scholarly journals Population Pharmacokinetics Study of Morinidazole in Patients with Moderate Hepatic Impairment

2018 ◽  
Author(s):  
Yue Kang ◽  
Fengyan Xu ◽  
Kun Wang ◽  
Jing Zhang ◽  
Xiaojie Wu ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Renal Dysfunction ◽  
Hepatic Impairment ◽  
Compartment Model ◽  
Control Group ◽  
Population Pharmacokinetic ◽  
Moderate Hepatic Impairment ◽  
Mild Renal Impairment ◽  
Mixed Effects Modeling ◽  
Adjustment Strategy

AbstractObjectiveMorinidazole is a novel third generation 5-nitroimidazole antimicrobial drug which has demonstrated substantial antibacterial activity against clinical isolates of anaerobe. The aim of this study was to build population pharmacokinetic (PPK) model of morinidazole among patients with hepatic impairment and to provide dosage adjustment strategy for morinidazole in patients with hepatic impairment and/or renal dysfunction.MethodsThe nonlinear mixed effects modeling tool NONMEM (version7.3, ICON Development Solutions) was used to develop the PPK model of morinidazole.ResultsOne-compartment model was conducted to establish the morinidazole PPK model. Disease condition was the significant covariate for CL and weight was the significant covariate for V. The AUC0-∞ was 120.44±37.05 (79.25-207.20) μg×h/mL in hepatic impairment group and was 79.46±23.71 (42.94-116.75) μg×h/mL in control group. The AUC0-∞ was 164.9±44.8 μg×h/mL and 77.2±23.1 μg×h/mLin in the 3 subjects with both hepatic impairment and mild renal impairment and in the 3 matched healthy subjects, respectively.ConclusionIt is not necessary to adjust morinidazole dosage for patients with moderate hepatic impairment without confirmed renal dysfunction. For patient with moderate hepatic and mild renal impairment, morinidazole regimen should be considered as 500mg every 24 hours. When used in patients with moderate/severe hepatic impairment combined with renal dysfunction, both dosage and interval adjustment of morinidazole should be considered.

scholarly journals Population Pharmacokinetic Assessment of a New Regimen of Mefloquine Used in Combination Treatment of Uncomplicated Falciparum Malaria

2006 ◽  
Vol 50 (7) ◽  
pp. 2281-2285 ◽  
Author(s):  
Elizabeth A. Ashley ◽  
Kasia Stepniewska ◽  
Niklas Lindegårdh ◽  
Rose McGready ◽  
Robert Hutagalung ◽  
...  
Keyword(s):  
Whole Blood ◽  
Dose Regimen ◽  
Pharmacokinetic Model ◽  
Parent Drug ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Kinetic Properties ◽  
Split Dose ◽  
Mixed Effects Modeling ◽  
Conventional Dose

ABSTRACT A fixed artesunate-mefloquine combination, comprising three daily doses of 8 mg of mefloquine/kg of body weight and 4 mg of artesunate/kg, has been developed recently. This study was designed to construct a population pharmacokinetic model describing this new dosage regimen of mefloquine given as loose tablets together with artesunate. In two randomized trials in Thailand which evaluated the efficacy, safety, and tolerability of this new regimen, the members of a subgroup of 50 patients were randomized to have capillary blood sampling before treatment and at five randomly assigned time points during the 63-day follow-up period. Mefloquine levels in capillary whole blood were assayed by liquid chromatography with UV detection. A pharmacokinetic model for mefloquine was constructed using mixed-effects modeling. A one-compartment model with first-order absorption and elimination was selected to describe the kinetic properties of mefloquine. For capillary whole-blood mefloquine, the area under the concentration curve (AUC) was 40% higher than previous estimates for patients given the equivalent conventional-dose regimen (mefloquine given as 15 mg/kg and then 10 mg/kg on the second and third days of treatment). The half-life (t 1/2) of the carboxylic acid metabolite was estimated as 26 days, and the metabolite was eliminated more slowly than the parent drug (population t 1/2 estimate, 10.5 days). Splitting the 25 mg/kg dose of mefloquine into three doses of 8 mg/kg each resulted in improved oral bioavailability compared to the conventional split-dose regimen results. This new regimen is well tolerated and results in an equivalent therapeutic response.

scholarly journals Nemonoxacin Dosage Adjustment in Patients with Severe Renal Impairment Based on Population Pharmacokinetic and Pharmacodynamic Analysis

2021 ◽  
Author(s):  
Yi Li ◽  
Jianda Lu ◽  
Yue Kang ◽  
Xiaoyong Xu ◽  
Xin Li ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Compartment Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Healthy Controls ◽  
Dosing Regimen ◽  
Open Label ◽  
Optimal Dosing

Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic/pharmacodynamic (PPK/PD) analysis. Methods: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 48 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) against S. Pneumoniae and S. aureus was calculated by Monte Carlo simulation. Results: The data best fitted to a two-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L), and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4±6.5% in severe renal impairment patients and 66.1±16.8% in healthy controls. PPK/PD modeling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in severe renal impairment patients, evidenced by higher PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if MIC ≤ 0.5 mg/L. Conclusion: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

scholarly journals Relation Between Mild Renal Dysfunction and Outcomes After Coronary Artery Bypass Grafting

Circulation ◽  
2005 ◽  
Vol 112 (9_supplement) ◽  
Author(s):  
Rosita Zakeri ◽  
Nick Freemantle ◽  
Vivian Barnett ◽  
Graham W. Lipkin ◽  
Robert S. Bonser ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Coronary Artery Bypass Grafting ◽  
Renal Impairment ◽  
Serum Creatinine ◽  
Hospital Mortality ◽  
Renal Dysfunction ◽  
Artery Bypass ◽  
Bypass Grafting ◽  
Mild Renal Impairment ◽  
Preoperative Serum

Background— Risk stratification algorithms for coronary artery bypass grafting (CABG) do not include a weighting for preoperative mild renal impairment defined as a serum creatinine 130 to 199 μmol/L (1.47 to 2.25 mg/dL), which may impact mortality and morbidity after CABG. Methods and Results— We reviewed prospectively collected data between 1997 and 2004 on 4403 consecutive patients undergoing first-time isolated CABG with a preoperative serum creatinine <200 μmol/L (2.26 mg/dL)] in a single institution. The in-hospital mortality was 2.5% (112 of 4403), the need for new dialysis/hemofiltration was 1.3% (57 of 4403), and the stroke rate was 2.5% (108 of 4403). There were 458 patients with a serum creatinine 130 to 199 μmol/L or 1.47 to 2.25 mg/dL (mild renal dysfunction group) and 3945 patients with a serum creatinine <130 μmol/L (<1.47 mg/dL). Operative mortality was higher in the mild renal dysfunction group (2.1% versus 6.1%; P <0.001) and increased with increasing preoperative serum creatinine level. New dialysis/hemofiltration (0.8%versus 5.2%; P <0.001) and postoperative stroke (2.2% versus 5.0%; P <0.01) were also more common in the patients with mild renal impairment. Multivariate analysis adjusting for known risk factors confirmed preoperative mild renal impairment (creatinine 130 to 199 μmol/L or 1.47 to 2.25 mg/dL; odd ratio, 1.91; 95% CI, 1.18 to 3.03; P =0.007) or glomerular filtration rate estimates <60 mL/min per 1.73 m 2 , derived using the Cockroft-Gault formula, (odds ratio, 1.98; 95% CI, 1.16 to 3.48; P =0.015) as independent predictors of in-hospital mortality. Preoperative mild renal dysfunction adversely affected the 3-year survival probability after CABG (93% versus 81%; P <0.001). Conclusions— Mild renal dysfunction is an important predictor of outcome in terms of in-hospital mortality, morbidity, and midterm survival in patients undergoing CABG.

scholarly journals Pharmacokinetics of Tedizolid in Subjects with Renal or Hepatic Impairment

2014 ◽  
Vol 58 (11) ◽  
pp. 6471-6476 ◽  
Author(s):  
S. Flanagan ◽  
S. L. Minassian ◽  
D. Morris ◽  
R. Ponnuraj ◽  
T. C. Marbury ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Hepatic Impairment ◽  
Peak Concentration ◽  
Matched Control ◽  
Severe Renal Impairment ◽  
Control Group ◽  
Crossover Fashion ◽  
Severe Hepatic Impairment ◽  
Control Subjects ◽  
Before And After

ABSTRACTTwo open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects. Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function. Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis. Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function. Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion. The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls (∼8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration (∼9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis. Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group. Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01452828 [renal study] and NCT01431833 [hepatic study].)

Phase I study of the effects of renal impairment on the pharmacokinetic (PK) and safety of satraplatin in patients (Pts) with refractory non-hematologic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2044-2044 ◽  
Author(s):  
D. S. Hong ◽  
M. Galsky ◽  
E. Chiorean ◽  
D. Mulkerian ◽  
D. Greene ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Renal Dysfunction ◽  
Double Blind ◽  
Mild Renal Impairment ◽  
Cohort Group ◽  
Platinum Sensitive ◽  
Hematologic Cancer ◽  
Severe Impairment ◽  
Hormone Refractory ◽  
Tumor Types

2044 Background: Satraplatin (S) is a novel oral platinum analog with demonstrated activity in the treatment of pts with platinum-sensitive malignancies. A worldwide, double-blind, placebo-controlled randomized trial evaluating S as 2nd line therapy for hormone refractory prostate cancer (HRPC) has recently completed enrollment. The current study wasis designed to understand the effect of varying degrees of renal impairiment on the safety and PK of satraplatin. Methods: The study includes 4 levels of renal dysfunction, and 8 pts/cohort: Group 1 (G1) = Normal Renal Controls; G2 = Mild renal impairment (CrCl 50–80 mL/min); G3 = Mod. impairment (CrCl 30-<50 ml/min); G4 = Severe impairment (CrCl <30 mL/min). S was administered orally at 80mg/m2/d on d1–5 every 35 days. Results: 21 pts (of a planned total of 32) have been enrolled (13M/8F), median age 63 (range 45–72). Tumor types: Bladder (6), Renal (3), Breast (2), Prostate (2), Colon (2), Other (6). Among 15 evaluable pts, the cohort distribution is G1: 6 pts, G2: 4, G3: 4, and G4: 1. Twenty-six cycles of S have been delivered, and 11 pts have completed at least 2 cycles of therapy. Hematologic toxicities during the first 2 cycles include grade (G) 3/4 neutropenia (0 pts), G 3/4 thrombocytopenia (1), and G 3/4 anemia (1). No significant cardiac, renal, hepatic, or neurologic toxicity has been observed. Nausea, vomiting, and diarrhea were mild to moderate, and controlled with oral therapy. Of 4 pts with evaluable disease, 1 has stable disease, and 3 have progressed. Conclusions: S is well tolerated in pts with varying degrees of renal dysfunction. Updated safety and PK data will be presented at the meeting. [Table: see text]

scholarly journals Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers

2015 ◽  
Vol 59 (11) ◽  
pp. 6791-6799 ◽  
Author(s):  
Kok-Yong Seng ◽  
Kim-Hor Hee ◽  
Gaik-Hong Soon ◽  
Nicholas Chew ◽  
Saye H. Khoo ◽  
...  
Keyword(s):  
Isonicotinic Acid ◽  
Compartment Model ◽  
Hepatic Function ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Mixed Effects Modeling ◽  
Two Compartment Model

ABSTRACTIn this study, we aimed to quantify the effects of theN-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolismin vivoand identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤Cmax≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.

scholarly journals Pharmacokinetics and safety of rucaparib in patients with advanced solid tumors and hepatic impairment

2021 ◽  
Author(s):  
Nikolay Grechko ◽  
Viera Skarbova ◽  
Monika Tomaszewska-Kiecana ◽  
Rodryg Ramlau ◽  
Piotr Centkowski ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Hepatic Impairment ◽  
Geometric Mean ◽  
Hepatic Function ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Moderate Hepatic Impairment ◽  
Advanced Solid Tumors ◽  
Castration Resistant Prostate Cancer ◽  
Normal Hepatic Function

Abstract Purpose The poly(ADP-ribose) polymerase inhibitor rucaparib is approved for the treatment of patients with recurrent ovarian and metastatic castration-resistant prostate cancer; however, limited data are available on its use in patients with hepatic dysfunction. This study investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of rucaparib in patients with advanced solid tumors. Methods Patients with normal hepatic function or moderate hepatic impairment according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were enrolled and received a single oral dose of rucaparib 600 mg. Concentrations of rucaparib and its metabolite M324 in plasma and urine were measured. Pharmacokinetic parameters were compared between hepatic function groups, and safety and tolerability were assessed. Results Sixteen patients were enrolled (n = 8 per group). Rucaparib maximum concentration (Cmax) was similar, while the area under the concentration–time curve from time 0 to infinity (AUC0–inf) was mildly higher in the moderate hepatic impairment group than in the normal control group (geometric mean ratio, 1.446 [90% CI 0.668–3.131]); similar trends were observed for M324. Eight (50%) patients experienced ≥ 1 treatment-emergent adverse event (TEAE); 2 had normal hepatic function and 6 had moderate hepatic impairment. Conclusion Patients with moderate hepatic impairment showed mildly increased AUC0–inf for rucaparib compared to patients with normal hepatic function. Although more patients with moderate hepatic impairment experienced TEAEs, only 2 TEAEs were considered treatment related. These results suggest no starting dose adjustment is necessary for patients with moderate hepatic impairment; however, close safety monitoring is warranted.

scholarly journals Population pharmacokinetic analysis of doripenem for Japanese patients in intensive care unit

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ko Nonoshita ◽  
Yosuke Suzuki ◽  
Ryota Tanaka ◽  
Tetsuya Kaneko ◽  
Yoshifumi Ohchi ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Population Analysis ◽  
Compartment Model ◽  
Japanese Patients ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Analysis Model ◽  
Mixed Effects Modeling

AbstractWe aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT). Twenty-one patients treated with DRPM (0.25 or 0.5 g) by intravenous infusion over 1 h were included in the study. Nine of the 21 patients were receiving CRRT. Plasma samples were obtained before and 1, 2, 4, 6 and 8 h after the first DRPM administration. PPK analysis was conducted by nonlinear mixed effects modeling using a two-compartment model. Total clearance (CLtotal) in the model was divided into CRRT clearance (CLCRRT) and body clearance (CLbody). The final model was: CLtotal (L h−1) = CLbody(non-CRRT) = 3.65 × (Ccr/62.25)0.64 in the absence of CRRT, or = CLbody(CRRT) + CLCRRT = 2.49 × (Ccr/52.75)0.42 + CLCRRT in the presence of CRRT; CLCRRT = QE × 0.919 (0.919 represents non-protein binding rate of DRPM); V1 (L) = 10.04; V2 (L) = 8.13; and Q (L h−1) = 3.53. Using this model, CLtotal was lower and the distribution volumes (V1 and V2) tended to be higher compared to previous reports. Also, Ccr was selected as a significant covariate for CLbody. Furthermore, the contribution rate of CLCRRT to CLtotal was 30–40%, suggesting the importance of drug removal by CRRT. The population analysis model used in this study is a useful tool for planning DRPM regimen and administration. Our novel model may contribute greatly to proper use of DRPM in patients requiring intensive care.

scholarly journals Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment

2016 ◽  
Vol 60 (5) ◽  
pp. 3025-3031 ◽  
Author(s):  
Amit Desai ◽  
Anne-Hortense Schmitt-Hoffmann ◽  
Salim Mujais ◽  
Robert Townsend
Keyword(s):  
Steady State ◽  
Hepatic Impairment ◽  
Healthy Subjects ◽  
Dose Adjustment ◽  
Fold Increase ◽  
Population Pharmacokinetic ◽  
Moderate Hepatic Impairment ◽  
Absorption Function ◽  
Trough Concentrations ◽  
Intravenous And Oral Administration

ABSTRACTIsavuconazole, administered as the prodrug isavuconazonium sulfate, was recently approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of adults with invasive aspergillosis and mucormycosis. The objective of this analysis was to develop a population pharmacokinetic model using NONMEM (version 7.2) for subjects with hepatic impairment, using intravenous and oral administration data from two hepatic studies, and to simulate concentration profiles to steady state, thus evaluating the need for dose adjustment. A two-compartment model with Weibull absorption function and first-order elimination process adequately described plasma isavuconazole concentrations. The population mean clearance in healthy subjects was 2.5 liters/h (5th and 95th percentiles: 2.0 and 3.1). The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 liters/h (5th and 95th percentiles: 1.3 and 1.8 liters/h) and 1.32 liters/h (5th and 95th percentiles: 1.05 and 1.35), respectively. Peripheral volume of distribution increased with body mass index. Simulations of mean concentration time profiles to steady state showed less than a 2-fold increase in mean trough concentrations for subjects with mild and moderate hepatic impairment compared with healthy subjects. After administration of the single dose, safety data for subjects with mild and moderate hepatic impairment were generally comparable to those for healthy subjects in both studies. Due to the <2-fold increase in trough concentrations and the established safety margin, dose adjustment appears to be unnecessary in subjects with mild or moderate hepatic impairment.

Sign in / Sign up

Export Citation Format

Share Document