Lack of Pharmacokinetic Interaction between Linezolid and Antacid in Healthy Volunteers

ABSTRACT Several antibiotics show significant pharmacokinetic interactions when they are given orally concomitantly with antacids. The objective of this study was to evaluate the effects of antacid (containing magnesium) on the pharmacokinetics of linezolid. A single dose of 600 mg linezolid was given orally alone and 10 min after administration of the antacid Maalox 70mVal, which contains 600 mg magnesium hydroxide and 900 mg aluminum hydroxide, to nine healthy males and nine healthy females in a crossover and randomized study. Linezolid plasma concentrations were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated for both treatments. Coadministration with antacids did not change the pharmacokinetics of linezolid. The ratios (90% confidence intervals) of the individual values of the area under the concentration-time curve and the maximum concentration in plasma (C max) (linezolid plus antacid versus linezolid alone) were 1.01 (0.99 to 1.02) and 0.99 (0.96 to 1.02), respectively. Likewise, no significant difference in any of the other pharmacokinetic parameters was observed between the treatment groups (the time to C max, lag time, volume of distribution [V/F], and clearance [CL/F]). However, a significant sex difference was observed for AUC, C max, V/F, and CL/F; and these differences could be almost completely explained by the differences in body weight between males and females. No clinically relevant adverse effects were detected under either condition. The coadministration of antacids had no effect on the pharmacokinetics of linezolid. This demonstrates that the oral absorption of linezolid was not affected by the presence of antacids containing magnesium hydroxide and aluminum hydroxide. Antacids can be safely administered together with linezolid.

Download Full-text

Lack of Acipimox-Digoxin Interaction in Patient Volunteers

Human & Experimental Toxicology ◽

10.1177/096032719201100509 ◽

1992 ◽

Vol 11 (5) ◽

pp. 357-359 ◽

Cited By ~ 1

Author(s):

Chioli Pascal Chijioke ◽

Richard Martin Pearson ◽

Strolin Benedetti

Keyword(s):

Oral Absorption ◽

Human Subjects ◽

Plasma Concentrations ◽

Time Curve ◽

Digoxin Interaction ◽

Concentration Time ◽

Elimination Half ◽

Significant Difference ◽

Before And After ◽

Renal Clearances

1 A study was carried out to find out if digoxin and acipimox interact. 2 Six elderly patients on digoxin were each given acipimox 150 mg three daily for a week, after informed consent. Digoxin and acipimox plasma concentrations and urinary excretion were measured after the first dose of acipimox and after a week of treatment. 3 Data were fitted to a one-compartment oral absorption model. Areas under the plasma concentration-time curve, plasma and renal clearances, and elimination half-life were computed. 4 There was no significant difference in digoxin plasma concentrations and kinetic parameters before and after acipimox administration. Acipimox kinetics were not affected by the concomitant ingestion of digoxin. 5 The patients' clinical condition remained stable during the study. 6 Thus there was no evidence for an adverse interaction between digoxin and acipimox in human subjects under the conditions of this study.

Download Full-text

Ritonavir-Enhanced Pharmacokinetics of Nelfinavir/M8 during Rifampin Use

Annals of Pharmacotherapy ◽

10.1345/aph.1c335 ◽

2003 ◽

Vol 37 (4) ◽

pp. 521-525 ◽

Cited By ~ 8

Author(s):

Alina S Bergshoeff ◽

Tom FW Wolfs ◽

Sibyl PM Geelen ◽

David M Burger

Keyword(s):

Steady State ◽

Protease Inhibitor ◽

Highly Active Antiretroviral Therapy ◽

Adult Population ◽

Plasma Concentrations ◽

Pharmacokinetic Interaction ◽

Male Infant ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Highly Active

OBJECTIVE: To describe a case of successful protease inhibitor–based highly active antiretroviral therapy (HAART) concomitant with rifampin. CASE SUMMARY: In a 7-month-old male infant with tuberculosis and HIV-1 infection, tuberculosis therapy including rifampin and HAART containing the protease inhibitor nelfinavir 40 mg/kg every 8 hours was started. Intensive steady-state pharmacokinetic sampling from baseline to 8 hours revealed very low plasma concentrations of nelfinavir: area under the plasma concentration–time curve (AUC0–24) <10% of adult population values for 750 mg every 8 hours and nonquantifiable concentrations of nelfinavir's principal metabolite (M8). Nelfinavir 40 mg/kg every 8 hours was then substituted with nelfinavir 30 mg/kg twice daily plus ritonavir 400 mg/m2 twice daily. Intensive steady-state (0–12 h) pharmacokinetic sampling was repeated. Nelfinavir concentrations had improved, but remained low when compared with adult population values of 1250 mg every 12 hours: AUC0–24 21.9 versus 47.6 mg/L•h (46%) and 12-hour trough level (C12) 0.25 versus 0.85 mg/L (29%). However, concentrations of M8 considerably exceeded population values: AUC0–24 57.5 versus 13.6 mg/L•h (443%) and C12 1.35 versus 0.28 mg/L (482%). Since M8 concentrations were highly elevated, pharmacokinetic parameters for (nelfinavir + M8) were used rather than those for nelfinavir alone. Thus, AUC0–24 (nelfinavir + M8) and C12 (nelfinavir + M8) comprised 130% and 142%, respectively of the adult population values. This, in addition to good clinical response and tolerability, favored continuation of the regimen. CONCLUSIONS: In an infant, nelfinavir-containing HAART was successfully used with rifampin after the addition of ritonavir. Ritonavir resolved the pharmacokinetic interaction between rifampin and nelfinavir by boosting nelfinavir and, especially, M8 concentrations. More research is needed to confirm these results.

Download Full-text

Effect of Pregnancy on the Pharmacokinetic Interaction between Efavirenz and Lumefantrine in HIV-Malaria Coinfection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01252-18 ◽

2018 ◽

Vol 62 (10) ◽

Cited By ~ 6

Author(s):

Adebanjo Adegbola ◽

Rana Abutaima ◽

Adeniyi Olagunju ◽

Omotade Ijarotimi ◽

Marco Siccardi ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Pregnant Women ◽

Plasma Concentrations ◽

Pharmacokinetic Interaction ◽

Malaria Treatment ◽

Interquartile Range ◽

Pharmacokinetic Parameters ◽

Standard Regimen ◽

Time Curve ◽

A Prospective Study

ABSTRACT Artemether-lumefantrine is often coadministered with efavirenz-based antiretroviral therapy for malaria treatment in HIV-infected women during pregnancy. Previous studies showed changes in lumefantrine pharmacokinetics due to interaction with efavirenz in nonpregnant adults. The influence of pregnancy on this interaction has not been reported. This pharmacokinetic study involved 35 pregnant and 34 nonpregnant HIV-malaria-coinfected women receiving efavirenz-based antiretroviral therapy and was conducted in four health facilities in Nigeria. Participants received a 3-day standard regimen of artemether-lumefantrine for malaria treatment, and intensive pharmacokinetic sampling was conducted from 0.5 to 96 h after the last dose. Plasma efavirenz, lumefantrine, and desbutyl-lumefantrine were quantified using validated assays, and pharmacokinetic parameters were derived using noncompartmental analysis. The median middose plasma concentrations of efavirenz were significantly lower in pregnant women (n = 32) than in nonpregnant women (n = 32) at 1,820 ng/ml (interquartile range, 1,300 to 2,610 ng/ml) versus 2,760 ng/ml (interquartile range, 2,020 to 5,640 ng/ml), respectively (P = 0.006). The lumefantrine area under the concentration-time curve from 0 to 96 h was significantly higher in pregnant women (n = 27) at 155,832 ng · h/ml (interquartile range, 102,400 to 214,011 ng · h/ml) than nonpregnant women at 90,594 ng · h/ml (interquartile range, 58,869 to 149,775 ng · h/ml) (P = 0.03). A similar trend was observed for the lumefantrine concentration at 12 h after the last dose of lumefantrine, which was 2,870 ng/ml (interquartile range, 2,180 to 4,880 ng/ml) versus 2,080 ng/ml (interquartile range, 1,190 to 2,970 ng/ml) in pregnant and nonpregnant women, respectively (P = 0.02). The lumefantrine-to-desbutyl-lumefantrine ratio also tended to be lower in pregnant women than in nonpregnant women (P = 0.076). Overall, pregnancy tempered the extent of efavirenz-lumefantrine interactions, resulting in increased lumefantrine exposure. However, any consideration of dosage adjustment for artemether-lumefantrine to enhance exposure in this population needs to be based on data from a prospective study with safety and efficacy endpoints.

Download Full-text

Pharmacokinetics of intramuscularly administered aminosidine in healthy subjects.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.5.982 ◽

1997 ◽

Vol 41 (5) ◽

pp. 982-986 ◽

Cited By ~ 12

Author(s):

T P Kanyok ◽

A D Killian ◽

K A Rodvold ◽

L H Danziger

Keyword(s):

Healthy Subjects ◽

Randomized Clinical Trials ◽

Elimination Rate ◽

Pharmacokinetic Parameters ◽

Multiple Drug ◽

Time Data ◽

Time Curve ◽

First Order ◽

Significant Difference

Aminosidine is an older, broad-spectrum aminoglycoside antibiotic that has been shown to be effective in in vitro and animal models against multiple-drug-resistant tuberculosis and the Mycobacterium avium complex. The objective of this randomized, parallel trial was to characterize the single-dose pharmacokinetics of aminosidine sulfate in healthy subjects (eight males, eight females). Sixteen adults (mean [+/- standard deviation] age, 27.6 +/- 5.6 years) were randomly allocated to receive a single, intramuscular aminosidine sulfate injection at a dose of 12 or 15 mg/kg of body weight. Serial plasma and urine samples were collected over a 24-h period and used to determine aminosidine concentrations by high-performance liquid chromatographic assay. A one-compartment model with first-order input, first-order output, and a lag time (Tlag) and with a weighting factor of 1/y2 best described the data. Compartmental and noncompartmental pharmacokinetic parameters were estimated with the microcomputer program WinNonlin. One subject was not included (15-mg/kg group) because of the lack of sampling time data. On average, subjects attained peak concentrations of 22.4 +/- 3.2 microg/ml at 1.34 +/- 0.45 h. All subjects had plasma aminosidine concentrations below 2 microg/ml at 12 h, and all but two subjects (one in each dosing group) had undetectable plasma aminosidine concentrations at 24 h. The dose-adjusted area under the concentration-time curve from 0 h to infinity of aminosidine was identical for the 12- and 15-mg/kg groups (9.29 +/- 1.5 versus 9.29 +/- 2.2 microg x h/ml per mg/kg; P = 0.998). Similarly, no significant differences (P > 0.05) were observed between dosing groups for peak aminosidine concentration in plasma, time to peak aminosidine concentration in plasma, Tlag, apparent clearance, renal clearance, elimination rate constant, and elimination half-life. A significant difference was observed for the volume of distribution (0.35 versus 0.41 liters/kg; P = 0.037) between the 12 and 15 mg/kg dosing groups. Now that comparable pharmacokinetic profiles between dosing groups have been demonstrated, therapeutic equivalency testing via in vitro pharmacokinetic and pharmacodynamic modelling and randomized clinical trials in humans should be conducted.

Download Full-text

A Pilot Study of Immune Activation and Rifampin Absorption in HIV-Infected Patients without Tuberculosis Infection: A Short Report

Tuberculosis Research and Treatment ◽

10.1155/2017/2140974 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7

Author(s):

Christopher Vinnard ◽

Isabel Manley ◽

Brittney Scott ◽

Mariana Bernui ◽

Joella Adams ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Pilot Study ◽

Bacterial Translocation ◽

Immune Activation ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Short Report ◽

Hiv Viral Load ◽

Time Curve ◽

Immunodeficiency Virus

Background. Rifampin malabsorption is frequently observed in tuberculosis patients coinfected with human immunodeficiency virus (HIV) but cannot be predicted by patient factors such as CD4+ T cell count or HIV viral load. Methods. We sought to describe the relationship between HIV-associated immune activation, measures of gut absorptive capacity and permeability, and rifampin pharmacokinetic parameters in a pilot study of 6 HIV-infected, tuberculosis-uninfected patients who were naïve to antiretroviral therapy. Results. The median rifampin area under the concentration-versus-time curve during the 8-hour observation period was 42.8 mg·hr/L (range: 21.2 to 57.6), with a median peak concentration of 10.1 mg/L (range: 5.3 to 12.5). We observed delayed rifampin absorption, with a time to maximum concentration greater than 2 hours, in 2 of 6 participants. There was a trend towards increased plasma concentrations of sCD14, a marker of monocyte activation in response to bacterial translocation, among participants with delayed rifampin absorption compared to participants with rapid absorption (p=0.06). Conclusions. Delayed rifampin absorption may be associated with elevated markers of bacterial translocation among HIV-infected individuals naïve to antiretroviral therapy. This trial is registered with NCT01845298.

Download Full-text

Development of Paroxetine Hydrochloride Single Layer Controlled-Release Tablets Based on 32 Factorial Design

Pharmaceutics ◽

10.3390/pharmaceutics10040243 ◽

2018 ◽

Vol 10 (4) ◽

pp. 243 ◽

Cited By ~ 1

Author(s):

Yao Yang ◽

Zhengwei Huang ◽

Xuan Zhang ◽

Jinyuan Li ◽

Ying Huang ◽

...

Keyword(s):

Controlled Release ◽

Single Layer ◽

Suicide Mortality ◽

Pharmacokinetic Parameters ◽

Release Mechanism ◽

Time Curve ◽

Layer Separation ◽

Significant Difference ◽

Paroxetine Hydrochloride ◽

Controlled Release Tablets

Major depressive disorder (MDD) is one of the main contributors to disability and suicide mortality globally. Paroxetine hydrochloride (PHH) is the most potent antidepressant used for MDD treatment. Due to its reduced side effects PAXIL® CR is a widely-used controlled-release formulation of PHH. However, the complicated double-layer production of PAXIL® CR faces the risk of layer separation. In this study, PHH enteric coating single layer controlled-release tablets (PHH-EC-SLTs) were designed as a simplified substitution of PAXIL® CR through a rational formulation screening. The optimized PHH-EC-SLTs showed similar release behaviors in vitro to PAXIL® CR and the release profiles corresponded to a zero-order release model (R2 = 0.9958). Polymer matrix erosion was the main release mechanism, according to the fitting exponents n > 1 in the Korsmeyer-Pappas model. Crucial pharmacokinetic parameters including peak-reaching time (Tmax), peak concentration (Cmax) and the area under the blood level-time curve (AUC0-48) of PHH-EC-SLTs and PAXIL® CR had no significant difference (p > 0.05) and the relative bioavailability (F = 97.97%) of PHH-EC-SLTs demonstrated their similar pharmacokinetic profiles in vivo. In view of avoiding layer separation risk and simplifying the preparation processing, the self-made PHH-EC-SLTs could be considered as a safe and economic alternative to PAXIL® CR.

Download Full-text

Pharmacodynamics of Five Anthraquinones (Aloe-emodin, Emodin, Rhein, Chysophanol, and Physcion) and Reciprocal Pharmacokinetic Interaction in Rats with Cerebral Ischemia

Molecules ◽

10.3390/molecules24101898 ◽

2019 ◽

Vol 24 (10) ◽

pp. 1898 ◽

Cited By ~ 4

Author(s):

Rong-Rong Li ◽

Xue-Fang Liu ◽

Su-Xiang Feng ◽

Sheng-Nan Shu ◽

Pei-Yang Wang ◽

...

Keyword(s):

Cerebral Ischemia ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Studies ◽

Plasma Exposure ◽

Significant Difference ◽

Aloe Emodin ◽

Exposure Levels

(1) Background: Rhubarb anthraquinones—a class of components with neuroprotective function—can be used to alleviate cerebral ischemia reperfusion injury. (2) Methods: The three pharmacodynamic indicators are neurological function score, brain water content, and cerebral infarction area; UPLC-MS/MS was used in pharmacokinetic studies to detect plasma concentrations at different time points, and DAS software was used to calculate pharmacokinetic parameters in a noncompartmental model. (3) Results: The results showed that the pharmacodynamics and pharmacokinetics of one of the five anthraquinone aglycones could be modified by the other four anthraquinones, and the degree of interaction between different anthraquinones was different. The chrysophanol group showed the greatest reduction in pharmacodynamic indicators comparing with other four groups where the rats were administered one of the five anthraquinones, and there was no significant difference between the nimodipine group. While the Aloe-emodin + Physcion group showed the most obvious anti-ischemic effect among the groups where the subjects were administered two of the five anthraquinones simultaneously. Emodin, rhein, chrysophanol, and physcion all increase plasma exposure levels of aloe-emodin, while aloe-emodin lower their plasma exposure levels. (4) Conclusions: This experiment provides a certain preclinical basis for the study of anthraquinone aglycones against cerebral ischemia and a theoretical basis for the study of the mechanism of interaction between anthraquinones.

Download Full-text

Simultaneous determination of Rivaroxaban and TAK-438 in rat plasma by LC–MS/MS: application to pharmacokinetic interaction study

Bioanalysis ◽

10.4155/bio-2019-0130 ◽

2020 ◽

Vol 12 (1) ◽

pp. 11-22 ◽

Cited By ~ 4

Author(s):

Libin Wang ◽

Shouchang Gai ◽

Xiaorui Zhang ◽

Xiaohui Xu ◽

Nan Gou ◽

...

Keyword(s):

Drug Interactions ◽

Internal Standard ◽

Pharmacokinetic Interaction ◽

Rat Plasma ◽

Pharmacokinetic Parameters ◽

Interaction Study ◽

Significant Difference ◽

Us Fda ◽

First Time

Aim: A sensitive and reliable LC–MS/MS method has been established and validated to the quantitation of rivaroxaban (RIV) and TAK-438 in rat plasma using carbamazepine as internal standard. Results: The procedure of method validation was conducted according to the guidelines of EMA and US FDA. At the same time, the method was applied to pharmacokinetic interactions study between RIV and TAK-438 for the first time. When RIV and TAK-438 co-administration to rats, main pharmacokinetic parameters of TAK-438 like AUC(0-t), AUC(0-∞) and Cmax had statistically significant increase. The main pharmacokinetic parameters of RIV have no statistically significant difference (p > 0.05) when co-administered except for t1/2 (p < 0.01). Conclusion: The results indicated that drug–drug interactions occurred between RIV and TAK-438 when co-administered to rats.

Download Full-text

Pharmacokinetic Profile of μSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats

Natural Product Communications ◽

10.1177/1934578x1501000921 ◽

2015 ◽

Vol 10 (9) ◽

pp. 1934578X1501000 ◽

Cited By ~ 1

Author(s):

Rosario Russo ◽

Angelo Mancinelli ◽

Michele Ciccone ◽

Fabio Terruzzi ◽

Claudio Pisano ◽

...

Keyword(s):

Oral Administration ◽

Plasma Concentrations ◽

Compartmental Analysis ◽

Pharmacokinetic Profile ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Sprague Dawley ◽

Time Curve ◽

Maximum Plasma Drug Concentration

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.

Download Full-text

Meropenem-RPX7009 Concentrations in Plasma, Epithelial Lining Fluid, and Alveolar Macrophages of Healthy Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01713-15 ◽

2015 ◽

Vol 59 (12) ◽

pp. 7232-7239 ◽

Cited By ~ 46

Author(s):

Eric Wenzler ◽

Mark H. Gotfried ◽

Jeffrey S. Loutit ◽

Stephanie Durso ◽

David C. Griffith ◽

...

Keyword(s):

Time Course ◽

Fixed Combination ◽

Limit Of Detection ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Epithelial Lining ◽

Time Curve ◽

Similar Time ◽

Epithelial Lining Fluid ◽

Tract Infections

ABSTRACTThe steady-state concentrations of meropenem and the β-lactamase inhibitor RPX7009 in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations were obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of meropenem (2 g) and RPX7009 (2 g) administered every 8 h, as a 3-h intravenous infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject at 1.5, 3.25, 4, 6, or 8 h after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. The mean pharmacokinetic parameters ± the standard deviations of meropenem and RPX7009 determined from serial plasma concentrations were as follows:Cmax= 58.2 ± 10.8 and 59.0 ± 8.4 μg/ml,Vss= 16.3 ± 2.6 and 17.6 ± 2.6 liters; CL = 11.1 ± 2.1 and 10.1 ± 1.9 liters/h, andt1/2= 1.03 ± 0.15 and 1.27 ± 0.21 h, respectively. The intrapulmonary penetrations of meropenem and RPX7009 were ca. 63 and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 h (AUC0–8) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetrations were 65 and 79% for meropenem and RPX7009, respectively. Meropenem concentrations in AMs were below the quantitative limit of detection, whereas median concentrations of RPX7009 in AMs ranged from 2.35 to 6.94 μg/ml. The results from the present study lend support to exploring a fixed combination of meropenem (2 g) and RPX7009 (2 g) for the treatment of lower respiratory tract infections caused by meropenem-resistant Gram-negative pathogens susceptible to the combination of meropenem-RPX7009.

Download Full-text