scholarly journals Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Wendy Ankrom ◽  
Ka Lai Yee ◽  
Rosa I. Sanchez ◽  
Adedayo Adedoyin ◽  
Li Fan ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Transcriptase Inhibitor ◽  
Maximum Plasma ◽  
Minor Effect ◽  
Minimal Impact

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed. A single dose of doravirine 100 mg was administered to subjects aged 18 to 75 years with an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 (severe renal impairment group) and healthy controls with an eGFR of ≥80 ml/min/1.73 m2, matched to the mean of the renal impairment group by age (±10 years) and weight (±10 kg). Doravirine plasma concentrations were determined at regular intervals, and safety was monitored throughout. The geometric mean ratios (90% confidence interval) for severe renal impairment/healthy subjects were 1.43 (1.00, 2.04), 1.38 (0.99, 1.92), and 0.83 (0.61, 1.15) for the plasma doravirine area under the curve from zero to infinity (AUC0–∞), plasma concentration at 24 h postdose (C24), and maximum plasma concentration (Cmax), respectively. Doravirine was generally well tolerated in both groups. Based on the overall efficacy, safety, and PK profile of doravirine, the minor effect of severe renal impairment on doravirine PK observed in this study is not considered clinically meaningful. (This study has been registered at ClinicalTrials.gov under identifier NCT02641067.)

scholarly journals Pharmacokinetic Properties of a Sufentanil Sublingual Tablet Intended to Treat Acute Pain

2018 ◽  
Vol 128 (5) ◽  
pp. 943-952 ◽  
Author(s):  
Dennis M. Fisher ◽  
Peter Chang ◽  
D. Russell Wada ◽  
Albert Dahan ◽  
Pamela P. Palmer
Keyword(s):  
Plasma Concentration ◽  
Acute Pain ◽  
Healthy Subjects ◽  
Time Course ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Rapid Onset ◽  
Maximum Plasma ◽  
Mixed Effect ◽  
Sublingual Tablet

Abstract Background Desirable product attributes for treatment of moderate-to-severe acute pain in many medically supervised settings are rapid onset and a route of administration not requiring intravenous access. The pharmacokinetic characteristics of sublingually administered tablets containing 15 or 30 µg of sufentanil are described. Methods Blood was sampled from healthy subjects (four studies, 122 subjects) and patients (seven studies, 944 patients). Studies in healthy subjects determined bioavailability, effect of inhibition of cytochrome P450 3A4, and the plasma concentration profile with single and hourly sublingual doses. Studies in patients evaluated effects of weight, age, sex, and organ impairment on apparent clearance. Noncompartmental and mixed-effect population methods were used. Results Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. Ketoconazole (CYP3A4 inhibitor) increased maximum plasma concentration 19% and increased the area under the curve 77%. After a single 30-µg dose, plasma concentrations reached the published sufentanil analgesic threshold (24 pg/ml) within 30 min, peaked at 1 h, and then decreased below therapeutic concentrations by ~3 h. With hourly administration, plasma concentrations plateaued by the fifth dose. Time for concentrations to decrease 50% from maximal values was similar after 1 dose (2.5 ± 0.85 h) and 12 doses (2.5 ± 0.72 h). Clearance increased with weight, decreased with age, and was not affected by renal or hepatic impairment. Conclusions The time course of a single 30-µg dose was consistent with onset of analgesia and redosing frequency observed in clinical trials. Sublingual sufentanil tablets provide the opportunity to noninvasively and rapidly treat moderate-to-severe pain in a monitored setting.

scholarly journals Effects of Etravirine Alone and with Ritonavir-Boosted Protease Inhibitors on the Pharmacokinetics of Dolutegravir

2011 ◽  
Vol 55 (7) ◽  
pp. 3517-3521 ◽  
Author(s):  
Ivy Song ◽  
Julie Borland ◽  
Sherene Min ◽  
Yu Lou ◽  
Shuguang Chen ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Protease Inhibitors ◽  
Geometric Mean ◽  
Area Under The Curve ◽  
Integrase Inhibitor ◽  
Dosage Interval ◽  
Maximum Plasma ◽  
Phase 3 ◽  
Once Daily ◽  
Period 2

ABSTRACTDolutegravir (DTG) is an unboosted, once-daily integrase inhibitor currently in phase 3 trials. Two studies evaluated the effects of etravirine (ETR) alone and in combination with ritonavir (RTV)-boosted protease inhibitors (PIs) on DTG pharmacokinetics (PK) in healthy subjects. DTG 50 mg every 24 h (q24h) was administered alone for 5 days in period 1, followed by combination with ETR at 200 mg q12h for 14 days in period 2 (study 1) or with ETR/lopinavir (LPV)/RTV at 200/400/100 mg q12h or ETR/darunavir (DRV)/RTV at 200/600/100 mg q12h for 14 days in period 2 (study 2). PK samples were collected on day 5 in period 1 and day 14 in period 2. All of the treatments were well tolerated. ETR significantly decreased exposures of DTG, with geometric mean ratios of 0.294 (90% confidence intervals, 0.257 to 0.337) for the area under the curve from time zero until the end of the dosage interval (AUC0-τ), 0.484 (0.433 to 0.542) for the observed maximum plasma concentration (Cmax), and 0.121 (0.093 to 0.157) for the plasma concentration at the end of the dosage interval (Cτ). ETR combined with an RTV-boosted PI affected the exposure of DTG to a lesser degree: ETR/LPV/RTV treatment had no effect on the DTG plasma AUC0-τandCmax, whereas theCτincreased by 28%. ETR/DRV/RTV modestly decreased the plasma DTG AUC0-τ,Cmax, andCτby 25, 12, and 37%, respectively. Such effects of ETR/LPV/RTV and ETR/DRV/RTV are not considered clinically relevant. The combination of DTG and ETR alone should be avoided; however, DTG may be coadministered with ETR without a dosage adjustment if LPV/RTV or DRV/RTV is concurrently administered.

Multiple-Dose Pharmacokinetics of Pentoxifylline and its Metabolites during Renal Insufficiency

1996 ◽  
Vol 30 (7-8) ◽  
pp. 724-729 ◽  
Author(s):  
Christopher M Paap ◽  
Karon S Simpson ◽  
Michael W Horton ◽  
Karen L Schaefer ◽  
Howard B Lassman ◽  
...  
Keyword(s):  
Renal Function ◽  
Steady State ◽  
Plasma Concentration ◽  
Renal Impairment ◽  
Renal Dysfunction ◽  
Severe Renal Impairment ◽  
Maximum Plasma ◽  
Gas Liquid Chromatography ◽  
Blood Samples ◽  
Group I

OBJECTIVE: To characterize pentoxifylline (PTF) and metabolite disposition after multiple oral doses given two and three times a day to patients with renal dysfunction. DESIGN: An open-label, randomized, crossover, parallel group design. SETTING: Community-based clinical research center. PATIENT POPULATION: Subjects with renal function stratified based on 24-hour urinary creatinine clearance (Clcr): group I = Clcr >80 mL/min (n = 9); group II = Clcr 30-80 mL/min (n = 6); and group III = Clcr <30 mL/min (n = 10). METHODS: PTF 400 mg bid or tid was administered on days 1–7 and 400 mg bid or tid was given on days 14-20 with a 1-week washout. Timed blood samples were taken on days 1, 7, and 20. Blood samples were analyzed for PTF and its metabolites (M-I, M-IV, M-V) by gas-liquid chromatography. MAIN OUTCOME MEASURES: Maximum plasma concentration (Cmax), time to maximum concentration (tmax), average steady-state plasma concentration (Cssavg), and area under the plasma concentration-time curve at steady-state (AUCss) were determined by visual and model independent methods. ANOVA, paired t-test, and linear regression were used with significance level set at p < 0.05. RESULTS: The ratio of PTF AUCss (tid):AUCss (bid) and M-I AUCss (bid and tid) were not significantly different between the groups. Significant differences were found in M-IV and M-V Cmax, AUCss, Cssavg, and AUCss ratios (M-IV:PTF and M-V:PTF) between renal function groups (p < 0.05 for all). A change in dosage regimen from tid to bid resulted in significant changes in M-IV and M-V Cssavg for subjects with normal renal function and in those with moderate dysfunction, although not in subjects with severe renal dysfunction. CONCLUSIONS: Renal dysfunction did not cause significant accumulation of PTF or M-I after multiple bid and tid dosing; however, M-IV and M-V had significant accumulation in patients with renal impairment. Dosage reduction to 400 mg bid for patients with moderate renal impairment and 200-400 mg/d for severe renal impairment, as well as close clinical monitoring, seem prudent until the complex pharmacologic interactions of PTF and its metabolites can be further delineated.

Design, Synthesis, Anticonvulsant Activity, Preclinical Study and Pharmacokinetic Performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin- 2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo Hexylidene] Hydrazinecarboxamide

2019 ◽  
Vol 19 (1) ◽  
pp. 31-45
Author(s):  
Meena K. Yadav ◽  
Laxmi Tripathi
Keyword(s):  
Anticonvulsant Activity ◽  
Computational Study ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Area Under The Curve ◽  
Preclinical Study ◽  
In Vivo Studies ◽  
Maximum Plasma ◽  
Seizure Models

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1. Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

scholarly journals Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 778
Author(s):  
Bettina Gerner ◽  
Oliver Scherf-Clavel
Keyword(s):  
Hepatic Impairment ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Enterohepatic Recirculation ◽  
Maximum Plasma ◽  
Good Precision ◽  
Physiologically Based Pharmacokinetic ◽  
Starting Point ◽  
Physiologically Based

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans.

1988 ◽  
Vol 6 (3) ◽  
pp. 517-526 ◽  
Author(s):  
K Mross ◽  
P Maessen ◽  
W J van der Vijgh ◽  
H Gall ◽  
E Boven ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Urinary Excretion ◽  
Half Life ◽  
Enterohepatic Circulation ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Volume Of Distribution ◽  
Maximum Plasma ◽  
Cumulative Urinary Excretion ◽  
Second Peak

Pharmacokinetics of doxorubicin (DOX), epidoxorubicin (EPI), and their metabolites in plasma have been performed in eight patients receiving 40 to 56 mg/m2 of both anthracyclines as a bolus injection in two sequential cycles. Terminal half-life and volume of distribution appeared to be smaller in case of EPI, whereas plasma clearance and cumulative urinary excretion was larger in comparison to DOX. The major metabolite of DOX was doxorubicinol (Aol) followed by 7-deoxy-doxorubicinol (7d-Aolon). Metabolism to glucuronides was found in case of EPI only. The area under the curves (AUC) of the metabolites of EPI decreased in the order of the glucoronides E-glu greater than Eol-glu, 7d-Aolon greater than epirubicinol (Eol). The AUC of Eol was half of the value in its counterpart Aol. In the case of EPI, the AUC of 7d-Aolon was twice the level of that of the corresponding metabolite of DOX. The terminal half-lives of the cytostatic metabolites Aol and Eol were similar, but longer than the corresponding values of their parent drugs. Half-lives of the glucuronides (E-glu, Eol-glu) were similar to the half-life of their parent drug. 7d-Aolon had a somewhat shorter half-life in comparison to both DOX and EPI. Approximately 6.2% of EPI and 5.9% of DOX were excreted by the kidney during the initial 48 hours. Aol was found in the urine of patients treated with DOX, whereas Eol, E-glu, and Eol-glu were detected in urine of patients treated with EPI. The cumulative urinary excretion appeared to be 10.5% for EPI and its metabolites, and 6.9% for DOX and its metabolite. The plasma concentration v time curves of (7d)-aglycones showed a second peak between two and 12 hours after injection, suggesting an enterohepatic circulation for metabolites lacking the daunosamine sugar moiety. The plasma concentrations of the glucuronides were maximal at 1.2 hours for E-glu and 1.9 hours for Eol-glu. All other compounds reached their maximum plasma concentration during the first minutes after the administration of DOX and EPI. Deviating plasma kinetics were observed in one patient, probably due to prior drug administration.

scholarly journals Catechin Bioavailability Is Reduced in Obese Persons Without Altering Gut Microbial-Derived Valerolactones Following Consumption of a Green Tea Extract Confection

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 468-468
Author(s):  
Geoffrey Sasaki ◽  
Yael Vodovotz ◽  
Zhongtang Yu ◽  
Richard Bruno
Keyword(s):  
Green Tea ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Relative Bioavailability ◽  
Green Tea Extract ◽  
Maximum Plasma ◽  
Gut Permeability ◽  
Epicatechin Gallate ◽  
Obesity Status ◽  
Tea Extract

Abstract Objectives Green tea extract (GTE) protects against obesity in rodents by reducing gut permeability that otherwise provokes endotoxemia-mediated inflammation. However, whether obesity affects catechin bioavailability and microbial metabolism is unknown. We hypothesized that obesity will reduce catechin bioavailability by increasing microbial biotransformation of catechins. Methods Obese persons (n = 10 M/7F; 33.5 ± 0.7 kg/m2) and age-matched healthy persons (n = 10 M/9F; 21.7 ± 0.4 kg/m2) completed a pharmacokinetics (PK) trial in which a GTE confection [290 mg epigallocatechin gallate (EGCG), 87 mg epigallocatechin (EGC), 39 mg epicatechin (EC), 28 mg epicatechin gallate (ECG)] was ingested prior to collecting plasma at 0, 0.25, 0.5, 1, 2, 3, 5, 8, 10, and 12 h and urine from 0–4, 4–8, 8–12, and 12–24 h. Stool samples were collected and gut permeability was assessed prior to the 12-h PK trial. Plasma and urinary catechin/catechin-derived microbial metabolites were assessed following enzymatic hydrolysis by LC-MS. Results Regardless of health status, relative bioavailability, based on plasma area under the curve (AUC0–12 h), of GTE catechins were: EGCG &gt; EGC &gt; ECG &gt; EC. However, obese persons had 24–27% lower plasma AUC0–12 h for the four catechins compared to lean persons (P &lt; 0.05). They also had 18–36% lower maximum plasma concentrations (Cmax) of GTE catechins but 12 h plasma catechin concentrations were unaffected by obesity status (P &gt; 0.05). 3ʹ,4ʹ-γ-valerolactone (3,4-VL) was detected in the plasma of all participants, while 3ʹ,4ʹ,5ʹ-γ-valerolactone (3,4,5-VL) was detected in 74% and 82% of lean and obese persons, respectively. Plasma AUC0–12 h for these VL metabolites did not differ by obesity status. EGC, EC, 3,4-VL, and 3,4,5-VL, but not EGCG and ECG, were primarily present in urine and urinary total VLs were increased compared with total urinary catechins. However, 24-h urinary excretion of catechins and VLs were unaffected by obesity. Conclusions Obesity reduces GTE catechin bioavailability and Cmax independent of any change in VL metabolite appearance or urinary elimination of catechins, suggesting a gut-level mechanism that limits catechin absorption. Funding Sources Supported by USDA-NIFA and the Foods for Health Discovery Theme at The Ohio State University.

Pharmacokinetics of an immunomodulating dose of levamisole in weaned pigs

2013 ◽  
Vol 61 (3) ◽  
pp. 376-382
Author(s):  
Jelena Šuran ◽  
Dubravka Flajs ◽  
Maja Peraica ◽  
Andreja Prevendar Crnić ◽  
Marcela Šperanda ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Area Under The Curve ◽  
Maximum Plasma ◽  
Weaned Pigs ◽  
Time Curve ◽  
Treatment Groups ◽  
Parallel Design ◽  
Concentration Time ◽  
Plasma Concentration Time Curve ◽  
Crossbred Pigs

Levamisole has been shown to stimulate the immune response in immunocompromised humans and animals. However, its use as an adjuvant in immunocompromised weaned pigs prone to colibacillosis has only been experimentally tested but not yet officially approved. Therefore, the aim of these studies was to study the pharmacokinetics (PK) of an immunomodulating dose of levamisole in weaned pigs. For that purpose, 20 weaned crossbred pigs were divided into two treatment groups. In this parallel-design study, a single dose of levamisole (2.5 mg/kg body weight) was administered by the intramuscular (i.m.) or oral (p.o.) route. Statistically significant differences between the i.m. and p.o. routes in terminal beta rate constant (β), maximum plasma concentration (Cmax), area under the curve (AUC) for plasma concentration-time curve from time zero to infinity (AUC0-inf), area under the plasma concentration-time curve from time 0 to the last quantifiable time point (AUC0-t) were determined. Further research is needed to establish a relationship between the PK and the immunomodulating effect of levamisole in pigs.

Sign in / Sign up

Export Citation Format

Share Document