scholarly journals Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers

2015 ◽  
Vol 59 (8) ◽  
pp. 4429-4435 ◽  
Author(s):  
Sang-In Park ◽  
Jaeseong Oh ◽  
Kyungho Jang ◽  
Jangsoo Yoon ◽  
Seol Ju Moon ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Therapeutic Drug ◽  
Maximum Plasma ◽  
Second Line ◽  
Aminosalicylic Acid ◽  
Open Label ◽  
Multiple Dosing ◽  
Time Curve ◽  
Once Daily ◽  
Antituberculosis Drugs

ABSTRACTTherapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg),p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUCτ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The meanCmaxand AUCτ, respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.3 mg · h/liter; PAS, 65.9 mg/liter and 326.5 mg · h/liter; prothionamide, 5.3 mg/liter and 22.1 mg · h/liter; levofloxacin, 6.6 mg/liter and 64.4 mg · h/liter; moxifloxacin, 4.7 mg/liter and 54.2 mg · h/liter; streptomycin, 42.0 mg/liter and 196.7 mg · h/liter; kanamycin, 34.5 mg/liter and 153.5 mg · h/liter. The results indicated that sampling at 1, 2.5, and 6 h postdosing is needed for TDM when all seven drugs are administered concomitantly. This study indicates that PK characteristics must be considered when prescribing optimal treatments for patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02128308.)

Phase I/IIa, randomized, open-label, drug-drug interaction study of trabectedin and rifampin in patients with advanced cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13512-e13512 ◽  
Author(s):  
Arthur P. Staddon ◽  
Trilok V. Parekh ◽  
Roland Elmar Knoblauch ◽  
Chi Keung ◽  
Apexa Bernard ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Locally Advanced ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Maximum Plasma ◽  
Metabolic Clearance ◽  
Open Label ◽  
Time Curve ◽  
Elimination Half ◽  
Cyp3a4 Inducer

e13512 Background: Trabectedin (Yondelis; T) is a tetrahydroisoquinoline compound initially isolated from the marine tunicate, Ecteinascidia turbinata, and currently produced synthetically. It is primarily metabolized by the cytochrome P450 (CYP)3A4 enzyme. Thus, potent inducers or inhibitors of this enzyme may alter the plasma concentrations of T. This study assessed the effects of rifampin (R), a strong CYP3A4 inducer, on the pharmacokinetics (PK) and safety of T. Methods: In this 2-way crossover study, patients (≥18 years of age) with locally advanced or metastatic disease were randomized (1:1) to receive one of the 2 treatment sequences: sequence 1: R plus T followed 28 days later by T; sequence 2: T followed 28 days later by R plus T. During each sequence, R (600 mg/day) was administered for 6 consecutive days and T (1.3 mg/m2, IV) was administered over a 3 hour infusion. Dexamethasone (20 mg, IV) was administered before T administration. PK and safety of T were evaluated with and without coadministration of R. Results: Of the 11 enrolled patients, 8 were PK evaluable. Coadministration of R with T decreased mean maximum plasma concentration (Cmax) by approximately 22% and mean area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast) by approximately 31% (Table 1). Coadministration of R with T also resulted in 23% shorter elimination half-life. Overall, the safety profile of T was comparable when administered alone or with R. Conclusions: In comparison with T alone, coadministration of R resulted in reduced systemic exposure of T in these 8 patients, as measured by Cmax and AUClast. The coadministration of potent inducers of CYP3A4 with T may increase the metabolic clearance of T. Clinical trial information: NCT01273480. [Table: see text]

Pharmacokinetics, safety and tolerability of ravidasvir, with and without danoprevir/ritonavir, in healthy subjects

2021 ◽  
Author(s):  
Guolan Wu ◽  
Huili Zhou ◽  
Jing Wu ◽  
Duo Lv ◽  
Lihua Wu ◽  
...  
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Fold Increase ◽  
Sequential Design ◽  
Maximum Plasma ◽  
Double Blind ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Multiple Doses

Ravidasvir (RDV) is a novel oral hepatitis C virus NS5A inhibitor. This study aimed to evaluate the pharmacokinetics and safety of RDV and the drug–drug interaction between RDV and ritonavir-boosted danoprevir (DNVr) in healthy adults. In 1 st study, healthy volunteers were administered oral single doses of 100, 200 and 300 mg RDV and 200 mg once daily for 7 days. The 2 nd study was randomized, double-blind and placebo-controlled sequential design (day 1 for 200 mg RDV alone, day 7 for 100 mg/100 mg DNVr, day 13 for 200 mg RDV plus 100mg/100mg DNVr, followed by RDV 200 mg once daily with DNVr 100mg/100mg twice daily for 10 days). The results showed that RDV exposure increased in a dose-proportional manner following a single dose with no evidence of accumulation with multiple doses. Co-administration with DNVr regimen (100 mg/100 mg, twice daily) resulted in a 2.92- and 1.99-fold increase in minimum plasma concentration at steady state (C min,ss ) and area under the concentration–time curve at steady state (AUC τ ) of RDV. With co-administration of RDV, maximum plasma concentration (C max ) and area under the concentration curve from zero to 12 h (AUC 0-12 ) of DNV increased 1.71-fold and 2.33-fold, respectively. We did not observe any significant changes in ritonavir exposure. Both single and multiple doses of RDV with or without DNVr were well tolerated. The favorable pharmacokinetic and safety results support ravidasvir’s continued clinical development and treatment.

scholarly journals Multiple-Dose Safety, Tolerability, and Pharmacokinetics of Oral Nemonoxacin (TG-873870) in Healthy Volunteers

2010 ◽  
Vol 54 (1) ◽  
pp. 411-417 ◽  
Author(s):  
David T. Chung ◽  
Cheng-Yuan Tsai ◽  
Shu-Jen Chen ◽  
Li-Wen Chang ◽  
Chi-Hsin R. King ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Healthy Volunteers ◽  
Bacterial Infections ◽  
Maximum Plasma Concentration ◽  
Maximum Plasma ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Atypical Pathogens ◽  
Plasma Concentration Time Curve

ABSTRACT Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with broad-spectrum activities against Gram-positive and Gram-negative aerobic, anaerobic, and atypical pathogens, as well as against methicillin-resistant Staphylococcus aureus, vancomycin-resistant S. aureus, and multiple-resistant bacterial pathogens. We conducted a randomized, double-blind, placebo-controlled, dose-escalating study to ascertain the safety, tolerability, and pharmacokinetics of nemonoxacin. We enrolled 46 healthy volunteers and used a once-daily oral-dosing range of 75 to 1,000 mg for 10 days. Additionally, the food effect was evaluated in subjects in the 500-mg cohort. Nemonoxacin was generally safe and well tolerated, with no significant changes in the clinical laboratory tests or electrocardiograms. Adverse effects, including headache, contact dermatitis, and rash, were mild and resolved spontaneously. Nemonoxacin was rapidly absorbed within 2 h postdosing, and generally, a steady state was reached after 3 days. The maximum plasma concentration and the area under the plasma concentration-time curve were dose proportional over the dosing range. The elimination half-life was approximately 7.5 h and 19.7 h on days 1 and 10, respectively. Approximately 37 to 58% of the drug was excreted in the urine. Food affected the pharmacokinetics, with decreases in the maximum plasma concentration and area under the plasma concentration-time curve of 46% and 27%, respectively. However, the free AUC/MIC90 of nemonoxacin was more than 100 under both the fasting and fed conditions, predicting the efficacy of nemonoxacin against most of the tested pathogens. In conclusion, the results support further clinical investigation of once-daily nemonoxacin administration for antibiotic-sensitive and antibiotic-resistant bacterial infections.

The Pharmacokinetics of Loratadine in Normal Geriatric Volunteers

1988 ◽  
Vol 16 (1) ◽  
pp. 50-60 ◽  
Author(s):  
J. Hilbert ◽  
V. Moritzen ◽  
A. Parks ◽  
E. Radwanski ◽  
G. Perentesis ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
High Performance ◽  
The Elderly ◽  
Maximum Plasma Concentration ◽  
Pharmacokinetic Analysis ◽  
Maximum Plasma ◽  
Open Label ◽  
Post Dose ◽  
Time Curve ◽  
Concentration Time

The pharmacokinetics of loratadine, a non-sedating anti-histamine, were studied in 12 normal geriatric volunteers. In an open label fashion, each volunteer received one 40 mg loratadine capsule. Blood was collected prior to and at specified times (up to 120 h) after dosing. Plasma loratadine concentrations were determined by a specific radioimmunoassay and those of an active metabolite, descarboethoxyloratadine, by high performance liquid chromatography. Concentrations of loratadine in the disposition phase were fitted to a biexponential equation and those of descarboethoxyloratadine to either a monoexponential or biexponential equation for pharmacokinetic analysis. Loratadine was rapidly absorbed, reaching a maximum plasma concentration of 50.5 ng/ml at 1.5 h after dosing. The disposition half-lives of loratadine in the distribution and elimination phases were 1.5 and 18.2 h, respectively. The area under the plasma concentration–time curve, was 146.7 h·ng/ml. Descarboethoxyloratadine had a maximum plasma concentration of 28.0 ng/ml at 2.9 h post-dose and an area under the concentration–time curve of 394.9 h·ng/ml. Its disposition half-lives in the distribution and elimination phases were 2.8 and 17.4 h, respectively. Comparison of these data with those from a previous study of loratadine in young adults showed no clear differences in the disposition half-lives between the two groups. The clearance of loratadine tends to be lower in the elderly, but inter-individual variation within each age group appears greater than any age effect.

scholarly journals Solithromycin Pharmacokinetics in Plasma and Dried Blood Spots and Safety in Adolescents

2016 ◽  
Vol 60 (4) ◽  
pp. 2572-2576 ◽  
Author(s):  
Daniel Gonzalez ◽  
Debra L. Palazzi ◽  
Leena Bhattacharya-Mithal ◽  
Amira Al-Uzri ◽  
Laura P. James ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Plasma Concentration ◽  
Bacterial Infections ◽  
Phase 1 ◽  
Dried Blood Spots ◽  
Maximum Plasma ◽  
Open Label ◽  
Time Curve ◽  
Small Cohort ◽  
The Mean

ABSTRACTWe assessed the pharmacokinetics and safety of solithromycin, a fluoroketolide antibiotic, in a phase 1, open-label, multicenter study of 13 adolescents with suspected or confirmed bacterial infections. On days 3 to 5, the mean (standard deviation) maximum plasma concentration and area under the concentration versus time curve from 0 to 24 h were 0.74 μg/ml (0.61 μg/ml) and 9.28 μg · h/ml (6.30 μg · h/ml), respectively. The exposure and safety in this small cohort of adolescents were comparable to those for adults. (This study has been registered at ClinicalTrials.gov under registration no. NCT01966055.)

scholarly journals No relevant pharmacokinetic drug–drug interaction between nintedanib and pirfenidone

2018 ◽  
Vol 53 (1) ◽  
pp. 1801060 ◽  
Author(s):  
Luca Richeldi ◽  
Sophie Fletcher ◽  
Huzaifa Adamali ◽  
Nazia Chaudhuri ◽  
Sabrina Wiebe ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Plasma Concentration ◽  
Geometric Mean ◽  
Maximum Plasma ◽  
Open Label ◽  
Time Curve ◽  
Drug Drug Interaction ◽  
Group 2 ◽  
Pharmacokinetic Drug ◽  
Group 1

Nintedanib and pirfenidone are approved treatments for idiopathic pulmonary fibrosis (IPF). This open-label, two-group trial investigated the pharmacokinetic drug–drug interaction between these two drugs in patients with IPF.Subjects not treated with antifibrotics at screening (group 1, n=20) received a single nintedanib dose (150 mg) followed by pirfenidone (titrated to 801 mg thrice daily) for 3 weeks, with a further single nintedanib dose (150 mg) on the last day (day 23). Subjects treated with pirfenidone at screening (group 2, n=17) continued to receive pirfenidone alone (801 mg thrice daily) for 7 days, then co-administered with nintedanib (150 mg twice daily) for a further 7 days, before single doses of both treatments on day 16.In group 1, adjusted geometric mean (gMean) ratios (with/without pirfenidone) were 88.6% and 80.6% for nintedanib area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax), respectively. In group 2, gMean ratios (with/without nintedanib) were 97.2% and 99.5% for pirfenidone AUC and Cmax, respectively. For all parameters, the 90% confidence intervals included 100%, suggesting similar exposure for administration alone and when co-administered. Both treatments were well tolerated.These data indicate there is no relevant pharmacokinetic drug–drug interaction between nintedanib and pirfenidone when co-administered in IPF patients.

scholarly journals Pharmacokinetics of Voriconazole Administered Concomitantly with Fluconazole and Population-Based Simulation for Sequential Use

2011 ◽  
Vol 55 (11) ◽  
pp. 5172-5177 ◽  
Author(s):  
Bharat Damle ◽  
Manthena V. Varma ◽  
Nolan Wood
Keyword(s):  
Drug Interaction ◽  
Plasma Concentration ◽  
Antifungal Therapy ◽  
Sequential Therapy ◽  
Population Based ◽  
Poor Metabolizers ◽  
Maximum Plasma ◽  
Extensive Metabolizers ◽  
Open Label ◽  
Time Curve

ABSTRACTIn clinical practice, antifungal therapy may be switched from fluconazole to voriconazole; such sequential use poses the potential for drug interaction due to cytochrome P450 2C19 (CYP2C19)-mediated inhibition of voriconazole metabolism. This open-label, randomized, two-way crossover study investigated the effect of concomitant fluconazole on voriconazole pharmacokinetics in 10 subjects: 8 extensive metabolizers and 2 poor metabolizers of CYP2C19. The study consisted of 4-day voriconazole-only and 5-day voriconazole-plus-fluconazole treatments, separated by a 14-day washout. Voriconazole pharmacokinetics were determined by noncompartmental analyses. A physiologically based pharmacokinetic model was developed in Simcyp (Simcyp Ltd., Sheffield, United Kingdom) to predict the magnitude of drug interaction should antifungal therapy be switched from fluconazole to voriconazole, following various simulated lag times for the switch. In CYP2C19 extensive metabolizers, fluconazole increased the maximum plasma concentration and the area under the plasma concentration-time curve (AUC) of voriconazole by 57% and 178%, respectively. In poor metabolizers, however, voriconazole pharmacokinetics were unaffected by fluconazole. The simulations based on pharmacokinetic modeling predicted that if voriconazole was started 6, 12, 24, or 36 h after the last dose of fluconazole, the voriconazole AUC ratios (sequential therapy versus voriconazole only) after the first dose would be 1.51, 1.41, 1.28, and 1.14, respectively. This suggests that the remaining systemic fluconazole would result in a marked drug interaction with voriconazole for ≥24 h. Although no safety issues were observed during coadministration, concomitant use of fluconazole and voriconazole is not recommended. Frequent monitoring for voriconazole-related adverse events is advisable if voriconazole is used sequentially after fluconazole.

Pharmacokinetic interaction between linagliptin and tadalafil in healthy Egyptian males using a novel LC–MS method

Bioanalysis ◽  
2019 ◽  
Vol 11 (14) ◽  
pp. 1321-1336 ◽  
Author(s):  
Sara S Mourad ◽  
Eman I El-Kimary ◽  
Magda A Barary ◽  
Dalia A Hamdy
Keyword(s):  
Plasma Concentration ◽  
Pharmacokinetic Interaction ◽  
Volume Of Distribution ◽  
Maximum Plasma Concentration ◽  
Maximum Plasma ◽  
Qtc Interval ◽  
Qtc Prolongation ◽  
Open Label ◽  
Time Curve ◽  
Concentration Time

Aim: Assessment of pharmacokinetic interaction between linagliptin (LNG) and tadalafil (TDL) in healthy males. Methods: First, a novel LC–MS method was developed; second, a Phase IV, open-label, cross-over study was performed. Volunteers took single 20-mg TDL dose on day 1 followed by wash out period of 2 weeks then multiple oral dosing of 5-mg/day LNG for 13 days. On day 13, volunteers were co-administered 20-mg TDL. Results: LNG and TDL single doses did not affect QTc interval. Smoking did not alter pharmacokinetics/pharmacodynamics of LNG and TDL. Co-administration of LNG with TDL resulted in TDL longer time to reach maximum plasma concentration (Tmax), decreased oral clearance (Cl/F) and oral volume of distribution (Vd/F), increased its maximum plasma concentration (Cmax), area under concentration-time curve (AUC), muscle pain and QTc prolongation. Conclusion: LNG and TDL co-administration warrants monitoring and/or TDL dose adjustment.

An Evaluation of the Potential for Pharmacokinetic Interaction between Tramadol and Cytochrome P450 2D6 Inhibitor Promethazine

2014 ◽  
Vol 989-994 ◽  
pp. 1041-1043
Author(s):  
Ping Liu ◽  
Liang Sun ◽  
Jian Zhang ◽  
Rui Chen Guo
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Pharmacokinetic Interaction ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Open Label ◽  
Tramadol Hydrochloride ◽  
Time Curve

In this single-center, randomized, open-label, 3-way crossover study, subjects received each of the following: a single dose of Tramadol Hydrochloride Injection (THI) 35 mg, a single dose of Promethazine Hydrochloride Injection (PHI) 45 mg, and single dose of Compound Tramadol Hydrochloride Injection (CTHI) 80mg. Blood was collected and plasma was analyzed for the pharmacokinetic parameters (maximum plasma concentration [Cmax], time to Cmax [Tmax], area under the plasma concentration-time curve, plasma elimination half-life, clearance, and apparent volume of distribution) of Tramadol and Promethazine. In general, several pharmacokinetic interactions were observed between Tramadol and Promethazine in the present study.

scholarly journals Fosamprenavir plus Ritonavir Increases Plasma Ketoconazole and Ritonavir Exposure, while Amprenavir Exposure Remains Unchanged

2007 ◽  
Vol 51 (8) ◽  
pp. 2982-2984 ◽  
Author(s):  
Mary B. Wire ◽  
Charles H. Ballow ◽  
Julie Borland ◽  
Mark J. Shelton ◽  
Yu Lou ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
Open Label ◽  
Time Curve ◽  
Once Daily ◽  
Open Label Study ◽  
Label Study ◽  
Concentration Time

ABSTRACT Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.

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