scholarly journals Enhanced elimination of betamethasone in dichorionic twin pregnancies

2021 ◽  
Author(s):  
Grazielle Rodrigues ◽  
Jhohann Benzi ◽  
Luísa Matos ◽  
Stella Freitas ◽  
Maria Marques ◽  
...  
Keyword(s):  
Placental Transfer ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Third Trimester ◽  
Intramuscular Dose ◽  
Cyp3a4 Enzyme ◽  
Require Dose ◽  
Twin Pregnancies

Aims: No study has evaluated the BET pharmacokinetics in twin pregnancies separated by chorionicity. The aim this study is to describe and compare the BET pharmacokinetic parameters in singleton, dichorionic (DC) and monochorionic (MC) twin pregnancies in the third trimester of pregnancy. Methods: Twenty-six pregnant women received an intramuscular dose of 6 mg of BET sodium phosphate plus 6 mg BET acetate. Serial blood samples were collected for 24 hours after the first intramuscular BET esters dose. BET plasma concentrations were quantified using a validated HPLC analytical method. BET pharmacokinetic parameters were obtained employing a non-compartment model, and were compared using ANOVA’s test with Tukey’s multiple comparisons test. Correlations between clinical features and pharmacokinetic parameters were analyzed using Pearson’s correlation. Preliminary data on the BET placental transfer were also presented. Results: The geometric mean (IC 95%) of AUC0-∞ 670.0 (504.3-805.2) vs 434.9 (311.2-539.6) ng.h/mL and the CL/F 18.38 (13.84-22.65) vs 29.40 (21.17-36.69) were significantly lower and higher, respectively, in DC twin pregnancies compared to singleton. Others pharmacokinetic parameters did not differ among the groups. Conclusions: Data from this study suggest that the presence of two fetoplacental units may increase the BET metabolism by CYP3A4 enzyme and increase its elimination. Pharmacokinetic-pharmacodynamic clinical studies are needed to investigate whether this BET pharmacokinetic changes have clinical repercussions for the newborns and require dose adjustment in DC twin pregnancies.

scholarly journals Tenofovir alafenamide plasma concentrations are reduced in pregnant women living with HIV: data from the PANNA Network

2021 ◽  
Author(s):  
Vera E Bukkems ◽  
Coca Necsoi ◽  
Carmen Hidalgo Tenorio ◽  
Coral Garcia ◽  
Irene Alba Alejandre ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Third Trimester ◽  
Safety Outcome ◽  
The Third ◽  
Women Living With Hiv ◽  
Tenofovir Alafenamide ◽  
Living With Hiv

Abstract Background Tenofovir alafenamide (TAF), a prodrug of tenofovir (TFV), is included in the majority of the recommended first-line antiretroviral regimens for patients living with HIV, but there are limited data on TAF use in pregnant women. We aimed to examine the plasma pharmacokinetics of TAF and TFV in pregnant women from Europe. Methods Pregnant women living with HIV were included from treatment centers across Europe, and intensive pharmacokinetic sampling in the third trimester and postpartum was performed. Pharmacokinetic parameters of TAF and TFV were determined with noncompartmental analysis. The proportion of women with a TAF AUCtau below the target of 53.1 ng*h/mL was determined. Clinical efficacy and safety outcome parameters were reported. Results In total, 20 pregnant women living with HIV were included. At the third trimester, geometric mean TAF AUClast and Cmax were decreased by 46% and 52%, respectively, compared with postpartum. TFV AUC0-24h, Cmax, and Ctrough decreased by 33%, 30% and 34%, respectively. The proportion of women with a TAF AUClast <53.1 ng*h/mL was 6% at third trimester and 0% postpartum. One out of 20 women had a viral load >50 copies/mL at third trimester and no mother-to-child transmission occurred. Conclusions TAF plasma concentrations were reduced by about half in women living with HIV during third trimester of pregnancy, but remained above the predefined efficacy target in the majority of the pregnant women. TFV concentrations were reduced by approximately 30% during third trimester. Despite the observed exposure decrease, high virologic efficacy was observed in this study.

scholarly journals Increased tenofovir monoester concentrations in patients receiving tenofovir disoproxil fumarate with ledipasvir/sofosbuvir

2019 ◽  
Vol 74 (8) ◽  
pp. 2360-2364 ◽  
Author(s):  
Kristina M Brooks ◽  
Jose R Castillo-Mancilla ◽  
Joshua Blum ◽  
Ryan Huntley ◽  
Samantha MaWhinney ◽  
...  
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Clinical Relevance ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Dried Blood Spots ◽  
Pharmacokinetic Parameters ◽  
Post Dose ◽  
P Values ◽  
Hydrolysis Of ◽  
Tenofovir Diphosphate

AbstractBackgroundIntracellular tenofovir diphosphate concentrations are markedly increased in HIV/HCV coinfected individuals receiving tenofovir disoproxil fumarate (TDF) with sofosbuvir-containing treatment. Sofosbuvir may inhibit the hydrolysis of TDF to tenofovir, resulting in increased concentrations of the disoproxil or monoester forms, which may augment cell loading. We sought to quantify tenofovir disoproxil and monoester concentrations in individuals receiving TDF with and without ledipasvir/sofosbuvir.MethodsHIV/HCV coinfected participants receiving TDF-based therapy were sampled pre-dose and 1 and 4 h post-dose prior to and 4 weeks after initiating ledipasvir/sofosbuvir. Tenofovir disoproxil was not detectable. Tenofovir monoester in plasma and tenofovir diphosphate in PBMC and dried blood spots (DBS) were quantified using LC-MS/MS. Geometric mean ratios (week 4 versus baseline) and 95% CIs were generated for the pharmacokinetic parameters. P values reflect paired t-tests.ResultsTen participants had complete data. At baseline, geometric mean (95% CI) tenofovir monoester plasma concentrations at 1 and 4 h post-dose were 97.4 ng/mL (33.0–287.5) and 0.74 ng/mL (0.27–2.06), respectively. With ledipasvir/sofosbuvir, tenofovir monoester concentrations at 4 h post-dose were 5.02-fold higher (95% CI 1.40–18.05; P = 0.019), but did not significantly differ at 1 h post-dose (1.72-fold higher, 95% CI 0.25–11.78; P = 0.54), possibly due to absorption variability. Tenofovir diphosphate in PBMC and DBS were increased 2.80-fold (95% CI 1.71–4.57; P = 0.001) and 7.31-fold (95% CI 4.47–11.95; P < 0.0001), respectively, after 4 weeks of ledipasvir/sofosbuvir.ConclusionsTenofovir monoester concentrations were increased in individuals receiving TDF with ledipasvir/sofosbuvir, consistent with inhibition of TDF hydrolysis. Additional studies are needed to determine the clinical relevance of this interaction.

scholarly journals CHARACTERIZATION OF PHARMACOKINETICS OF 2-((3-(CHLOROMETHYL)BENZOYL)OXY) BENZOIC ACID IN RATS BY USING HPLC-DAD METHOD

2019 ◽  
pp. 279-283
Author(s):  
Caroline ◽  
Nathania Sie ◽  
Kuncoro Foe ◽  
Senny Yesery Esar ◽  
Maria Anabella Jessica
Keyword(s):  
Benzoic Acid ◽  
Oral Administration ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Log P ◽  
Potential Candidate ◽  
Onset Of Action ◽  
Fasting Period

Objective: A new compound of salicylic acid derivative, namely 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid (3CBB), was synthesized to find a compound exhibiting higher analgesic activity and smaller ulcer irritation than acetylsalicylic acid (ASA). Therefore, this study aimed to investigate the pharmacokinetics of this new compound in rats, following a single dose oral administration of 3CBB (45 mg/kg BW). Methods: Plasma samples of 9 healthy rats were collected before and up to 3 h after its oral administration, following an 18 h fasting period. Plasma concentrations of 3CBB were determined using a validated HPLC-DAD assay. Pharmacokinetic parameters were determined using the compartment model technique. All experiments were carried out in triplicate. Results: The pharmacokinetic parameters of 3CBB obtained were as follows: Tmax= 28.9±1.1 min, Cmax = 0.57±0.02 µg/ml, AUCtotal = 66.3±1.0 µg min/ml, Kel = 0.018±0.002 min-1, and T1/2el = 39.4±3.9 min. The long elimination half-life and low Cmax indicated that 3CBB was extensively distributed in the deep and very deep tissues. This confirmed the unique and special characteristics of a highly lipophilic compound like 3CBB (log P = 3.73). Conclusion: 3CBB demonstrated a slower onset of action and longer elimination time from the body compared to ASA. Thus this new compound is a potential candidate to be developed as a new drug.

scholarly journals Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study

2017 ◽  
Vol 77 (2) ◽  
pp. 228-233 ◽  
Author(s):  
Xavier Mariette ◽  
Frauke Förger ◽  
Bincy Abraham ◽  
Ann D Flynn ◽  
Anna Moltó ◽  
...  
Keyword(s):  
Missing Data ◽  
Placental Transfer ◽  
Inflammatory Diseases ◽  
Certolizumab Pegol ◽  
Plasma Concentrations ◽  
Third Trimester ◽  
Limit Of Quantification ◽  
Highly Sensitive ◽  
Registration Number ◽  
Umbilical Cords

ObjectivesThere is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants.MethodsCRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 μg/mL).ResultsSixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0–49.4] μg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 μg/mL), and 1 had a minimal CZP level of 0.042 μg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, 1 was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 μg/mL).ConclusionsThere was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary.Trial registration numberNCT02019602; Results.

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 Estimation of Pharmacokinetic Parameters of Continuous Intravenous Flucloxacillin infusion in the Outpatient Settings (PKFLUCLOX)

2018 ◽  
Author(s):  
Nilar Lwin ◽  
Zheng Liu ◽  
Mark Loewenthal ◽  
Pauline Dobson ◽  
Ji Woong Yoo ◽  
...  
Keyword(s):  
Steady State ◽  
Continuous Infusion ◽  
Time Course ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Device Removal ◽  
Standard Dosage

Flucloxacillin, a beta-lactam antibiotic of the penicillin class, is considered first line therapy for methicillin sensitive Staphylococcus aureus (MSSA) in Australia. At our tertiary referral hospital in the home (HITH) program, it has been prescribed in a standard dosage of 8 grams per day by continuous infusion for more than 20 years. The aim of this observational study was to characterize the pharmacokinetic profile of flucloxacillin in patients who receive continuous infusion in the HITH setting, and to undertake population pharmacokinetic analysis performed with NONMEM software by comparing various structural models. This study utilised flucloxacillin concentrations from 44 separate specimens obtained from 23 patients. Twenty-five of these were collected immediately after elastomeric device removal, representing steady-state concentrations, and the remaining 19 were each collected at least 45 minutes after device removal to determine clearance of the drug. Plasma concentrations ranged from 13 to 194 mg/L with median steady-state concentration of 51.5 mg/L and inter-quartile range of 24.6 mg/L. The time-course of flucloxacillin was best described by a 1-compartment model. The best three covariates, CrCL (ΔOFV= -11.7), eGFR (ΔOFV= -5.9) and serum albumin (ΔOFV= -5.8) were found to be equivalent in terms of decreasing the OFV. CrCL was superior in explaining inter individual variability. The best model for flucloxacillin clearance was a one compartment model with CrCL as the sole covariate. The estimated population parameters were 9.5 L for volume of distribution and 8.1 L/h for flucloxacillin clearance.

scholarly journals Clofazimine pharmacokinetics in patients with TB: dosing implications

2020 ◽  
Vol 75 (11) ◽  
pp. 3269-3277 ◽  
Author(s):  
Mahmoud Tareq Abdelwahab ◽  
Sean Wasserman ◽  
James C M Brust ◽  
Neel R Gandhi ◽  
Graeme Meintjes ◽  
...  
Keyword(s):  
Body Fat ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Drug Resistant ◽  
Elimination Half ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Fat Fraction

Abstract Background Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. Objectives To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Patients and methods Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

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 Differential Impact of Nevirapine on Artemether-Lumefantrine Pharmacokinetics in Individuals Stratified by CYP2B6 c.516G>T Genotypes

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Sa’ad T. Abdullahi ◽  
Julius O. Soyinka ◽  
Adeniyi Olagunju ◽  
Rahman A. Bolarinwa ◽  
Olusola J. Olarewaju ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Genetic Polymorphisms ◽  
Drug Disposition ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Clinical Malaria ◽  
Pharmacokinetic Parameters ◽  
Drug Drug Interaction ◽  
The Impact ◽  
Hiv Negative

ABSTRACT There is an increased recognition of the need to identify and quantify the impact of genetic polymorphisms on drug-drug interactions. This study investigated the pharmacogenetics of the pharmacokinetic drug-drug interaction between nevirapine and artemether-lumefantrine in HIV-positive and HIV-negative adult Nigerian subjects. Thirty each of HIV-infected patients on nevirapine-based antiretroviral therapy and HIV-negative volunteers without clinical malaria, but with predetermined CYP2B6 c.516GG and TT genotypes, were administered a complete treatment dose of 3 days of artemether-lumefantrine. Rich pharmacokinetic sampling prior to and following the last dose was conducted, and the plasma concentrations of artemether/dihydroartemisinin and lumefantrine/desbutyl-lumefantrine were quantified using tandem mass spectrometry. Pharmacokinetic parameters of artemether-lumefantrine and its metabolites in HIV-infected patients on nevirapine were compared to those in the absence of nevirapine in HIV-negative volunteers. Overall, nevirapine reduced exposure to artemether and desbutyl-lumefantrine by 39 and 34%, respectively. These reductions were significantly greater in GG versus TT subjects for artemether (ratio of geometric mean [90% confidence interval]: 0.42 [0.29 to 0.61] versus 0.81 [0.51 to 1.28]) and for desbutyl-lumefantrine (0.56 [0.43 to 0.74] versus 0.75 [0.56 to 1.00]). On the contrary, it increased exposure to dihydroartemisinin and lumefantrine by 47 and 30%, respectively. These increases were significantly higher in TT versus GG subjects for dihydroartemisinin (1.67 [1.20 to 2.34] versus 1.25 [0.88 to 1.78]) and for lumefantrine (1.51 [1.20 to 1.90] versus 1.08 [0.82 to 1.42]). This study underscores the importance of incorporating pharmacogenetics into all drug-drug interaction studies with potential for genetic polymorphisms to influence drug disposition.

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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