (95.36% ~ 105.33%) under high-fat meal condition. Serious adverse event was not observed.Conclusions: The trial confirmed that levamlodipine at a single dose of 5 mg and amlodipine at a single dose of 10 mg were bioequivalent under both fasting condition and high-fat meal condition.Trial registration: Cinicaltrials, NCT04411875. Registered 3 June 2020 - Retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0009W1Q&selectaction=Edit&uid=U00050YQ&ts=3&cx=-6iqkm8

scholarly journals Pharmacokinetics of Single-Dose and Multi-Dose of Lovastatin/Niacin ER Tablet in Healthy Volunteers

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Yan-yan Jia ◽  
Song Ying ◽  
Chen-tao Lu ◽  
Jing Yang ◽  
Li-kun Ding ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Healthy Volunteers ◽  
Least Square ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Mixed Dyslipidemia ◽  
Dose Oral ◽  
Dose Combination ◽  
Healthy Chinese

An extended-release (ER) niacin and lovastatin fixed-dose combination has been developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The purpose of the present study was to examine the drug interaction between niacin and lovastatin after multi-dose oral administration of lovastatin/niacin ER combination in healthy Chinese volunteers. A single-center, randomized, open-label, 5-period crossover study was conducted in thirty healthy volunteers aged 18 to 45 years with a washout period of 8 days. Subjects were randomized to receive multiple doses of treatment A (1 500 mg niacin ER tablet), B (1 20 mg lovastatin tablet), C (1 20 mg lovastatin and 500 mg niacin-ER tablet), D (2 10 mg lovastatin and 350 mg niacin-ER tablets) or E (2 10 mg lovastatin and 500 mg niacin-ER tablets) in 1 of 5 sequences (ABCDE, BCDEA, CDEAB, DEABC, EABCD) per period. Lovastatin, niacin and its metabolites (nicotinuric acid and nicotinamide) were determined in plasma by LC/MS method. Pharmacokinetic parameters were calculated, and least square mean ratios and 90% confidence intervals for Cmax⁡ and AUC (0–24) were determined for lovastatin/niacin ER versus niacin ER or lovastatin. It revealed that the formulation had no potential drug interaction in healthy Chinese volunteers when the dosage was increased from 500 mg to 1000 mg.

scholarly journals Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
S. Nardi-Hiebl ◽  
J. W. Ndieyira ◽  
Y. Al Enzi ◽  
W. Al Akkad ◽  
T. Koch ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Intravenous Administration ◽  
Intranasal Administration ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Published Data ◽  
Open Label ◽  
Single Dose Study ◽  
Transmucosal Administration

Background. For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug’s high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods. 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results. 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h  ∗  pg/ml, CV% = 32.86), followed by intravenous (672 h  ∗  pg/ml, CV% = 32.18) and intranasal administration (515 h  ∗  pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted relative bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion. Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option.

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

2021 ◽  
Vol 73 (2) ◽  
pp. 604-614
Author(s):  
Piotr J. Rudzki ◽  
Katarzyna Jarus-Dziedzic ◽  
Monika Filist ◽  
Edyta Gilant ◽  
Katarzyna Buś-Kwaśnik ◽  
...  
Keyword(s):  
Confidence Intervals ◽  
Multiple Dose ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Human Pharmacokinetics ◽  
Magnesium Ions ◽  
Open Label ◽  
Multiple Dose Study ◽  
Dose Study

Abstract Background Magnesium 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. Methods Tramadol 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. Results A 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+. Conclusions The 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

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