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.

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.)

Integrative assessment of the effect of renal function on ribociclib treatment and dose recommendation in advanced breast cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13037-e13037
Author(s):  
Yan Ji ◽  
Vitaly Yartsev ◽  
Yingbo Wang ◽  
Michelle Quinlan ◽  
Paolo Serra ◽  
...  
Keyword(s):  
Renal Function ◽  
Steady State ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Moderate Renal Impairment ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Integrative Assessment

e13037 Background: Ribociclib is an orally administered CDK4/6 inhibitor used in combination with endocrine therapy (ET) to treat women with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative advanced breast cancer (ABC). An integrative assessment was conducted to evaluate the effect of renal function on the pharmacokinetics (PK), efficacy and safety of ribociclib. Methods: To assess the effect of mild and moderate renal impairment, a subgroup analysis was performed to evaluate PK parameters of ribociclib following oral administration of 600 mg QD 3 weeks on/1 week off in two Phase 1/2 and one Phase 3 clinical trials. Steady-state PK exposures in ABC patients at the 600 mg dose was estimated by a population PK model developed based on a pooled dataset from five Phase 1 to 3 trials and were compared by renal function. Efficacy and safety were also analyzed by renal function in a Phase 2 and three Phase 3 trials in ABC patients. The effect of severe renal impairment on ribociclib PK was assessed in a Phase I study in non-cancer subjects following a single oral 400 mg dose. Results: PK analyses in cancer patients showed that both single-dose and steady-state exposure of ribociclib at the 600 mg dose in patients with mild or moderate renal impairment were comparable to patients with normal renal function. Estimated steady-state PK exposure in patients with mild or moderate renal impairment is also comparable to patients with normal renal function. The primary efficacy results of progression free survival (PFS) and the safety profiles were comparable across renal-function cohorts in ABC patients. In non-cancer subjects administered a single oral dose of 400 mg, ribociclib AUCinf and Cmax increased 2.67- and 2.30-fold in subjects with severe renal impairment, respectively, compared to subjects with normal renal function. Conclusions: PK, efficacy and safety of ribociclib are consistent across patients with normal renal function, mild or moderate renal impairment. Hence, no dose adjustment is required in mild or moderate renal impaired patients. Severe renal impaired patients are recommended to have a reduced dose based on PK data in non-cancer subjects.

scholarly journals Population Pharmacokinetics of Peramivir in Healthy Volunteers and Influenza Patients

2015 ◽  
Vol 59 (11) ◽  
pp. 6755-6762 ◽  
Author(s):  
Yumiko Matsuo ◽  
Toru Ishibashi ◽  
Alan S. Hollister ◽  
Toshihiro Wajima
Keyword(s):  
Renal Function ◽  
Plasma Concentration ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
The United States ◽  
Volume Of Distribution ◽  
Elderly Subjects ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Concentration Data

ABSTRACTPeramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. subjects. Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.

Nephrotoxicity and its prevention by catechin in ferric nitrilotriacetate promoted oxidative stress in rats

2004 ◽  
Vol 23 (3) ◽  
pp. 137-143 ◽  
Author(s):  
Kanwaljit Chopra ◽  
Devinder Singh ◽  
Vikas Chander
Keyword(s):  
Oxidative Stress ◽  
Renal Function ◽  
Renal Dysfunction ◽  
Thiobarbituric Acid ◽  
Control Group ◽  
Morphological Alterations ◽  
Group Iii ◽  
Ferric Nitrilotriacetate ◽  
Group I ◽  
Rats And Mice

Intraperitoneal injection of ferric nitrilotriacetate (Fe-NTA) to rats and mice results in iron-induced free radical injury and cancer in kidneys. This study was designed to investigate the effect of catechin, a bioflavonoid with antioxidant potential, on Fe-NTA-induced nephrotoxicity in rats. Four groups were employed in the present study. Group I served as control group, Group II animals received Fe-NTA (8 mg iron/kg body weight i.p.), Group III animals were given 40 mg/kg catechin p.o. twice a day for 4 days and on the 5th day Fe-NTA was challenged, and Group IV animals received catechin alone for 4 days. Renal function was assessed by measuring plasma creatinine and blood urea nitrogen. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase, glutathione reductase and superoxide dismutase. One hour after a single intraperitoneal (i.p.) injection of Fe-NTA (8 mg iron/kg), a marked deterioration of renal architecture, renal function and severe oxidative stress was observed. Pretreatment of animals with catechin markedly attenuated renal dysfunction, reduced elevated thiobarbituric acid reacting substances (TBARS), restored the depleted renal antioxidant enzymes and normalized the renal morphological alterations. These results clearly demonstrate the role of oxidative stress and its relation to renal dysfunction, and suggest a protective effect of catechin on Fe-NTA-induced nephrotoxicity in rats.

scholarly journals Pharmacokinetics of lamivudine in human immunodeficiency virus-infected patients with renal dysfunction.

1996 ◽  
Vol 40 (6) ◽  
pp. 1514-1519 ◽  
Author(s):  
A E Heald ◽  
P H Hsyu ◽  
G J Yuen ◽  
P Robinson ◽  
P Mydlow ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Moderate Renal Impairment ◽  
Pharmacokinetic Parameters ◽  
Geometric Means ◽  
Immunodeficiency Virus

The purpose of this study was to determine the safety and pharmacokinetics of lamivudine (3TC), a nucleoside analog that has shown potent in vitro and recent in vivo activity against human immunodeficiency virus. Sixteen human immunodeficiency virus-infected patients, six with normal renal function (creatinine clearance [CLCR], > or = 60 ml/min), four with moderate renal impairment (CLCR, 10 to 40 ml/min), and six with severe renal impairment (CLCR, < 10 ml/min), were enrolled in the study. After an overnight fast, patients were administered 300 mg of 3TC orally. Blood was obtained before 3TC administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, and 48 h afterward. Timed urine collections were performed for patients able to produce urine. Serum and urine were assayed for 3TC by reverse-phase high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were calculated by using standard noncompartmental techniques. The peak concentration of 3TC increased with decreasing renal function; geometric means were 2,524, 3,538, and 5,684 ng/ml for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. The terminal half-life also increased with decreasing renal function; geometric means were 11.5, 14.1, and 20.7 h for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. Both oral and renal clearances were linearly correlated with CLCR. A 300-mg dose of 3TC was well tolerated by all three patient groups. The pharmacokinetics of 3TC is profoundly affected by impaired renal function. Dosage adjustment, by either dose reduction or lengthening of the dosing interval, is warranted.

Increased Potency and Decreased Elimination of Lamifiban, a GPIIb-IIIa Antagonist, in Patients with Severe Renal Dysfunction

1998 ◽  
Vol 79 (06) ◽  
pp. 1119-1125 ◽  
Author(s):  
Knut Nordal ◽  
Karsten Midtvedt ◽  
Timothy Goggin ◽  
Frank Brosstad ◽  
Gustav Lehne
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Ex Vivo ◽  
Severe Renal Impairment ◽  
Thrombus Formation ◽  
Drug Dosage ◽  
The Novel ◽  
Platelet Membrane Receptor ◽  
Group 3 ◽  
Group 2

SummaryActivation of the platelet membrane receptor glycoprotein (GP) IIb-IIIa is essential for thrombus formation. The novel nonpeptide GPIIb-IIIa antagonist, lamifiban, represents a promising approach for antiplatelet therapy in patients with cardiovascular disease. Since renal impairment frequently occurs in these patients, we designed a phase I study to assess the tolerability, pharmacodynamics and pharmacokinetics of lamifiban in patients with renal impairment. Four healthy volunteers (Group 1) with creatinine clearance (CLCR) >75 ml/min, eight patients (Group 2) with mild to moderately impaired renal function (CLCR 30-74 ml/min) and eight patients (Group 3) with severe renal impairment (CLCR 10-29 ml/min) were studied. They received stepwise increased doses of lamifiban intravenously (IV). There was a linear relationship between the systemic clearance of the drug and renal function (R2 = 0.86). The mean plasma concentration required for half-maximal inhibition of thrombin-receptor agonist peptide (TRAP) induced platelet aggregation (EC50) ex vivo was 21, 28 and 11 ng/ml in Groups 1, 2 and 3. The patients in Group 3 were sensitized to the anti-platelet effect allowing an 18-fold dosage reduction without compromising the pharmacodynamics. In conclusion, the decreased clearance of lamifiban may act in concert with increased potency of the drug in patients with severe renal impairment, and the drug dosage should be reduced accordingly.

scholarly journals Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine.

1997 ◽  
Vol 41 (8) ◽  
pp. 1765-1769 ◽  
Author(s):  
S C Chien ◽  
A T Chow ◽  
M C Rogge ◽  
R R Williams ◽  
C W Hendrix
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Plasma Concentration ◽  
The Body ◽  
Maximum Plasma Concentration ◽  
Maximum Plasma ◽  
Cell Counts ◽  
Pharmacokinetic Profiles ◽  
Study Results ◽  
Immunodeficiency Virus

This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.

scholarly journals Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Renal Impairment

2007 ◽  
Vol 51 (12) ◽  
pp. 4231-4235 ◽  
Author(s):  
Xiao-Jian Zhou ◽  
Suzanne Swan ◽  
William B. Smith ◽  
Thomas C. Marbury ◽  
Gloria Dubuc-Patrick ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Normal Function ◽  
Plasma Exposure ◽  
Mild Renal Impairment ◽  
Severe Impairment ◽  
Stage Renal Disease ◽  
End Stage

ABSTRACT This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CLCR), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CLR), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CLR and CLCR. In ESRD subjects, a routine 3.5- to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of ∼45%, representing a ∼23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.

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