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Article ; Online: Population Pharmacokinetic Analysis of Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis.

Wang, Xiaofeng / Mallikaarjun, Suresh / Gibiansky, Ekaterina

2020 Volume 65, Issue 1

Abstract: A population pharmacokinetic (PopPK) model of delamanid in patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) was developed using data from four delamanid clinical trials. The final PopPK data set contained 20,483 plasma samples from 744 ... ...

Abstract	A population pharmacokinetic (PopPK) model of delamanid in patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) was developed using data from four delamanid clinical trials. The final PopPK data set contained 20,483 plasma samples from 744 patients with MDR-TB receiving an optimized background regimen (OBR). Delamanid PK was adequately described for all observed dosing regimens and subpopulations by a two-compartment model with first-order elimination and absorption, an absorption lag time, and decreased relative bioavailability with increasing dose. Relative bioavailabilities of 200-mg and higher doses (250 and 300 mg) were 76% and 58% of a 100-mg dose, respectively. Relative bioavailability was 26% higher after evening doses than morning doses and 9% higher in outpatient settings than inpatient settings. The rate of absorption was higher, and lag time was shorter, following a morning dose than an evening dose. Relative bioavailabilities in patients in Northeast Asian and Southeast Asian regions were 53% and 40% higher, respectively, than in patients in non-Asian regions. Apparent clearance was higher (to the power of -0.892) in patients with hypoalbuminemia (albumin levels of <3.4 g/dl). Coadministration of efavirenz in patients with HIV increased delamanid clearance by 35%. Delamanid exposure was not affected by age (18 to 64 years), mild or moderate renal impairment, anti-TB antibiotic resistance status, HIV status, or markers of hepatic dysfunction or by concomitant administration of OBR, lamivudine, tenofovir, pyridoxine, CYP3A4 inhibitors and inducers, or antacids. Model evaluation suggested reasonable model fit and predictive power, indicating that the model should prove reliable to derive PK metrics for subsequent PK/PD analyses.
MeSH term(s)	Adolescent ; Adult ; Antitubercular Agents/therapeutic use ; Humans ; Middle Aged ; Nitroimidazoles/therapeutic use ; Oxazoles ; Tuberculosis, Multidrug-Resistant/drug therapy ; Tuberculosis, Pulmonary/drug therapy ; Young Adult
Chemical Substances	Antitubercular Agents ; Nitroimidazoles ; OPC-67683 ; Oxazoles
Language	English
Publishing date	2020-12-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01202-20
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Zs.A 809: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Population Pharmacokinetic Modeling and Exposure-Response Analysis for Aripiprazole Once Monthly in Subjects With Schizophrenia.

Wang, Xiaofeng / Raoufinia, Arash / Bihorel, Sébastien / Passarell, Julie / Mallikaarjun, Suresh / Phillips, Luann

Clinical pharmacology in drug development

2022 Volume 11, Issue 2, Page(s) 150–164

Abstract: An intramuscular formulation of aripiprazole monohydrate dosed once monthly (AOM) was developed to address nonadherence with the approved oral tablets. A 3-compartment linear population pharmacokinetic model for oral and AOM doses was developed; relative ...

Abstract	An intramuscular formulation of aripiprazole monohydrate dosed once monthly (AOM) was developed to address nonadherence with the approved oral tablets. A 3-compartment linear population pharmacokinetic model for oral and AOM doses was developed; relative bioavailability was estimated for AOM relative to oral dosing and body mass index and sex were significant predictors of AOM absorption rate constant (longer absorption half-life for women and absorption half-life increases with increasing body mass index). Aripiprazole apparent oral clearance for subjects with cytochrome P450 (CYP) 2D6 poor metabolizer status and in the presence of strong CYP2D6 inhibitors was approximately half that of subjects with CYP2D6 extensive metabolizer status and 24% lower in the presence of strong CYP3A4 inhibitors. Simulations of the population pharmacokinetics were conducted to evaluate the effect of different dose initiation strategies for AOM, the effects of CYP2D6 metabolizer status, coadministration of CYP2D6 and CYP3A4 inhibitors, and missed doses. An exposure-response model with an exponential hazard function of the model-predicted minimum concentration (C
MeSH term(s)	Antipsychotic Agents ; Aripiprazole ; Female ; Humans ; Piperazines/pharmacokinetics ; Quinolones/pharmacokinetics ; Schizophrenia/drug therapy
Chemical Substances	Antipsychotic Agents ; Piperazines ; Quinolones ; Aripiprazole (82VFR53I78)
Language	English
Publishing date	2022-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.1022
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Article ; Online: Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis.

Sasaki, Tomohiro / Svensson, Elin M / Wang, Xiaofeng / Wang, Yanlin / Hafkin, Jeffrey / Karlsson, Mats O / Mallikaarjun, Suresh

Antimicrobial agents and chemotherapy

2021 Volume 66, Issue 2, Page(s) e0160821

Abstract: A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from ... ...

Abstract	A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 and 17 years, enrolled in 2 clinical trials, were utilized for the analysis. The final data set contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two-compartment models for each component with linear elimination were selected to characterize the dispositions of delamanid and DM-6705, respectively. The covariates included in the model were body weight on the apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible versus film-coated tablet) on the mean absorption time; age, formulation, and dose on the bioavailability of delamanid; and age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB [QT corrected by Bazett's formula]) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the model-predicted upper bounds of the 90% confidence intervals of ΔQTc values were <10 ms at the simulated maximum concentration (
MeSH term(s)	Adolescent ; Adult ; Antitubercular Agents/pharmacokinetics ; Antitubercular Agents/therapeutic use ; Child ; Child, Preschool ; Humans ; Infant ; Nitroimidazoles/therapeutic use ; Oxazoles/therapeutic use ; Tuberculosis, Multidrug-Resistant/drug therapy
Chemical Substances	Antitubercular Agents ; Nitroimidazoles ; OPC-67683 ; Oxazoles
Language	English
Publishing date	2021-11-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01608-21
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Zs.A 809: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: An Integrated Pharmacokinetic-Pharmacodynamic-Pharmacoeconomic Modeling Method to Evaluate Treatments for Adults with Schizophrenia.

Piena, Marjanne A / Houwing, Natalie / Kraan, Carla W / Wang, Xiaofeng / Waters, Heidi / Duffy, Ruth A / Mallikaarjun, Suresh / Bennison, Craig

PharmacoEconomics

2021 Volume 40, Issue 1, Page(s) 121–131

Abstract: Introduction: Schizophrenia is a chronic mental disorder that worsens with each relapse. Long-acting injectable (LAI) antipsychotics may prevent the exacerbation of symptoms and occurrence of relapses through improved continuity of care. Different dose ... ...

Abstract	Introduction: Schizophrenia is a chronic mental disorder that worsens with each relapse. Long-acting injectable (LAI) antipsychotics may prevent the exacerbation of symptoms and occurrence of relapses through improved continuity of care. Different dose regimens are available for the LAIs aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL), but their cost effectiveness is unclear. Objectives: The study aim was to compare costs and effects (relapses) of the different aripiprazole LAI dose regimens to inform clinical and US payer decisions. Methods: A state-transition model calculated the outcomes of eight LAI dose regimens based on their relapse rates. As effectiveness data from randomized controlled trials were unavailable, relapse rates were modeled using pharmacokinetic and pharmacodynamic evidence. These described blood plasma levels of aripiprazole as a function of AM and AL dose regimens and described the probability of relapse as a function of aripiprazole blood plasma levels. The analysis had a time horizon of 1 year and took the US healthcare payer perspective. The incremental cost per relapse avoided and the probability of cost effectiveness were calculated in deterministic and probabilistic analyses. Scenario analyses explored the model's main assumptions, and results were validated against external data and other cost-effectiveness analyses. Results: Monthly administration of AM 400 mg consistently yielded the lowest predicted number of relapses across deterministic, probabilistic, and scenario analyses. The costs of treatment and relapses were projected to be the lowest with a monthly administration of AL 441 mg. The incremental cost per relapse avoided with AM 400 mg ranged from AM 400 mg being dominant to $US83,300. From willingness-to-pay thresholds of $US30,000 per relapse avoided, the probability of cost effectiveness was highest for AM 400 mg. The validation showed alignment with external data. Conclusion: The analysis highlighted the robustness of the novel framework based on pharmacokinetic and pharmacodynamic evidence and demonstrated an application in a postmarketing setting.
MeSH term(s)	Adult ; Antipsychotic Agents/therapeutic use ; Cost-Benefit Analysis ; Economics, Pharmaceutical ; Humans ; Recurrence ; Schizophrenia/drug therapy
Chemical Substances	Antipsychotic Agents
Language	English
Publishing date	2021-10-08
Publishing country	New Zealand
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1100273-6
ISSN	1179-2027 ; 1170-7690
ISSN (online)	1179-2027
ISSN	1170-7690
DOI	10.1007/s40273-021-01077-8
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Zs.A 3579: Show issues

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Article: Pharmacokinetic and Pharmacodynamic Interaction Between Tolvaptan and Warfarin in Healthy Subjects.

Shoaf, Susan E / Mallikaarjun, Suresh

Clinical pharmacology in drug development

2012 Volume 1, Issue 2, Page(s) 67–75

Abstract: Purpose: Tolvaptan, a nonpeptide V2 receptor antagonist approved in Japan and in the United States, is likely to be co-administered with warfarin in patients with heart failure (HF). Therefore, the effect of tolvaptan on warfarin pharmacokinetics, ... ...

Abstract	Purpose: Tolvaptan, a nonpeptide V2 receptor antagonist approved in Japan and in the United States, is likely to be co-administered with warfarin in patients with heart failure (HF). Therefore, the effect of tolvaptan on warfarin pharmacokinetics, pharmacodynamics, and protein binding was evaluated. Methods: An open-label, randomized, 2-period crossover trial was conducted involving healthy subjects (N = 24) administered 25 mg warfarin sodium on day 4 of a 13-day regimen of either 60 mg once daily tolvaptan or matching placebo. Blood samples were taken over 240 hours postdose for analysis of tolvaptan, R- and S-warfarin, and 7- and 10-hydroxywarfarin concentrations and for the measurement of activated partial thromboplastin time, prothrombin time, and international normalized ratio. Results: For S-warfarin, the geometric mean ratios (warfarin+tolvaptan/warfarin alone; 90% confidence interval) for maximum plasma concentration (Cmax ) and area under the concentration-time curve from time 0 to infinity (AUC∞ ) were 1.09 (1.05, 1.12) and 1.09 (1.04, 1.13), respectively. Corresponding ratios for R-warfarin were 1.06 (1.02, 1.09) and 1.05 (1.01, 1.11), respectively. No changes were observed in 7- or 10-hydroxywarfarin Cmax or AUC∞ values, prothrombin time, activated partial thromboplastin time, and international normalized ratio. The protein binding of racemic warfarin and tolvaptan was not significantly altered by the presence of the other compound. Conclusion: Warfarin doses do not need to be altered when co-administered with tolvaptan.
Language	English
Publishing date	2012-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1177/2160763X12439702
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Article ; Online: Pharmacokinetics and pharmacodynamics of oral tolvaptan in patients with varying degrees of renal function.

Shoaf, Susan E / Bricmont, Patricia / Mallikaarjun, Suresh

Kidney international

2013 Volume 85, Issue 4, Page(s) 953–961

Abstract: The selective vasopressin V2-receptor antagonist tolvaptan is eliminated almost exclusively by non-renal mechanisms. As renal impairment can influence the pharmacokinetics of drugs even when eliminated by non-renal mechanisms, we evaluated the effect of ... ...

Abstract	The selective vasopressin V2-receptor antagonist tolvaptan is eliminated almost exclusively by non-renal mechanisms. As renal impairment can influence the pharmacokinetics of drugs even when eliminated by non-renal mechanisms, we evaluated the effect of renal insufficiency on the pharmacokinetics/pharmacodynamics of tolvaptan. Thirty-seven patients were grouped by a 24-h creatinine clearance (CrCL) and evaluated for 48 h after a single 60 mg oral dose in the fasting state. Mean tolvaptan exposure was 90% higher in the under 30-ml/min group compared with the over 60-ml/min group with individual values significantly but negatively correlated with increasing baseline CrCL. There was a greater and more rapid increase in urine output and free water clearance in the over 60-ml/min compared with the renal impaired groups, but they returned to baseline more quickly. Serum sodium increased more rapidly in the over 60 as opposed to the under 30-ml/min group, but overall maximum increases were similar across groups. Small decreases in mean CrCL and small increases in mean serum creatinine/potassium were independent of baseline CrCL. The percent fractional free water clearance with respect to CrCL was significantly but negatively correlated with increasing baseline CrCL. No unexpected adverse events were reported. Thus, renal impairment attenuated the increase in 24-h urine volume and free water clearance caused by tolvaptan, consistent with decreased nephron function in renal impairment. The delay in serum sodium increase was consistent with the longer duration needed to excrete sufficient water to cause the increase.
MeSH term(s)	Administration, Oral ; Aged ; Antidiuretic Hormone Receptor Antagonists/administration & dosage ; Antidiuretic Hormone Receptor Antagonists/pharmacokinetics ; Benzazepines/administration & dosage ; Benzazepines/pharmacokinetics ; Female ; Humans ; Male ; Middle Aged ; Renal Insufficiency, Chronic/metabolism ; Tolvaptan
Chemical Substances	Antidiuretic Hormone Receptor Antagonists ; Benzazepines ; Tolvaptan (21G72T1950)
Language	English
Publishing date	2013-09-18
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1038/ki.2013.350
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Zs.A 797: Show issues

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Article ; Online: Cytomegalovirus Antibody Responses Associated With Increased Risk of Tuberculosis Disease in Ugandan Adults.

Stockdale, Lisa / Nash, Stephen / Farmer, Ruth / Raynes, John / Mallikaarjun, Suresh / Newton, Robert / Fletcher, Helen A

The Journal of infectious diseases

2019 Volume 221, Issue 7, Page(s) 1127–1134

Abstract: Background: Recent evidence highlights human cytomegalovirus (HCMV) and immune activation as risk factors for tuberculosis disease. It is not known whether other herpesviruses are also implicated, nor whether a dose-response relationship exists between ... ...

Abstract	Background: Recent evidence highlights human cytomegalovirus (HCMV) and immune activation as risk factors for tuberculosis disease. It is not known whether other herpesviruses are also implicated, nor whether a dose-response relationship exists between tuberculosis risk and herpes coinfection. Methods: This nested case-control study used stored serum samples from 25 persons with tuberculosis up to 10 years before tuberculosis diagnosis and between 3 and 6 matched controls without tuberculosis from a rural Ugandan cohort. Samples were investigated for Epstein-Barr virus, herpes simplex virus, and HCMV-specific immunoglobulin G (IgG), serum markers of inflammation, and mycobacterial antibody levels. Results: Humoral response to HCMV, but not Epstein-Barr or herpes simplex virus, was associated with increased risk of active tuberculosis disease up to 10 years before diagnosis. Individuals with medium HCMV IgG were 2.8 times more likely to have tuberculosis (P = .055), and those with high HCMV IgG 3.4 times more likely to have tuberculosis (P = .007). Mycobacterial antibody levels were not associated with differences in odds of tuberculosis disease. Interferon-induced protein 10 was independently associated with increased odds of tuberculosis (odds ratio, 4.2; P = .009). Conclusions: These data provide evidence of a dose response between magnitude of HCMV IgG with risk of tuberculosis disease. An inflammatory environment, characterized by serum interferon-induced protein 10 and interleukin 1α, is independently associated with increased risk of tuberculosis disease.
MeSH term(s)	Adolescent ; Adult ; Antibodies, Viral/blood ; Case-Control Studies ; Chemokine CXCL10/blood ; Child ; Child, Preschool ; Cytomegalovirus/immunology ; Cytomegalovirus Infections/complications ; Cytomegalovirus Infections/epidemiology ; Cytomegalovirus Infections/immunology ; Female ; Humans ; Male ; Middle Aged ; Mycobacterium tuberculosis/immunology ; Rural Population ; Tuberculosis/complications ; Tuberculosis/epidemiology ; Tuberculosis/immunology ; Uganda ; Young Adult
Chemical Substances	Antibodies, Viral ; CXCL10 protein, human ; Chemokine CXCL10
Language	English
Publishing date	2019-10-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiz581
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Uh II Zs.50: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article: Absolute bioavailability of tolvaptan and determination of minimally effective concentrations in healthy subjects.

Shoaf, Susan E / Bricmont, Patricia / Mallikaarjun, Suresh

International journal of clinical pharmacology and therapeutics

2012 Volume 50, Issue 2, Page(s) 150–156

Abstract: Tolvaptan is a selective vasopressin V2 receptor antagonist that can be given orally once daily for treatment of clinically significant hypervolemic and euvolemic hyponatremia (US) or cardiac edema (Japan). Tolvaptan absolute bioavailability was ... ...

Abstract	Tolvaptan is a selective vasopressin V2 receptor antagonist that can be given orally once daily for treatment of clinically significant hypervolemic and euvolemic hyponatremia (US) or cardiac edema (Japan). Tolvaptan absolute bioavailability was determined in a single-center, open-label, sequential administration trial in which intravenous (i.v.) placebo (Day -2), i.v. 1 mg tolvaptan (Day 1) and an oral 30 mg tablet (Day 8) were administered to 14 healthy subjects. Urine volume and osmolality were determined on Days -2, 1 and 8 at multiple intervals postdose; 24-h fluid balance was also assessed. On Days 1 and 8, blood samples for tolvaptan were collected for 48 h postdose. Mean absolute bioavailability was determined to be 56% (range 42 - 80). Mean peak tolvaptan concentration at 1 h (end-of-infusion) was 32.7 (range 18 - 45) ng/ml compared to 231 (range 87 - 410) ng/ml for the oral dose. In the 4-h period from start of the 1 mg tolvaptan i.v. infusion, 12 of 14 subjects experienced increased urine volume and decreased urine osmolality; both parameters were affected for 24 h postdose following the 30 mg oral dose. Minimally effective concentrations are rapidly achieved after oral dosing as all subjects had tolvaptan concentrations > 20 ng/ml at 1 h postdose.
MeSH term(s)	Administration, Oral ; Adult ; Antidiuretic Hormone Receptor Antagonists ; Benzazepines/administration & dosage ; Benzazepines/pharmacokinetics ; Biological Availability ; Female ; Humans ; Infusions, Intravenous ; Male ; Osmolar Concentration ; Tablets ; Tolvaptan ; Urine/chemistry
Chemical Substances	Antidiuretic Hormone Receptor Antagonists ; Benzazepines ; Tablets ; Tolvaptan (21G72T1950)
Language	English
Publishing date	2012-01-06
Publishing country	Germany
Document type	Controlled Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	124384-6
ISSN	0946-1965 ; 0340-0026 ; 0300-9718 ; 0174-4879
ISSN	0946-1965 ; 0340-0026 ; 0300-9718 ; 0174-4879
DOI	10.5414/cp201621
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Zs.A 467: Show issues

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Article ; Online: Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non-peptide AVP antagonist in healthy subjects.

Shoaf, Susan E / Bricmont, Patricia / Mallikaarjun, Suresh

British journal of clinical pharmacology

2012 Volume 73, Issue 4, Page(s) 579–587

Abstract: What is already known about this subject: Before these trials were done, the effects of CYP3A4 inhibition and induction on the pharmacokinetics (PK) and pharmacodynamics (PD) of tolvaptan in healthy subjects were unknown. As tolvaptan is a CYP3A4 ... ...

Abstract	What is already known about this subject: Before these trials were done, the effects of CYP3A4 inhibition and induction on the pharmacokinetics (PK) and pharmacodynamics (PD) of tolvaptan in healthy subjects were unknown. As tolvaptan is a CYP3A4 substrate, knowing the effects of inhibition and induction on CYP3A4-mediated metabolism was important for dosing recommendations. What this study adds: This paper describes the changes in tolvaptan PK and PD following inhibition or induction of CYP3A4 and explores the mechanisms behind the disparity seen between tolvaptan PK and effects on urine output. It also discusses the concentrations at which tolvaptan produces its maximal response on urine output and the timing of the onset and offset of this response. AIMS In vitro studies indicated CYP3A4 alone was responsible for tolvaptan metabolism. To determine the effect of a CYP3A4 inhibitor (ketoconazole) and a CYP3A4 inducer (rifampicin) on tolvaptan pharmacokinetics (PK) and pharmacodynamics (PD), two clinical trials were performed. Methods: For CYP3A4 inhibition, a double-blind, randomized (5:1), placebo-controlled trial was conducted in 24 healthy subjects given either a single 30 mg dose of tolvaptan (n= 19) or matching placebo (n= 5) on day 1 with a 72 h washout followed by a 3 day regimen of 200 mg ketoconazole, once daily with 30 mg tolvaptan or placebo also given on day 5. For CYP3A4 induction, 14 healthy subjects were given a single dose of 240 mg tolvaptan with 48 h washout followed by a 7 day regimen of 600 mg rifampicin, once daily, with 240 mg tolvaptan also given on the seventh day. Results: When co-administered with ketoconazole, mean C(max) and AUC(0,∞) of tolvaptan were increased 3.48- and 5.40-fold, respectively. Twenty-four hour urine volume increased from 5.9 to 7.7 l. Erythromycin breath testing showed no difference following a single dose of tolvaptan. With rifampicin, tolvaptan mean C(max) and AUC were reduced to 0.13- and 0.17-fold of tolvaptan administered alone. Twenty-four hour urine volume decreased from 12.3 to 8.8 l. Conclusions: Tolvaptan is a sensitive CYP3A4 substrate with no inhibitory activity. Due to the saturable nature of tolvaptan's effect on urine excretion rate, changes in the pharmacokinetic profile of tolvaptan do not produce proportional changes in urine output.
MeSH term(s)	14-alpha Demethylase Inhibitors/pharmacokinetics ; 14-alpha Demethylase Inhibitors/pharmacology ; Adolescent ; Adult ; Antidiuretic Hormone Receptor Antagonists ; Area Under Curve ; Benzazepines/pharmacokinetics ; Benzazepines/pharmacology ; Benzazepines/urine ; Cytochrome P-450 CYP3A/metabolism ; Cytochrome P-450 CYP3A Inhibitors ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; Ketoconazole/pharmacology ; Male ; Middle Aged ; Rifampin/pharmacology ; Tolvaptan ; Urination/drug effects ; Young Adult
Chemical Substances	14-alpha Demethylase Inhibitors ; Antidiuretic Hormone Receptor Antagonists ; Benzazepines ; Cytochrome P-450 CYP3A Inhibitors ; Enzyme Inhibitors ; Tolvaptan (21G72T1950) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Ketoconazole (R9400W927I) ; Rifampin (VJT6J7R4TR)
Language	English
Publishing date	2012-02-07
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/j.1365-2125.2011.04114.x
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Article ; Online: Cumulative Fraction of Response for Once- and Twice-Daily Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis.

Mallikaarjun, Suresh / Chapagain, Moti L / Sasaki, Tomohiro / Hariguchi, Norimitsu / Deshpande, Devyani / Srivastava, Shashikant / Berg, Alexander / Hirota, Kuniko / Inoue, Yusuke / Matsumoto, Makoto / Hafkin, Jeffrey / Geiter, Lawrence / Wang, Xiaofeng / Gumbo, Tawanda / Liu, Yongge

Antimicrobial agents and chemotherapy

2020 Volume 65, Issue 1

Abstract: Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), ... ...

Abstract	Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. First, in the mouse model of chronic TB, the PK/PD index for delamanid efficacy was determined to be area under the drug concentration-time curve over 24 h divided by MIC (AUC
MeSH term(s)	Animals ; Antitubercular Agents/therapeutic use ; Humans ; Mice ; Mycobacterium tuberculosis ; Nitroimidazoles/therapeutic use ; Oxazoles ; Tuberculosis, Multidrug-Resistant/drug therapy
Chemical Substances	Antitubercular Agents ; Nitroimidazoles ; OPC-67683 ; Oxazoles
Language	English
Publishing date	2020-12-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01207-20
Database	MEDical Literature Analysis and Retrieval System OnLINE

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