scholarly journals Assessment of Micafungin Dosage Regimens in Patients with Cancer Using Pharmacokinetic/Pharmacodynamic Modeling and Monte Carlo Simulation

Antibiotics ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1363
Author(s):  
Saeed Alqahtani ◽  
Asma Alfarhan ◽  
Abdullah Alsultan ◽  
Emad Alsarhani ◽  
Abdulaziz Alsubaie ◽  
...  
Keyword(s):  
High Performance ◽  
Compartment Model ◽  
Pharmacodynamic Modeling ◽  
Pharmacokinetic Parameters ◽  
Candida Spp ◽  
Patients With Cancer ◽  
Treatment And Prevention ◽  
Two Compartment Model ◽  
Linear Elimination ◽  
Empirical Antifungal Therapy

Micafungin is widely used for invasive candidiasis, especially in critically ill patients and those with cancer, and for empirical antifungal therapy in patients with neutropenic fever. This is the first study to investigate the pharmacokinetics and disposition parameters of micafungin in patients with cancer. In this observational pharmacokinetic study, blood samples were collected and analyzed using high-performance liquid chromatography. Pharmacokinetic parameters were estimated using Monolix 4.4 software. The plasma micafungin concentrations were measured in a total of 133 samples from 19 patients. In the final two-compartment model with linear elimination, the estimated micafungin clearance (CL) was significantly higher in patients with cancer than in those without cancer (1.2 vs. 0.6 L/h, p = 0.012), whereas other parameters did not significantly differ between the two groups. Aspartate and alanine transaminases and body weight significantly influenced micafungin CL in patients, with and without cancer. Overall, the probability of target attainment increased with increasing doses and decreased with higher MICs in both groups. In simulations, the patients without cancer achieved higher pharmacokinetic/pharmacodynamic targets with a 90% probability for all simulated doses, compared to the patients with cancer. Micafungin demonstrated dose-proportional linear pharmacokinetics in both the patients with and those without cancer. The estimated micafungin CL was significantly higher in patients with cancer, suggesting a need for increased dosage, especially for Candida spp. with high MICs, in these patients. Further studies should assess the efficacy and optimum dosage of micafungin for the treatment and prevention of febrile neutropenia (FN) in patients with cancer.

scholarly journals Serum bactericidal activities and comparative pharmacokinetics of meropenem and imipenem-cilastatin.

1996 ◽  
Vol 40 (1) ◽  
pp. 105-109 ◽  
Author(s):  
M Dreetz ◽  
J Hamacher ◽  
J Eller ◽  
K Borner ◽  
P Koeppe ◽  
...  
Keyword(s):  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Dose Administration ◽  
Microdilution Method ◽  
Two Compartment Model ◽  
Elimination Half ◽  
Renal Clearances ◽  
The Mean ◽  
Bactericidal Activities

The pharmacokinetics and serum bactericidal activities (SBAs) of imipenem and meropenem were investigated in a randomized crossover study. Twelve healthy male volunteers received a constant 30-min infusion of either 1 g of imipenem plus 1 g of cilastatin or 1 g of meropenem. The concentrations of the drugs in serum and urine were determined by bioassay and high-pressure liquid chromatography. Pharmacokinetic parameters were based on an open two-compartment model and a noncompartmental technique. At the end of infusion, the mean concentrations of imipenem and meropenem measured in serum were 61.2 +/- 9.8 and 51.6 +/- 6.5 mg/liter, respectively; urinary recoveries were 48.6% +/- 8.2% and 60.0% +/- 6.5% of the dose in 12 h, respectively; and the areas under the concentration-time curve from time zero to infinity were 96.1 +/- 14.4 and 70.5 +/- 10.3 mg.h/liter, respectively (P < or = 0.02). Imipenem had a mean half-life of 66.7 +/- 10.4 min; that of meropenem was 64.4 +/- 6.9 min. The volumes of distribution at steady state of imipenem and meropenem were 15.3 +/- 3.3 and 18.6 +/- 3.0 liters/70 kg, respectively, and the mean renal clearances per 1.73 m2 were 85.6 +/- 17.6 and 144.6 +/- 26.0 ml/min, respectively. Both antibiotics were well tolerated in this single-dose administration study. The SBAs were measured by the microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977) against 40 clinically isolated strains. Mean reciprocal bactericidal titers were measured 1 and 6 h after administration. After 1 and 6 h the median SBAs for imipenem and meropenem, were 409 and 34.9 and 97.9 and 5.8, respectively, against Staphylococcus aureus, 19.9 and 4.4 and 19.4 and 4.8, respectively, against Pseudomonas aeruginosa, 34.3 and 2.2 and 232 and 15.5, respectively, against Enterobacter cloacae, and 13.4 and 2.25 and 90.7 and 7.9, respectively, against Proteus mirabilis. Both drugs had rather short biological elimination half-lives and a predominantly renal route of elimination. Both carbapenems revealed high SBAs against clinically important pathogens at 1 h; meropenem had a higher SBA against E. cloacae and P. mirabilis, and the SBA of imipenem against S. aureus was greater than the SBA of meropenem.

scholarly journals Characterizing the non-linear pharmacokinetics of miltefosine in paediatric visceral leishmaniasis patients from Eastern Africa

2020 ◽  
Vol 75 (11) ◽  
pp. 3260-3268
Author(s):  
Semra Palić ◽  
Anke E Kip ◽  
Jos H Beijnen ◽  
Jane Mbui ◽  
Ahmed Musa ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Cumulative Dose ◽  
Drug Exposure ◽  
Compartment Model ◽  
Eastern Africa ◽  
Model Following ◽  
Two Compartment Model ◽  
Non Linear ◽  
Linear Elimination ◽  
Dosing Regimens

Abstract Background Conventional miltefosine dosing (2.5 mg/kg/day) for treatment of visceral leishmaniasis (VL) is less effective in children than in adults. A higher allometric dose (median 3.2 mg/kg/day) was therefore investigated in paediatric VL patients in Eastern Africa. Results of this trial showed an unforeseen, lower than dose-proportional increase in exposure. Therefore, we performed a pooled model-based analysis of the paediatric data available from both dosing regimens to characterize observed non-linearities in miltefosine pharmacokinetics (PK). Methods Fifty-one children with VL were included in this analysis, treated with either a conventional (n = 21) or allometric (n = 30) miltefosine dosing regimen. PK data were analysed using non-linear mixed-effects modelling. Results A two-compartment model following first-order absorption and linear elimination, with two separate effects on relative oral bioavailability, was found to fit these data best. A 69% lower bioavailability at treatment start was estimated, presumably due to initial malnourishment and malabsorption. Stagnation in miltefosine accumulation in plasma, hampering increased drug exposure, was related to the increase in cumulative dose (mg/kg/day). However, the allometric regimen increased exposure 1.7-fold in the first treatment week and reduced the time to reach the PK target by 17.4%. Conclusions Miltefosine PK in children suffering from VL are characterized by dose-dependent non-linearities that obstruct the initially expected exposure levels. Bioavailability appeared to be affected by the cumulative dose, possibly as a consequence of impaired absorption. Despite this, allometric dosing led to a faster target achievement and increased exposure compared with conventional dosing.

Pharmacokinetic Model-driven Infusion of Fentanyl in Children

1996 ◽  
Vol 85 (6) ◽  
pp. 1268-1275. ◽  
Author(s):  
Brian Ginsberg ◽  
Scott Howell ◽  
Peter S. A. Glass ◽  
Judith O. Margolis ◽  
Allison K. Ross ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Pediatric Population ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Context Sensitive ◽  
Model Driven ◽  
Two Compartment Model ◽  
Performance Error ◽  
Adults And Children ◽  
Residual Performance

Background This study determined the accuracy of previously defined adult fentanyl pharmacokinetics in children having surgery; from this population, the pharmacokinetics of fentanyl were characterized in children when administered via a computerized assisted continuous-infusion device. Methods Twenty children between the ages of 2.7 and 11 y scheduled to undergo elective noncardiac surgery were studied. After induction, anesthesia was maintained with 60% nitrous oxide in oxygen supplemented with fentanyl (n = 10) or fentanyl plus isoflurane (n = 10). Fentanyl was administered via computerized assisted continuous-infusion to target concentrations determined by clinical requirements. Plasma fentanyl concentrations were measured and used to evaluate the performance of the fentanyl pharmacokinetics and then to determine a new set of pharmacokinetic parameters and the variance in the context-sensitive half-times simulated for these patients. Results The original adult fentanyl pharmacokinetics resulted in a positive bias (10.4%), indicating that measured concentrations were mostly greater than predicted. A two-compartment model with age and weight as covariates provided the optimal pharmacokinetic parameters. These resulted in a residual performance error of -1.1% and a median absolute performance error of 17.4%. The context-sensitive times determined from this pediatric population were considerably shorter than the context-sensitive times previously published for adults. Conclusions The pharmacokinetics of fentanyl administered by computerized assisted continuous-infusion differ between adults and children. The newly derived parameters are probably more suitable to determine infusion schemes of up to 4 h in children between the ages of 2 and 11 y.

scholarly journals Pharmacokinetic Study of Anti-osteoarthritic Compounds of a Standardized Fraction from Sphaeralcea Angustifolia

2021 ◽  
Vol 14 (7) ◽  
pp. 610
Author(s):  
Jade Serrano-Román ◽  
Pilar Nicasio-Torres ◽  
Elizabeth Hernández-Pérez ◽  
Enrique Jiménez-Ferrer
Keyword(s):  
High Performance ◽  
Compartment Model ◽  
Information Criteria ◽  
Time Range ◽  
Suspension Cell Culture ◽  
Inflammatory Conditions ◽  
Two Compartment Model ◽  
Use Of Knowledge ◽  
Pharmacokinetic Assay ◽  
Pharmacokinetic Behavior

Sphaeralcea angustifolia has been widely used in inflammatory conditions such as blows, bruises, fractures, and wounds. The compounds identified as active in plants and suspension cell culture of S. angustifolia were tomentin, scopoletin, and sphaeralcic acid. To consolidate the integral use of knowledge about the S. angunstifolia and strengthen its pharmacological use in patients with knee osteoarthritis, the pharmacokinetic behavior of the active compounds was characterized. The SaTSS (S. angustifoloia standardized in Tomentin, Scopoletin, and Sphaeralcic acid) anti-ostearthritic fraction was obtained from cell suspension. The analytical method of High-Performance Liquid Chromatography (HPLC) for tomentin, scopoletin, and sphaeralcic acid were validated determining the accuracy, precision linearity, sensibility, specificity, detection limits, and quantification time-range parameters, as well as extraction efficiency and stability of compounds. The pharmacokinetic assay was performed with ICR mice strain, in which the mice were administrated with a single oral or intravenous dose (400 mg/kg with 7.1 mg/kg of scopoletin and tomentin in mixture and 34.6 mg/kg of sphaeralcic acid) of the SaTSS standardized active fraction. The results of the validated analytical methods allowed establishing, in a validated manner, that a coumarin mixture and sphaeralcic acid present in the SaTES fraction were detected in plasma. According to the values of Akaike Information Criteria (AIC), Sum of Squares (SS), Schwarz Criteria (SC), and by the determination coefficient (R2), the compounds follow a two-compartment model.

scholarly journals Safety, Tolerance, and Pharmacokinetics of a Small Unilamellar Liposomal Formulation of Amphotericin B (AmBisome) in Neutropenic Patients

1998 ◽  
Vol 42 (9) ◽  
pp. 2391-2398 ◽  
Author(s):  
Thomas J. Walsh ◽  
Vijay Yeldandi ◽  
Maureen McEvoy ◽  
Corina Gonzalez ◽  
Stephen Chanock ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Therapy ◽  
High Performance ◽  
Fungal Infections ◽  
Empirical Therapy ◽  
Liposomal Formulation ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Empirical Antifungal Therapy ◽  
Neutropenic Patients

ABSTRACT The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.

scholarly journals Pharmacokinetics of Micafungin in Critically Ill Patients

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Silke Gastine ◽  
Christian Lanckohr ◽  
Magalie Blessou ◽  
Dagmar Horn ◽  
Manfred Fobker ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Study Cohort ◽  
Linear Mixed Effects ◽  
Two Compartment Model ◽  
The Status ◽  
Linear Elimination ◽  
Central Volume

AbstractWe investigated covariates of pharmacokinetics of micafungin in critically ill patients. After application of micafungin, plasma samples were collected. Non-linear mixed effects modelling (NONMEM 7.3) was used to develop the pharmacokinetic model. Using this model, the adequacy of a fixed 100 mg dosing regimen was evaluated in the study cohort. A two-compartment model with linear elimination was found to describe the obtained data. SOFA score was identified as a significant covariate on both clearance and central volume of distribution, respectively. Patients in highly critical condition, represented by a SOFA above 10 showed a 30.8% lower central volume of distribution than the less critically ill patients. For patients with bilirubin levels above 4 mg/dl, clearance was decreased by 21.1%. Renal replacement therapy (RRT) did not influence micafungin clearance or the volumes of distribution. In a posthoc evaluation of the modeled population, 100 mg micafungin was suitable when assessing the PKPD targets (AUC/MIC) for C. albicans and C. glabrata, with insufficient target attainment for C. parapsilosis. Micafungin pharmacokinetics appear not to be influenced by the status of RRT. A dose of 100 mg micafungin is suitable for infections with C. albicans and C. glabrata in critically ill patients.

Some Pitfalls in Selecting Descriptive Pharmacokinetic Models

1984 ◽  
Vol 18 (9) ◽  
pp. 708-713 ◽  
Author(s):  
Tom B. Vree ◽  
Yechiel A. Hekster ◽  
Marijn J.M. Oosterbaan ◽  
Emiel F.S. Termond
Keyword(s):  
Plasma Concentration ◽  
Renal Excretion ◽  
Parent Drug ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Models ◽  
Time Curve ◽  
Concentration Time ◽  
Two Compartment Model ◽  
Plasma Concentration Time Curve

Some pitfalls in selecting pharmacokinetic models are enumerated. To calculate the pharmacokinetic parameters of a drug that exhibits a biphasic convex plasma concentration-time curve, a two-compartment model does not automatically have to be applied. When only the parent drug in plasma is considered, a two-compartment model seems to be most appropriate. However, when the kinetic behavior of the metabolite has to be taken into account, and when a metabolic equilibrium underlies the metabolic elimination, the two-compartment model may not be appropriate. Also, when calculating the kinetic parameters of a drug with a concave biphasic plasma concentration-time curve, a capacity-limited metabolic conversion is not the automatic explanation for this observation. Limitations in renal excretion and bioavailability may be the reasons for this behavior. Convex and concave biphasic plasma concentration-time curves are illustrated, using sulfonamides as test compounds.

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 Cystatin C and myeloperoxidase based mycophenolic acid dosage optimization in pediatric anti-neutrophilic cytoplasmic antibody-associated nephritis

2021 ◽  
Author(s):  
Ziwei Li ◽  
Yidie Huang ◽  
Hong Xu ◽  
Zhiping Li
Keyword(s):  
Renal Function ◽  
Cystatin C ◽  
Mycophenolic Acid ◽  
Compartment Model ◽  
Individual Variability ◽  
Pharmacokinetic Parameters ◽  
Large Individual ◽  
Population Pharmacokinetic ◽  
Inflammatory Factor ◽  
Linear Elimination

Aims Mycophenolic acid (MPA) is typically used for anti-neutrophilic cytoplasmic antibody associated nephritis (AAN) but with large individual variability of pharmacokinetics. This study aims to investigate clinical factors impacting MPA disposal so as to simulate dosage regimen in pediatric AAN. Methods We conducted a retrospective study in 25 children with AAN treated with MPA. A population pharmacokinetic model was developed to explore the effects of demographics and biochemical covariates on MPA. Monte Carlo simulations were performed to optimize dosage regimens. Results A total of 391 MPA concentrations from 25 patients were analyzed. MPA pharmacokinetics best fitted a two-compartment model with first-order absorption and linear elimination. The pharmacokinetic parameters for Ka, CL, Vc, Vp, and Q were 0.45 h-1, 9.86 L/h, 19.69 L, 408.32 L and 23.01 L/h, respectively. Dosage form significantly affected drug absorption. CL significantly decreased with increasing cystatin C, while with decreasing myeloperoxidase. Cystatin C was superior to serum creatinine in predicting CL of MPA. A dose of 650 mg/m2 was required to achieve the target exposure in children with normal renal function and no inflammation. Dose of MPA in patients with renal failure was almost 1/3 that of normal kidney function. The combined effects of myeloperoxidase and renal function resulted in a 6-fold range in MPA dose. Conclusions Myeloperoxidase was not only a biomarker of AAN, but also an inflammatory factor to impact drug CL. The influence of renal function and underlying diseases on drug metabolism should be fully considered in personalized medication for AAN children.

scholarly journals Pharmacokinetics of the Antiviral Agent β-d-2′,3′-Didehydro-2′,3′-Dideoxy-5-Fluorocytidine in Rhesus Monkeys

1999 ◽  
Vol 43 (2) ◽  
pp. 381-384 ◽  
Author(s):  
Li Ma ◽  
Selwyn J. Hurwitz ◽  
Junxing Shi ◽  
Jeffrey J. McAtee ◽  
Dennis C. Liotta ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Rhesus Monkeys ◽  
Antiviral Agent ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Administration Route ◽  
Two Compartment Model ◽  
Immunodeficiency Virus ◽  
Median Effective Concentration

ABSTRACT The values of the pharmacokinetic parameters of the nucleoside antiretroviral agent β-d-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (D-D4FC) in rhesus monkeys were determined with a two-compartment model after the administration of a single dose. The average values for the terminal half-life, renal clearance, and total systemic clearance for the intravenous administration route were 3.6 h and 0.31 and 0.43 liter · kg−1 · h−1, respectively. The oral bioavailability of D-D4FC averaged 41%. For the intravenous administration route, 76% of the compound was recovered intact in the urine within 8 h, indicating that D-D4FC was eliminated mainly by renal excretion. D-D4FC was detected in the cerebrospinal fluid (CSF) at similar concentrations after administration by both the intravenous and oral routes. D-D4FC levels in plasma and CSF were higher than the median effective concentration for human immunodeficiency virus type 1 in vitro.

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