scholarly journals A PK/PD model of saxagliptin: to simulate its pharmacokinetics and pharmacodynamics in healthy adults and patients with impaired hepatic function

2021 ◽  
Vol 30 (2) ◽  
pp. 119-132
Keyword(s):  
Hepatic Function ◽  
Healthy Adults ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Impaired Hepatic Function

Altered pharmacokinetics and pharmacodynamics of repaglinide by ritonavir in rats with healthy, diabetic and impaired hepatic function

2016 ◽  
Vol 31 (2) ◽  
Author(s):  
Thirumaleswara Goud ◽  
Srinivas Maddi ◽  
Devanna Nayakanti ◽  
Rajendra Prasad Thatipamula
Keyword(s):  
Cytochrome P450 ◽  
Plasma Concentration ◽  
Organic Anion ◽  
Hepatic Function ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Impaired Hepatic Function ◽  
Significant Difference

AbstractRitonavir is an antiretroviral drug to treat HIV AIDS and inhibits cytochrome P450 3A4. To treat diabetes mellitus in HIV, repaglinide is coadministered with ritonavir in the clinic. Multiple cytochrome P450 (CYP) isoforms are involved in the metabolism of repaglinide like CYP2C8 and CYP 3A4. In order to predict and understand drug-drug interactions of these two drugs, the pharmacokinetics and pharmacodynamics (PK/PD) of repaglinide and ritonavir were studied in normal, diabetic and hepatic impaired rats. The purpose of the study was to assess the influence of ritonavir on the PK/PD of repaglinide in rats with normal, diabetic and impaired hepatic function.Human oral therapeutic doses of ritonavir and repaglinide were extrapolated to rats based on the body surface area. Ritonavir (20 mg/kg, p.o.), alone and along with repaglinide (0.5 mg/kg, p.o.), was given to normal, diabetic and hepatic impaired rats, and the PK/PD were studied.The pharmacokinetic parameters like peak plasma concentration (Cmax), area under the plasma concentration time profile (AUC) and elimination half life of repaglinide were significantly (p<0.0001) increased when compared to repaglinide control rats. The repaglinide clearance (CL) was significantly (p<0.0001) decreased in the presence of ritonavir treatment. In the presence of ritonavir, repaglinide hypoglycemic activity was increased significantly (p<0.0005) when compared with repaglinide control group.The significant difference in the PK/PD changes have been due to the increased plasma exposure and decreased total body clearance of repaglinide, which may be due to the inhibition of the CYP P450 metabolic system and organic anion-transporting polypeptide transporter by ritonavir.

scholarly journals Pharmacokinetics and Pharmacodynamics of Itepekimab in Healthy Adults and Patients With Asthma: Phase I First‐in‐Human and First‐in‐Patient Trials

2021 ◽  
Author(s):  
Matthew P. Kosloski ◽  
George D. Kalliolias ◽  
Christine R. Xu ◽  
Sivan Harel ◽  
Ching‐Ha Lai ◽  
...  
Keyword(s):  
Phase I ◽  
Healthy Adults ◽  
Pharmacokinetics And Pharmacodynamics

USE OF VECURONIUM IN PATIENTS WITH IMPAIRED HEPATIC FUNCTION

1985 ◽  
Vol 63 (Supplement) ◽  
pp. A336
Author(s):  
C. Y. LIN ◽  
Y. P. CHOU ◽  
B. D. SCHREIDER
Keyword(s):  
Hepatic Function ◽  
Impaired Hepatic Function

The Prominent Role of the Liver in the Elimination of Asymmetric Dimethylarginine (ADMA) and the Consequences of Impaired Hepatic Function

2008 ◽  
Vol 32 (6) ◽  
pp. 613-621 ◽  
Author(s):  
Milan C. Richir ◽  
Roderick H. Bouwman ◽  
Tom Teerlink ◽  
Michiel P.C. Siroen ◽  
Theo P.G.M. de Vries ◽  
...  
Keyword(s):  
Asymmetric Dimethylarginine ◽  
Hepatic Function ◽  
Impaired Hepatic Function

scholarly journals Effect of Notoginseng Extracts and Its Components on Lipopolysaccharide and Galactosamine Mixture-induced Impaired Hepatic Function in Mice

2012 ◽  
Vol 132 (7) ◽  
pp. 831-836 ◽  
Author(s):  
Ken-ichi Komatsu ◽  
Hiroko Tanaka ◽  
Daisuke Nakagawa ◽  
Keiko Kawashima
Keyword(s):  
Hepatic Function ◽  
Impaired Hepatic Function

scholarly journals Impaired hepatic function and central dopaminergic denervation in a rodent model of Parkinson's disease: A self-perpetuating crosstalk?

2012 ◽  
Vol 1822 (2) ◽  
pp. 176-184 ◽  
Author(s):  
Mariapia Vairetti ◽  
Andrea Ferrigno ◽  
Vittoria Rizzo ◽  
Giulia Ambrosi ◽  
Alberto Bianchi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Hepatic Function ◽  
Rodent Model ◽  
Impaired Hepatic Function

scholarly journals Pharmacokinetics of Temsavir, the Active Moiety of the Prodrug Fostemsavir, in Subjects with Hepatic Impairment

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S430-S430 ◽  
Author(s):  
Heather Sevinsky ◽  
Mindy Magee ◽  
Peter Ackerman ◽  
Robert Adamczyk ◽  
Jennifer Karkas ◽  
...  
Keyword(s):  
Hepatic Impairment ◽  
Geometric Mean ◽  
Hepatic Function ◽  
Open Label ◽  
Post Dose ◽  
Viral Attachment ◽  
Linear Mixed Effects ◽  
Active Moiety ◽  
Impaired Hepatic Function ◽  
Hiv 1

Abstract Background Fostemsavir (FTR) is a prodrug of temsavir (TMR), a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells. TMR is primarily metabolized via hydrolytic and oxidative pathways; impaired hepatic function may alter TMR pharmacokinetics (PK). Methods AI438053 (NCT02467335) was an open-label, nonrandomized study in healthy subjects (HS) and subjects with hepatic impairment (HI), defined by Child-Pugh (CP) score: mild (CPA), moderate (CPB), or severe (CPC). HS were matched for age, body weight, and sex. Subjects received a single oral dose of FTR 600 mg fasted and serial PK samples for TMR were collected up to 96 hours post-dose. Unbound TMR at 1 and 3 hours post-dose was determined. Total and unbound PK parameters were derived by noncompartmental methods. Geometric mean ratios (GMR) and 90% confidence intervals (CI) for HI vs.. HS were derived using linear mixed-effects models. Subjects were monitored for adverse events (AEs). Results 18 subjects with HI (N = 6/CP group) and 12 HS received FTR and completed the study. Total and unbound TMR exposures increased with increasing HI severity (see Table). Total and unbound TMR CLT/F decreased with increasing HI severity. Mean % protein binding of TMR was 81.0% in HS and 79.9%, 81.9%, and 76.5% in CPA, CPB, and CPC HI, respectively, and was independent of TMR concentration. There were no deaths, serious AEs, or discontinuations during the treatment period. Conclusion TMR exposures increase with increasing severity of HI. The increase in TMR exposures in patients with mild or moderate HI is not expected to alter the safety profile of FTR. The risk/benefit of higher TMR exposures in severe HI is under evaluation. Disclosures H. Sevinsky, ViiV Healthcare: Employee, Salary; M. Magee, GlaxoSmithKline: Employee and Shareholder, Salary; P. Ackerman, ViiV Healthcare/GSK: Employee and Shareholder, Salary and Stock; R. Adamczyk, Bristol-Myers Squibb: Employee, Salary; J. Karkas, Bristol Myers Squibb: Employee and Shareholder, Salary; S. Lubin, Bristol-Myers Squibb: Employee, Salary; P. Ravindran, Bristol-Myers Squibb: Employee, Salary; C. Llamoso, ViiV Healthcare: Employee, Salary; T. Eley, Bristol-Myers Squibb: Former Employee during study conduct, Salary; K. Moore, ViiV Healthcare: Employee, Salary

Gemcitabine and Paclitaxel: Pharmacokinetic and Pharmacodynamic Interactions in Patients With Non–Small-Cell Lung Cancer

1999 ◽  
Vol 17 (7) ◽  
pp. 2190-2190 ◽  
Author(s):  
Judith R. Kroep ◽  
Giuseppe Giaccone ◽  
Daphne A. Voorn ◽  
Egbert F. Smit ◽  
Jos H. Beijnen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Hepatic Function ◽  
Small Cell ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Small Cell Lung ◽  
Percentage Decrease ◽  
Pharmacodynamic Interactions ◽  
Significant Difference

PURPOSE: To assess possible pharmacokinetic and pharmacodynamic interactions between gemcitabine and paclitaxel in a phase I/II study in non–small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Eighteen patients with advanced NSCLC received the following in a 3-week schedule: gemcitabine 1,000 mg/m2 (30 minutes, days 1 and 8) and paclitaxel 150 (n = 9) or 200 mg/m2 (n = 9) before gemcitabine (3 hours, day 1). Plasma pharmacokinetics and pharmacodynamics in mononuclear cells were studied. RESULTS: Gemcitabine did not influence paclitaxel pharmacokinetics at 150 and 200 mg/m2 (area under the concentration-time curve [AUC], 7.7 and 8.8 μmol/ L · h, respectively; maximum plasma concentration [Cmax], 3.2 and 4.0 μmol/L, respectively), and paclitaxel did not influence that of gemcitabine (Cmax, 30 ± 3 μmol/L) and 2′,2′-difluorodeoxyuridine. Paclitaxel, however, dose-dependently increased the Cmax of gemcitabine triphosphate (dFdCTP), the active metabolite of gemcitabine, from 55 ± 10 to 106 ± 16 pmol/106 cells. No significant difference in the AUC of dFdCTP was observed. Moreover, the gemcitabine-paclitaxel combination significantly increased ribonucleotide levels, most pronounced for adenosine triphosphate (six- to seven-fold). Postinfusion paclitaxel AUC was related to pretreatment hepatic function (bilirubin: r = 0.79; P < .001) and to the percentage decrease in platelets (r = 0.61; P = .009). The latter was also related to the duration of paclitaxel concentration above 0.1 μmol/L (r = 0.62; P = .007). Gemcitabine Cmax was related to the percentage decrease in platelets (r = 0.58; P = .01), pretreatment hepatic function (bilirubin: r = 0.77; P < .001), and to plasma creatinine (r = 0.5; P = .03). The pharmacokinetics and pharmacodynamics were not related to response or survival. CONCLUSION: Gemcitabine and paclitaxel pharmacokinetics were related to the percentage decrease in platelets. Paclitaxel did not affect the pharmacokinetics of gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increased dFdCTP accumulation. This might enhance the antitumor activity of gemcitabine.

Sign in / Sign up

Export Citation Format

Share Document