scholarly journals Evaluation of potential drug interactions with sodium zirconium cyclosilicate: a single-center, open-label, one sequence crossover study in healthy adults

2020 ◽  
Author(s):  
Mats Någård ◽  
William G Kramer ◽  
David W Boulton
Keyword(s):  
Plasma Concentration ◽  
Drug Interactions ◽  
Ph Sensitive ◽  
Gastric Ph ◽  
Healthy Adults ◽  
Maximum Plasma ◽  
Open Label ◽  
Interaction Range ◽  
Sodium Zirconium ◽  
Sodium Zirconium Cyclosilicate

Abstract Background Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is an oral potassium binder for the treatment of hyperkalemia in adults. SZC acts in the gastrointestinal tract and additionally binds hydrogen ions in acidic environments like the stomach, potentially transiently increasing gastric pH and leading to drug interactions with pH-sensitive drugs. This study assessed potential pharmacokinetic (PK) interactions between SZC and nine pH-sensitive drugs. Methods In this single-dose, open-label, single-sequence cross-over study in healthy adults, amlodipine, atorvastatin, clopidogrel, dabigatran, furosemide, glipizide, levothyroxine, losartan or warfarin were each administered alone and, following a washout interval, with SZC 10 g. Maximum plasma concentration (Cmax), area under the plasma concentration–time curve from 0 to the last time point (AUC0–t) and AUC extrapolated to infinity (AUCinf) were evaluated. No interaction was concluded if the 90% confidence interval for the geometric mean ratio (SZC coadministration versus alone) of the PK parameters was within 80–125%. Results During SZC coadministration, all PK parameters for amlodipine, glipizide, levothyroxine and losartan showed no interaction, while reductions in clopidogrel and dabigatran Cmax, AUC0–t and AUCinf (basic drugs) were <50% and increases in atorvastatin, furosemide and warfarin Cmax (acidic drugs) exceeded the no-interaction range by ˂2-fold. Conclusions SZC coadministration was associated with small changes in plasma concentration and exposure of five of the nine drugs evaluated in this study. These PK drug interactions are consistent with transient increases in gastric pH with SZC and are unlikely to be clinically meaningful.

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]

scholarly journals Investigations on the Influence of Zidovudine in the Pharmacokinetics of Isoniazid and Its Hepatotoxic Metabolites in Rats

2017 ◽  
Vol 32 (1) ◽  
pp. 9-18
Author(s):  
Raghu Ramanathan ◽  
Karthikeyan Sivanesan
Keyword(s):  
Plasma Concentration ◽  
Drug Interactions ◽  
Bacterial Infections ◽  
Plasma Clearance ◽  
Combined Therapy ◽  
Maximum Plasma Concentration ◽  
Pharmacokinetic Studies ◽  
Maximum Plasma ◽  
Group I ◽  
Pharmacokinetic Drug

The HIV-infected patients are co-infected with many bacterial infections in which tuberculosis is most common found worldwide. These patients are often administered with combined therapy of anti-retroviral and anti-tubercular drugs which leads to several complications including hepatotoxicity or adverse drug interactions. The drug-drug interactions between the anti-retroviral and anti-tubercular drugs are not clearly defined and hence, this study was conducted to evaluate the pharmacokinetic drug-drug interactions of Zidovudine (AZT) with Isoniazid (INH) and its hepatotoxic metabolites. Seventy two rats were randomly divided into two major groups with their sub-groups each comprising 6 animals. The Group I received INH alone at a dose of 25 mg/kg; b.w and Group II received AZT (50 mg/kg; b.w) along with INH orally. Pharmacokinetic studies of INH and its metabolites i.e., acetyl hydrazine (ACHY) and hydrazine (HYD) shows that INH and ACHY attains maximum plasma concentration ( Cmax) within 30 minutes and HYD attains Cmax at 1 hour after INH administration and all these analytes disappear from plasma within 4 hours. Pharmacokinetic studies also revealed that AZT treatment did not showed any drug-drug interactions and have no effect on the T1/2, plasma clearance, AUC, Cmax and Tmax of INH and its hepatotoxic metabolites.

scholarly journals Reviewing Data Integrated for PBPK Model Development to Predict Metabolic Drug-Drug Interactions: Shifting Perspectives and Emerging Trends

2021 ◽  
Vol 12 ◽  
Author(s):  
Kenza Abouir ◽  
Caroline F Samer ◽  
Yvonne Gloor ◽  
Jules A Desmeules ◽  
Youssef Daali
Keyword(s):  
Plasma Concentration ◽  
Drug Interactions ◽  
Pbpk Model ◽  
Model Development ◽  
Pbpk Modeling ◽  
Maximum Plasma ◽  
Extrinsic Factors ◽  
Pbpk Models ◽  
Emerging Trends ◽  
Clearance Prediction

Physiologically-based pharmacokinetics (PBPK) modeling is a robust tool that supports drug development and the pharmaceutical industry and regulatory authorities. Implementation of predictive systems in the clinics is more than ever a reality, resulting in a surge of interest for PBPK models by clinicians. We aimed to establish a repository of available PBPK models developed to date to predict drug-drug interactions (DDIs) in the different therapeutic areas by integrating intrinsic and extrinsic factors such as genetic polymorphisms of the cytochromes or environmental clues. This work includes peer-reviewed publications and models developed in the literature from October 2017 to January 2021. Information about the software, type of model, size, and population model was extracted for each article. In general, modeling was mainly done for DDI prediction via Simcyp® software and Full PBPK. Overall, the necessary physiological and physio-pathological parameters, such as weight, BMI, liver or kidney function, relative to the drug absorption, distribution, metabolism, and elimination and to the population studied for model construction was publicly available. Of the 46 articles, 32 sensibly predicted DDI potentials, but only 23% integrated the genetic aspect to the developed models. Marked differences in concentration time profiles and maximum plasma concentration could be explained by the significant precision of the input parameters such as Tissue: plasma partition coefficients, protein abundance, or Ki values. In conclusion, the models show a good correlation between the predicted and observed plasma concentration values. These correlations are all the more pronounced as the model is rich in data representative of the population and the molecule in question. PBPK for DDI prediction is a promising approach in clinical, and harmonization of clearance prediction may be helped by a consensus on selecting the best data to use for PBPK model development.

scholarly journals Drug Interactions with the Direct-Acting Antiviral Combination of Ombitasvir and Paritaprevir-Ritonavir

2015 ◽  
Vol 60 (1) ◽  
pp. 105-114 ◽  
Author(s):  
Prajakta S. Badri ◽  
Sandeep Dutta ◽  
Haoyu Wang ◽  
Thomas J. Podsadecki ◽  
Akshanth R. Polepally ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Drug Interactions ◽  
Dose Adjustment ◽  
Maximum Plasma ◽  
Time Curve ◽  
Geometric Means ◽  
Direct Acting Antiviral ◽  
Concentration Time ◽  
Direct Acting ◽  
Subtype 1B

ABSTRACTThe two direct-acting antiviral (2D) regimen of ombitasvir and paritaprevir (administered with low-dose ritonavir) is being developed for treatment of genotype subtype 1b and genotypes 2 and 4 chronic hepatitis C virus (HCV) infection. Drug-drug interactions were evaluated in healthy volunteers to develop dosing recommendations for HCV-infected subjects. Mechanism-based interactions were evaluated for ketoconazole, pravastatin, rosuvastatin, digoxin, warfarin, and omeprazole. Interactions were also evaluated for duloxetine, escitalopram, methadone, and buprenorphine-naloxone. Ratios of geometric means with 90% confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve were estimated to assess the magnitude of the interactions. For most medications, coadministration with the 2D regimen resulted in a <50% change in exposures. Ketoconazole, digoxin, pravastatin, and rosuvastatin exposures increased by up to 105%, 58%, 76%, and 161%, respectively, and omeprazole exposures decreased by approximately 50%. Clinically meaningful changes in ombitasvir, paritaprevir, or ritonavir exposures were not observed. In summary, all 11 medications evaluated can be coadministered with the 2D regimen, with most medications requiring no dose adjustment. Ketoconazole, digoxin, pravastatin, and rosuvastatin require lower doses, and omeprazole may require a higher dose. No dose adjustment is required for the 2D regimen.

scholarly journals An Open-Label Crossover Study To Evaluate Potential Pharmacokinetic Interactions between Oral Oseltamivir and Intravenous Zanamivir in Healthy Thai Adults

2011 ◽  
Vol 55 (9) ◽  
pp. 4050-4057 ◽  
Author(s):  
Sasithon Pukrittayakamee ◽  
Podjanee Jittamala ◽  
Kasia Stepniewska ◽  
Niklas Lindegardh ◽  
Sunee Chueasuwanchai ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Interaction ◽  
Influenza Viruses ◽  
Maximum Plasma ◽  
Parenteral Formulation ◽  
Oseltamivir Carboxylate ◽  
Open Label ◽  
Oseltamivir Resistance

ABSTRACTThere is no parenteral formulation of the neuraminidase inhibitor oseltamivir, the most widely used anti-influenza virus drug. Oseltamivir resistance is an increasing problem. Zanamivir is effective against the most prevalent oseltamivir-resistant influenza viruses. A parenteral formulation of zanamivir is in development for the treatment of severe influenza. It is not known if there is any pharmacokinetic interaction between the two drugs. Sixteen healthy Thai adult volunteers were studied in an open-label, four-period, randomized two-sequence crossover pharmacokinetic study in which zanamivir was given by constant-rate infusion or slow intravenous injection either alone or together with oral oseltamivir. Plasma concentration profiles of oseltamivir, the active metabolite oseltamivir carboxylate, and zanamivir were measured by liquid chromatography-mass spectrometry-mass spectrometry. Both drugs were well tolerated alone and in combination. The maximum plasma concentrations and the areas under the plasma concentration-time curves (AUC) of oseltamivir and oseltamivir carboxylate were not significantly different when oseltamivir was given separately or together with zanamivir. Maximum plasma concentrations of zanamivir were 10% (95% confidence interval, 7 to 12%) higher when zanamivir was infused concurrently with oral oseltamivir than with infusions before or after oral oseltamivir. The plasma zanamivir total AUC was positively correlated with the total oseltamivir carboxylate AUC (Pearson's correlation coefficient [rP] = 0.720,P= 0.002,n= 16) but not with the oseltamivir AUC (rp= 0.121,n= 16). There is no clinically significant pharmacokinetic interaction between oseltamivir and zanamivir.

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 Effects of CYP3A4 and P-glycoprotein inhibition or induction on the pharmacokinetics of ubrogepant in healthy adults: Two phase 1, open-label, fixed-sequence, single-center, crossover trials

2021 ◽  
Vol 4 ◽  
pp. 251581632110373
Author(s):  
Abhijeet Jakate ◽  
Ramesh Boinpally ◽  
Matthew Butler ◽  
Wendy Ankrom ◽  
Marissa F Dockendorf ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Phase 1 ◽  
Geometric Mean ◽  
Healthy Adults ◽  
Single Center ◽  
Open Label ◽  
Two Phase ◽  
Fixed Sequence ◽  
P Glycoprotein ◽  
Crossover Trials

Background: Ubrogepant is metabolized by cytochrome P450 3A4 (CYP3A4) and is a P-glycoprotein (P-gp) substrate. Objective: To assess effects of multiple-dose moderate-strong CYP3A4 and strong P-gp inhibitors and inducers on ubrogepant pharmacokinetic (PK) parameters. Methods: Two phase 1, open-label, fixed-sequence, single-center, crossover trials enrolled healthy adults to receive ubrogepant 20 mg with/without verapamil 240 mg (a moderate CYP3A4 inhibitor) or ketoconazole 400 mg (a strong CYP3A4 and P-gp transporter inhibitor) (Study A), or ubrogepant 100 mg with/without rifampin 600 mg (a strong CYP3A4 inducer and P-gp inducer) (Study B). Outcomes included ubrogepant PK parameters (area under plasma concentration-time curve, time 0 through infinity [AUC0-∞], peak plasma concentration [Cmax]), and safety (treatment-emergent adverse events [TEAEs]). PK parameters were compared between ubrogepant with/without coadministered medications using linear mixed-effects models. Cmax and AUC0-∞ least-squares geometric mean ratios (GMR) of ubrogepant with/without coadministration were constructed. Results: Twelve participants enrolled in Study A and 30 in Study B. AUC0-∞ and Cmax GMR (90% CI) were 3.53 (3.32–3.75) and 2.80 (2.48–3.15), respectively, for ubrogepant with verapamil; 9.65 (7.27–12.81) and 5.32 (4.19–6.76) with ketoconazole; and 0.22 (0.20–0.24) and 0.31 (0.27–0.36) with rifampin. TEAEs were predominantly mild; no treatment-related serious TEAEs or TEAE-related discontinuations occurred. Conclusion: The PK of ubrogepant were significantly affected by the concomitant use of CYP3A4 moderate-strong inhibitors and strong inducers.

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.)

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 Efficacy and Safety of Sodium Zirconium Cyclosilicate for Treatment of Hyperkalemia: An 11-Month Open-Label Extension of HARMONIZE

2019 ◽  
Vol 50 (6) ◽  
pp. 473-480 ◽  
Author(s):  
Simon D. Roger ◽  
Bruce S. Spinowitz ◽  
Edgar V. Lerma ◽  
Bhupinder Singh ◽  
David K. Packham ◽  
...  
Keyword(s):  
Point Of Care ◽  
Efficacy And Safety ◽  
Open Label ◽  
Once Daily ◽  
End Point ◽  
Sodium Zirconium ◽  
Open Label Extension ◽  
Median Daily Dose ◽  
Sodium Zirconium Cyclosilicate ◽  
Secondary Results

Background: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for treatment of hyperkalemia. An open-label extension (OLE) of the ­HARMONIZE study evaluated efficacy and safety of SZC for ≤11 months. Methods: Patients from HARMONIZE with point-of-care device i-STAT K+ 3.5–6.2 mmol/L received once-daily SZC 5–10 g for ≤337 days. End points included achievement of mean serum K+ ≤5.1 mmol/L (primary) or ≤5.5 mmol/L (secondary). Results: Of 123 patients who entered the extension (mean serum K+ 4.8 mmol/L), 79 (64.2%) completed the study. The median daily dose of SZC was 10 g (range 2.5–15 g). The primary end point was achieved by 88.3% of patients, and 100% achieved the secondary end point. SZC was well tolerated with no new safety concerns. Conclusion: In the HARMONIZE OLE, most patients maintained mean serum K+ within the normokalemic range for ≤11 months during ongoing SZC treatment.

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