scholarly journals Ethambutol Pharmacokinetic Variability Is Linked to Body Mass in Overweight, Obese, and Extremely Obese People

2011 ◽  
Vol 56 (3) ◽  
pp. 1502-1507 ◽  
Author(s):  
Ronald G. Hall ◽  
Mark A. Swancutt ◽  
Claudia Meek ◽  
Richard D. Leff ◽  
Tawanda Gumbo
Keyword(s):  
Body Mass ◽  
Compartment Model ◽  
Obese Patients ◽  
Obese People ◽  
Time Curve ◽  
Female Ratio ◽  
Two Compartment Model ◽  
Dosing Regimens ◽  
A Prospective Study ◽  
Male To Female

ABSTRACTWe conducted a prospective study of 18 adult volunteers (male-to-female ratio of 1) whose body mass index fell into categories of <25, 25 to 40, or >40 kg/m2, who received a single oral dose of 1,600 mg ethambutol. Only individuals with normal renal function were recruited. The minimum body mass (M) was 45.6 kg, the median was 90.8 kg, and the maximum weight was 160.4 kg. Ethambutol pharmacokinetics were best described by a two-compartment model. Inclusion of weight as a covariate dramatically improved the model, with a relative likelihood approaching infinity. The typical clearance was 42.6 liters/h. Ethambutol systemic clearance was proportional to (M/45.6)3/4and thus obeyed fractal geometry-based laws. This means that the area under the concentration-time curve (AUC) actually decreased for obese patients compared to that for leaner patients, reducing chances of concentration-dependent toxicity. On the other hand, such reduced AUCs could lead to therapy failure. Thus, new and individualized ethambutol dosing regimens need to be designed for obese and extremely obese patients.

scholarly journals Fractal Geometry and the Pharmacometrics of Micafungin in Overweight, Obese, and Extremely Obese People

2011 ◽  
Vol 55 (11) ◽  
pp. 5107-5112 ◽  
Author(s):  
Ronald G. Hall ◽  
Mark A. Swancutt ◽  
Tawanda Gumbo
Keyword(s):  
Fractal Geometry ◽  
Hospital Admissions ◽  
Minimum Weight ◽  
Expectation Maximization Algorithm ◽  
Compartment Model ◽  
Obese People ◽  
Female Ratio ◽  
The Metabolic Syndrome ◽  
Two Compartment Model ◽  
A Prospective Study

ABSTRACTThe majority of Americans are overweight, and the incidence of obesity continues to increase. This trend predisposes people to a number of deleterious consequences, including the metabolic syndrome and other conditions that lead to a greater number of hospital admissions. Invasive candidiasis is an important nosocomial infection that results from these admissions. Echinocandins such as micafungin are indicated for treatment. We have previously demonstrated that overweight patients exhibit higher micafungin systemic clearance (SCL) than leaner patients. We hypothesized that obese and extremely obese people would show even higher SCL than merely overweight patients. To test this, we performed a prospective study of 36 adult volunteers randomized to receive a single dose of either 100 mg or 300 mg of micafungin whose body mass index fell within one of the following categories: <25, 25 to 40, and >40 kg/m2. The male-to-female ratio was 1:1. The minimum weight was 43 kg, the median 97 kg, and the maximum weight 155 kg. A two-compartment model was examined using the maximum likelihood solution via the expectation-maximization algorithm. Men had a higher median SCL of 1.53 liters/h versus 1.29 liters/h (P= 0.01) in the Mann-Whitney U-test. The typical SCL was 1.04 liters/h but increased by a factor of (weight/66)0.75as weight increased above 66 kg. Thus, the relationship between micafungin SCL and weight in adults is best described by fractal-geometry-based laws. Furthermore, micafungin SCL continues to increase as weight increases, with no obvious plateau. This leads to a requirement for strategies to determine individualized dosing levels for obese and extremely obese patients.

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.

Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis

2021 ◽  
Author(s):  
Antonin Praet ◽  
Laurent Bourguignon ◽  
Florence Vetele ◽  
Valentine Breant ◽  
Charlotte Genestet ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dose Adjustment ◽  
Total Body Weight ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Two Compartment Model ◽  
Total Body

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC 24 /MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC 24 /MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

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.

scholarly journals A prospective study on morphological alteration of megakaryocytes amongst megaloblastic anemia cases along with their clinic-haematological manifestations

2017 ◽  
Vol 5 (9) ◽  
pp. 4127
Author(s):  
Benazeer Mansuri ◽  
Komal P. Thekdi
Keyword(s):  
Bone Marrow ◽  
Megaloblastic Anemia ◽  
Bone Marrow Aspiration ◽  
Morphological Alteration ◽  
Age Group ◽  
Female Ratio ◽  
Hematological Disorders ◽  
Common Complaint ◽  
A Prospective Study ◽  
Male To Female

Background: Megaloblastic anemias are hematologic disorders in which abnormal DNA synthesis causes blood and bone marrow disorders. The cause of thrombocytopenia in megaloblastic anemia has been postulated as hypoproduction in some studies, whereas ineffective thrombopoeisis has been proposed in other. Objective was to study spectrum of clinic-hematological features in megaloblastic anemia and comparative bone marrow aspiration study of thrombocytopenia secondary to megaloblastic anemia, hypoproduction and hyper-destruction. This study was done to understand the various megakaryocytic alterations in hematological disorders presenting with thrombocytopenia due to different mechanisms.Methods: Total 85 cases of thrombocytopenia included in the study. Bone marrow finding in 33 cases of thrombocytopenia of megaloblastic etiology were compared with 34 cases of marrow proven hypo productive thrombocytopenia (aplastic anemia, acute leukemia) and 19 cases of hyper destructive thrombocytopenia (immune thrombocytopenia).Results: Most common age group presenting megaloblastic anemia is 11-20 year, with male to female ratio is1.2:1, most common complaint were generalized weakness and fever. In megaloblastic anemia 24.33%, 60% and 15.67% of the cases shows increase, decrease and normal megakaryocytes respectively. Dysplastic megakaryocytes were observed in 24.3%, 27% and 20.5% of the cases of megaloblastic anemia, acute leukaemia and immune thrombocytopenic purpura respectively.Conclusions: Both hypoproduction and ineffective thrombopoiesis are the underlying path mechanisms in megaloblastic thrombocytopenia as evidenced by the marrow findings. We hereby infer that megaloblastic thrombocytopenia is to be included as a separate category apart from hypo proliferative and hyper destructive groups. The presence of dysplastic megakaryocyte should not prompt an interpretation

Pharmacokinetics/Pharmacodynamics of caspofungin in plasma and peritoneal fluid of liver transplant recipients

2021 ◽  
Author(s):  
Claire Pressiat ◽  
Nawel Ait-Ammar ◽  
Matthieu Daniel ◽  
Anne Hulin ◽  
Françoise Botterel ◽  
...  
Keyword(s):  
Liver Transplant ◽  
Peritoneal Fluid ◽  
Compartment Model ◽  
Transplant Recipients ◽  
Mixed Effect ◽  
First Order ◽  
Transplant Patients ◽  
Two Compartment Model ◽  
Dosing Regimens ◽  
Liver Transplant Recipients

Background: The weaker diffusion of echinocandins in the peritoneal fluid (PF) could promote Candida resistant isolates. The aim of this study was to analyse the pharmacokinetics/pharmacodynamics (PK/PD) of caspofungin in plasma and PF of liver transplant recipients. Methods: Liver transplant patients received caspofungin as postoperative prophylaxis. Caspofungin concentrations were quantified in plasma and in PF on Days 1, 3 and 8. Data were analysed using non-linear mixed-effect modelling and Monte Carlo simulations. Area under curve (AUC) in plasma and PF were simulated under three dosing regimens. Probabilities of target attainment (PTA) were calculated using fAUC 0-24 /minimal inhibitory concentration (MIC) ratios with MICs ranging from 0.008 to 8 mg/litre. All the patients included were monitored weekly for Candida colonisation and for Candida infections. Results: Twenty patients were included. Median daily dose of caspofungin was 0.81 mg/kg. Plasma (n=395) and peritoneal (n=50) concentrations at steady state were available. A two-compartment model with first-order absorption and elimination was described. Our two-compartment model with first-order absorption and elimination model produced an effective PK/PD relationship in plasma, achieving a PTA ≥90% and MIC ranging from 0.008 to 0.12 mg/L for C. albicans and glabrata . In PF, PTAs at D8 were only optimal for a MIC of 0.008 in patients weighing 60 kg under the three dosing regimens. Among the 16 patients colonized, all MIC values were below the maximal concentration (Cmax) in plasma but not in PF. Conclusion: Peritoneal concentrations of caspofungin were low. Simulations showed that the PTA for Candida spp. in PF were not optimal, that might suggesting a potential risk of resistance.

PATHOLOGICAL STUDY OF BODY FLUIDS IN A TERTIARY CARE CENTER IN SOUTH INDIA.

2021 ◽  
pp. 60-61
Author(s):  
Earla Lakshmi Bai ◽  
Buddaiahgari Swathi ◽  
Siva Chaithanya Bangi
Keyword(s):  
Cell Count ◽  
Care Center ◽  
Tertiary Care ◽  
Clinical Pathology ◽  
Major Type ◽  
Pathology Laboratory ◽  
Female Ratio ◽  
Atypical Cells ◽  
A Prospective Study ◽  
Male To Female

Body cavities uid analysis is done routinely in both clinical pathology and cytology departments of Pathological laboratory. Any imbalance between uid 1. formation and removal leads to effusion, as stated by Starling's law The peritoneal, pleural, cerebrospinal and pericardial uids comprise the major chunk of 2 body uids . Accumulation of uid in various body cavities can occur in vast range of benign conditions and it also a frequent clinical presentation and complication of malignant disorder. METHODS: A prospective study was conducted in the Department of Pathology, Osmania general hospital Hyderabad, Telangana, India, during January 2020 to December 2020 and analyzed 880 uid samples collected from patients for cell count and cytology. The data collected was tabulated using Microsoft excel and analyzed using standard statistical tools. RESULTS -Of total 880 uids analyzed peritoneal uid (42%) constitutes the major type of uid sent frequently for analysis followed by cerebrospinal uid (41%) with male to female ratio of 1.9:1. 62.7% of uids had clear gross appearance . Of total 880 uid samples analyzed 649 samples (73.7%) had shown lymphocyte predominance. Of total 880 uids samples analyzed 9 samples (1%) were found positive for atypical cells, conrmed on cytology suggesting there malignant origin. CONCLUSION: uid aspiration from body cavities constitutes one of the common day care procedures for clinicians. Effusion uid analysis is key in delineating the background cause in the patient ranging from reactive, inammatory and malignant conditions. Fluid cell count coupled by cytological analysis of uids in pathology laboratory is a time tested tool having good sensitivity and specicity when interpreted along with biochemical parameters.

scholarly journals DETERMINATION OF SENSITIVITY AND SPECIFICITY OF ULTRASONOGRAPHY IN ACUTE APPENDICITIS: COMPARISON WITH PER-OPERATIVE FINDINGS AND HISTOPATHOLOGICAL REPORT

2017 ◽  
Vol 10 (9) ◽  
pp. 151
Author(s):  
Sasmita Parida ◽  
Bibekananda Nayak ◽  
Jayashree Mohanty
Keyword(s):  
Acute Appendicitis ◽  
Reproductive Period ◽  
Bowel Loop ◽  
Predictive Values ◽  
Female Ratio ◽  
Operative Findings ◽  
Sensitivity Specificity ◽  
A Prospective Study ◽  
Histopathological Results ◽  
Male To Female

  Objective: This study was under taken to compare the ultrasonographic findings with pre-operative findings and histo-pathological report and to evaluate the sensitivity, specificity, positive and negative predictive values and accuracy of ultrasonography in the diagnosis of acute appendicitis.Methods: It was a prospective study done in the department of radio-diagnosis, SCBMCH, Cuttack. Patients with provisional diagnosis of acute appendicitis were subjected to ultrasound of abdomen and pelvis. Patients with positive USG findings were followed up for pre-operative findings and histo-pathological results. All the obtained data were tabulated and subjected to statistical analysis.Results: Among the 100 cases studied, 77 cases were proved as acute appendicitis based on surgical and histopathological results. Male to female ratio was 1.5:1. The disease was found to be more prevalent in second and third decade of life. Location of affected appendix was most commonly retro caecal. Mean diameter of the appendix was 8.56 mm. Target sign and non-compressible bowel loop was the most commonly detected ultrasonographic sign and the ultrasonographic sensitivity was 96.1% and specificity was 95.65% in our study.Conclusion: High resolution sonography with graded compression is a very useful diagnostic tool for diagnosis of appendicitis in problematic cases and in women in their reproductive period. It is also helpful in detecting complications of appendicitis and other abdominal diseases that mimic acute appendicitis.

Carboplatin dosage: prospective evaluation of a simple formula based on renal function.

1989 ◽  
Vol 7 (11) ◽  
pp. 1748-1756 ◽  
Author(s):  
A H Calvert ◽  
D R Newell ◽  
L A Gumbrell ◽  
S O'Reilly ◽  
M Burnell ◽  
...  
Keyword(s):  
Single Agent ◽  
Compartment Model ◽  
Hematological Toxicity ◽  
High Dose ◽  
Target Area ◽  
Time Curve ◽  
Two Compartment Model ◽  
Patient Groups ◽  
Previously Treated ◽  
Consistent Method

A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.

scholarly journals Integrated Population Pharmacokinetic Analysis of Voriconazole in Children, Adolescents, and Adults

2012 ◽  
Vol 56 (6) ◽  
pp. 3032-3042 ◽  
Author(s):  
Lena E. Friberg ◽  
Patanjali Ravva ◽  
Mats O. Karlsson ◽  
Ping Liu
Keyword(s):  
Pediatric Population ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Loading Dose ◽  
Time Curve ◽  
Individual Parameter ◽  
Dosing Regimens

ABSTRACTTo further optimize the voriconazole dosing in the pediatric population, a population pharmacokinetic analysis was conducted on pooled data from 112 immunocompromised children (2 to <12 years), 26 immunocompromised adolescents (12 to <17 years), and 35 healthy adults. Different maintenance doses (i.e., 3, 4, 6, 7, and 8 mg/kg of body weight intravenously [i.v.] every 12 h [q12h]; 4 mg/kg, 6 mg/kg, and 200 mg orally q12h) were evaluated in these children. The adult dosing regimens (6 mg/kg i.v. q12h on day 1, followed by 4 mg/kg i.v. q12h, and 300 mg orally q12h) were evaluated in the adolescents. A two-compartment model with first-order absorption and mixed linear and nonlinear (Michaelis-Menten) elimination adequately described the voriconazole data. Larger interindividual variability was observed in pediatric subjects than in adults. Deterministic simulations based on individual parameter estimates from the final model revealed the following. The predicted total exposure (area under the concentration-time curve from 0 to 12 h [AUC0-12]) in children following a 9-mg/kg i.v. loading dose was comparable to that in adults following a 6-mg/kg i.v. loading dose. The predicted AUC0-12s in children following 4 and 8 mg/kg i.v. q12h were comparable to those in adults following 3 and 4 mg/kg i.v. q12h, respectively. The predicted AUC0-12in children following 9 mg/kg (maximum, 350 mg) orally q12h was comparable to that in adults following 200 mg orally q12h. To achieve voriconazole exposures comparable to those of adults, dosing in 12- to 14-year-old adolescents depends on their weight: they should be dosed like children if their weight is <50 kg and dosed like adults if their weight is ≥50 kg. Other adolescents should be dosed like adults.

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