scholarly journals Pharmacokinetics of Clindamycin in Obese and Nonobese Children

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Michael J. Smith ◽  
Daniel Gonzalez ◽  
Jennifer L. Goldman ◽  
Ram Yogev ◽  
Janice E. Sullivan ◽  
...  
Keyword(s):  
Total Body Weight ◽  
The United States ◽  
Volume Of Distribution ◽  
Model Parameters ◽  
Obese Children ◽  
Obesity Status ◽  
Postmenstrual Age ◽  
Total Body ◽  
Using Data ◽  
Require Dose

ABSTRACT Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size. The final model included TBW and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (liters/hour) = 13.8 × (TBW/70)0.75 × [PMA2.83/(39.52.83+PMA2.83)]; volume of distribution (V) was associated with TBW, albumin (ALB), and alpha-1 acid glycoprotein (AAG): V (liters) = 63.6 × (TBW/70) × (ALB/3.3)−0.83 × (AAG/2.4)−0.25. After accounting for differences in TBW, obesity status did not explain additional interindividual variability in model parameters. Our findings support TBW-based dosing for obese and nonobese children.

Pharmacokinetics and Drug Dosing in Obese Children

2010 ◽  
Vol 15 (2) ◽  
pp. 94-109
Author(s):  
Jennifer G. Kendrick ◽  
Roxane R. Carr ◽  
Mary H. H. Ensom
Keyword(s):  
Body Weight ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Drug Dose ◽  
Normal Weight ◽  
Obese Children ◽  
Physiochemical Properties ◽  
Drug Dosing ◽  
Hydrophilic Drugs ◽  
Total Body

ABSTRACT OBJECTIVES To review pharmacokinetics in obese children and to provide medication dosing recommendations. METHODS EMBASE, MEDLINE, and International Pharmaceutical Abstracts databases were searched using the following terms: obesity, morbid obesity, overweight, pharmacokinetics, drug, dose, kidney function test, creatinine, pediatric, and child. RESULTS We identified 10 studies in which the authors examined drug dosing or pharmacokinetics for obese children. No information was found for drug absorption or metabolism. Obese children have a higher percent fat mass and a lower percent lean mass compared with normal-weight children. Therefore, in obese children, the volume of distribution of lipophilic drugs is most likely higher, and that of hydrophilic drugs is most likely lower, than in normal-weight children. Serum creatinine concentrations are higher in obese than normal-weight children. Total body weight is an appropriate size descriptor for calculating doses of antineoplastics, cefazolin, and succinylcholine in obese children. Initial tobramycin doses may be determined using an adjusted body weight, although using total body weight in the context of monitoring serum tobramycin concentrations would also be an appropriate strategy. We found no information for any of the opioids; antibiotics such as penicillins, carbapenems, vancomycin, and linezolid; antifungals; cardiac drugs such as digoxin and amiodarone; corticosteroids; benzodiazepines; and anticonvulsants. In particular, we found no information about medications that are widely distributed to adipose tissue or that can accumulate there. CONCLUSIONS The available data are limited because of the small numbers of participating children, study design, or both. The number and type of drugs that have been studied limit our understanding of the pharmacokinetics in obese children. In the absence of dosing information for obese children, it is important to consider the nature and severity of a child's illness, comorbidities, organ function, and side effects and physiochemical properties of the drug. Extrapolating from available adult data is possible, as long as practitioners consider the effects of growth and development on the pharmacokinetics relevant to the child's age.

scholarly journals O35 Midazolam pharmacokinetics in children with obesity

2019 ◽  
Vol 104 (6) ◽  
pp. e15.2-e16
Author(s):  
C Gade ◽  
E Sverrisdóttir ◽  
K Dalhoff ◽  
J Sonne ◽  
H Rolighed Christensen ◽  
...  
Keyword(s):  
Body Weight ◽  
Status Epilepticus ◽  
Intravenous Administration ◽  
Plasma Concentrations ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Convulsive Status Epilepticus ◽  
List Type ◽  
Obese Children ◽  
Total Body

BackgroundMidazolam is a first-line drug for treatment of status epilepticus,1 2 both by buccal and intravenous administration. In children with obesity, the midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient.The aim of the study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese children, aged 11–18 years.MethodsTrial subjects were divided into groups by Body Mass Standard Deviation Score (SDS). All children received 1 µg midazolam administered an intravenous bolus dose. Thirteen blood samples were collected per participant at prespecified timepoints over 9 hours. Plasma concentration-time data was fitted to pharmacokinetic models using non-linear mixed effects modelling (NONMEM, 7.4).ResultsSeventy-two children were enrolled in the study, of these 67 children were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The changes in pharmacokinetics in children with obesity were best described with a linear function of BMI SDS on inter-compartmental clearance and peripheral volume. Thus, the rate of distribution was faster, and the peripheral volume of distribution was larger in children with obesity as compared to non-obese children. Simulations revealed that long-term infusions based on total body weight, could lead to high plasma concentrations in children with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose showed that children with obesity may be at risk of subtherapeutic plasma concentrations.ConclusionBMI SDS was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current Danish dosing guidelines for status epilepticus (http://www.paediatri.dk), where midazolam dose is adjusted to total body weight or age, may lead to both supra- and subtherapeutic doses respectively, in children with obesity. However, confirmatory studies are needed.ReferencesSmith R, Brown J. Midazolam for status epilepticus. Aust Prescr. februar 2017;40(1):23–5.Ulvi H, Yoldas T, Müngen B, Yigiter R. Continuous infusion of midazolam in the treatment of refractory generalized convulsive status epilepticus. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol oktober 2002;23(4):177–82.Disclosure(s)Nothing to disclose

scholarly journals Population Pharmacokinetics of Doxycycline in Children

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Elizabeth J. Thompson ◽  
Huali Wu ◽  
Chiara Melloni ◽  
Stephen Balevic ◽  
Janice E. Sullivan ◽  
...  
Keyword(s):  
Model Performance ◽  
Standard Of Care ◽  
Volume Of Distribution ◽  
Clinical Value ◽  
Final Model ◽  
Childhood Infections ◽  
Obesity Status ◽  
Improve Model ◽  
Using Data ◽  
Improve Model Performance

ABSTRACT Doxycycline is a tetracycline-class antimicrobial labeled by the U.S. Food and Drug Administration for children >8 years of age for many common childhood infections. Doxycycline is not labeled for children ≤8 years of age, due to the association between tetracycline-class antibiotics and tooth staining, although doxycycline may be used off-label under severe conditions. Accordingly, there is a paucity of pharmacokinetic (PK) data to guide dosing in children 8 years and younger. We leveraged opportunistically collected plasma samples after intravenous (i.v.) and oral doxycycline doses received per standard of care to characterize the PK of doxycycline in children of different ages and evaluated the effect of obesity and fasting status on PK parameters. We developed a population PK model of doxycycline using data collected from 47 patients 0 to 18 years of age, including 14 participants ≤8 years. We developed a 1-compartment PK model and found doxycycline clearance to be 3.32 liters/h/70 kg of body weight and volume to be 96.8 liters/70 kg for all patients, comparable to values reported in adults. We estimated a bioavailability of 89.6%, also consistent with adult data. Allometrically scaled clearance and volume of distribution did not differ between children 2 to ≤8 years of age and children >8 to ≤18 years of age, suggesting that younger children may be given the same per-kilogram dosing. Obesity status and fasting status were not selected for inclusion in the final model. Additional doxycycline PK samples collected in future studies may be used to improve model performance and maximize its clinical value.

scholarly journals Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers

2011 ◽  
Vol 55 (6) ◽  
pp. 2927-2936 ◽  
Author(s):  
J. B. Bulitta ◽  
M. Kinzig ◽  
C. B. Landersdorfer ◽  
U. Holzgrabe ◽  
U. Stephan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Healthy Volunteers ◽  
High Performance ◽  
Standard Dose ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Nonparametric Bootstrap ◽  
Population Pk ◽  
Total Body ◽  
Similar Body

ABSTRACTCystic fibrosis (CF) patients are often reported to have higher clearances and larger volumes of distribution per kilogram of total body weight (WT) for beta-lactams than healthy volunteers. As pharmacokinetic (PK) data on cefpirome from studies of CF patients are lacking, we systematically compared its population PK and pharmacodynamic breakpoints for CF patients and healthy volunteers of similar body size. Twelve adult CF patients (median lean body mass [LBM] = 45.7 kg) and 12 healthy volunteers (LBM = 50.0 kg) received a single 10-min intravenous infusion of 2 g cefpirome. Plasma and urine concentrations were determined by high-performance liquid chromatography (HPLC). Population PK and Monte Carlo simulations were performed using NONMEM and S-ADAPT and a duration of an unbound plasma concentration above the MIC ≥ 65% of the dosing interval as a pharmacodynamic target. Unscaled clearances for CF patients were similar to those seen with healthy volunteers, and the volume of distribution was 6% lower for CF patients. Linear scaling of total clearance by WT resulted in clearance that was 20% higher (P≤ 0.001 [nonparametric bootstrap]) in CF patients. Allometric scaling by LBM explained the differences between the two subject groups with respect to average clearance and volume of distribution and reduced the unexplained between-subject variability of renal and nonrenal clearance by 10 to 14%. For the CF patients, robust (>90%) probabilities of target attainment (PTA) were achieved by the administration of a standard dose of 2 g/70 kg WT every 12 h (Q12h) given as 30-min infusions for MICs ≤ 1.5 mg/liter. As alternative dosage regimens, a 5-h infusion of 1.33 g/70 kg WT Q8h achieved robust PTAs for MICs ≤ 8 to 12 mg/liter and a continuous infusion of 4 g/day for MICs ≤ 12 mg/liter. Prolonged infusion of cefpirome is expected to be superior to short-term infusions for MICs between 2 and 12 mg/liter.

scholarly journals Medication Dosage in Overweight and Obese Children

2017 ◽  
Vol 22 (1) ◽  
pp. 81-83 ◽  
Author(s):  
Kelly L. Matson ◽  
Evan R. Horton ◽  
Amanda C. Capino ◽  
Keyword(s):  
Hepatic Clearance ◽  
Position Statement ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Overweight Children ◽  
Obese Children ◽  
Patients Âgés ◽  
Adult Dose ◽  
Total Body ◽  
State Concentration

Approximately 31.8% of U.S. children ages 2 to 19 years are considered overweight or obese. This creates significant challenges to dosing medications that are primarily weight based (mg/kg) and in predicting pharmacokinetics parameters in pediatric patients. Obese individuals generally have a larger volume of distribution for lipophilic medications. Conversely, the Vd of hydrophilic medications may be increased or decreased due to increased lean body mass, blood volume, and decrease percentage of total body water. They may also experience decreased hepatic clearance secondary to fatty infiltrates of the liver. Hence, obesity may affect loading dose, dosage interval, plasma half-life, and time to reach steady-state concentration for various medications. Weight-based dosing is also a cause for potential medication errors. This position statement of the Pediatric Pharmacy Advocacy Group recommends that weight-based dosing should be used in patients ages < 18 years who are < 40 kg; weight-based dosing should be used in patients ≥ 40 kg, unless, unless the recommended adult dose for the specific indication is exceeded; clinicians should use pharmacokinetic analysis for adjusting medications in overweight/obese children; and research efforts continue to evaluate dosing of medications in obese/overweight children.

Vancomycin volume of distribution estimation in adults with class III obesity

2019 ◽  
Author(s):  
Ryan D Dunn ◽  
Ryan L Crass ◽  
Joseph Hong ◽  
Manjunath P Pai ◽  
Lynne C Krop
Keyword(s):  
Body Weight ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Patient Specific ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Parameter Estimates ◽  
Class Iii ◽  
Class Iii Obesity ◽  
Total Body

Abstract Purpose To compare methods of estimating vancomycin volume of distribution (V) in adults with class III obesity. Methods A retrospective, multicenter pharmacokinetic analysis of adults treated with vancomycin and monitored through measurement of peak and trough concentrations was performed. Individual pharmacokinetic parameter estimates were obtained via maximum a posteriori Bayesian analysis. The relationship between V and body weight was assessed using linear regression. Mean bias and root-mean-square error (RMSE) were calculated to assess the precision of multiple methods of estimating V. Results Of 241 patients included in the study sample, 159 (66.0%) had a BMI of 40.0–49.9 kg/m2, and 82 (34.0%) had a BMI of ≥50.0 kg/m2. The median (5th, 95th percentile) weight of patients was 136 (103, 204) kg, and baseline characteristics were similar between BMI groups. The mean ± S.D. V was lower in patients with a BMI of 40.0–49.9 kg/m2 than in those with a BMI of ≥50.0 kg/m2 (72.4 ± 19.6 L versus 79.3 ± 20.6 L, p = 0.009); however, body size poorly predicted V in regression analyses (R2 < 0.20). A fixed estimate of V (75 L) or use of 0.52 L/kg by total body weight yielded similar bias and error in this population. Conclusion Results of the largest analysis of vancomycin V in class III obesity to date indicated that use of a fixed V value (75 L) and use of a TBW-based estimate (0.52 L/kg) for estimation of vancomycin V in patients with a BMI of ≥40.0 kg/m2 have similar bias. Two postdistribution vancomycin concentrations are needed to accurately determine patient-specific pharmacokinetic parameters, estimate AUC, and improve the precision of vancomycin dosing in this patient population.

scholarly journals 1381. Impact of Total Body Weight on Efficacy of Ceftriaxone in Obese Patients

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S423-S423
Author(s):  
Jamie L Wagner ◽  
J Taylor Loper ◽  
Austin R Morrison ◽  
Kayla R Stover ◽  
Katie E Barber
Keyword(s):  
Treatment Failure ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Source Control ◽  
Causative Organism ◽  
Obese Patients ◽  
Discharge Disposition ◽  
Single Temperature ◽  
Total Body ◽  
Nonobese Patients

Abstract Background Ceftriaxone (CRO), while highly protein bound, retains a small volume of distribution. Obese patients have larger volumes of distributions and higher clearance than nonobese patients. The effect of these differences on the pharmacokinetics and efficacy of CRO remain unclear. Methods This retrospective cohort study included adult in-patients who received CRO for ≥72 hours as definitive monotherapy from July 2015 to July 2017. Patients were excluded if there was a lack of adequate source control at 72 hours or if there was a polymicrobial infection requiring multiple antibiotics. Obesity was defined as BMI ≥30 kg/m2. The primary outcome was clinical treatment failure, defined as changing therapy at &gt;72 hours due to clinical worsening, leukocytosis (WBC &gt; 10 × 109/L), fever (single temperature &gt;100.9°F) for &gt;72 hours, or readmission to the hospital within 30 days for re-infection. Secondary outcomes included discharge disposition and 30-day readmission. Results One hundred one patients were included: 39 obese patients and 62 nonobese patients. Median [IQR] age was 62 [51–70] years; 55% males. Median weight was 103 [95–120] kg in obese patients vs. 66 [58–77] kg in nonobese patients (P &lt; 0.001). There were no differences in comorbidities (Charlson 3[1–5] obese vs. 2[1–4] nonobese; P = 0.293). Infection sources were similar: urinary tract (54% obese vs. 52% nonobese; P = 0.827), respiratory (28% obese vs. 23% nonobese; P = 0.524), bloodstream (20% obese vs. 23% nonobese; P = 0.806). The most common causative organism was E. coli (48%). There were no differences in CRO regimen between groups (1g q24h: obese 54% vs. nonobese 69%; P = 0.115). Treatment failure occurred in 24 (61%) obese patients compared with 25(40%) nonobese patients (P = 0.038). Obese patients had delayed resolution of leukocytosis (54% vs. 29%, P = 0.013). Eight patients died (13% obese vs. 5% nonobese; P = 0.255); 82% of patients were not readmitted within 30 days. Conclusion Obese patients treated with ceftriaxone had higher rates of treatment failure compared with nonobese patients. While not statistically significant, there was numerically higher mortality in obese patients compared with nonobese patients. Obese patients may be slow to recover from infection when treated with CRO. Disclosures All authors: No reported disclosures.

Abstract 6273: Changes in Metabolic Parameters, Adiponectin, and High Sensitivity C-reactive Protein in South Asian Women Migrating to the United States: A 3-Year Follow-Up Study

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Anjali Arora ◽  
Aaditya Vora ◽  
Danny J Eapen ◽  
Bobby Khan
Keyword(s):  
Physical Activity ◽  
Diabetes Mellitus ◽  
South Asian ◽  
High Sensitivity ◽  
Total Body Weight ◽  
The United States ◽  
Asian Women ◽  
South Asian Women ◽  
Total Body

Background: The incidence of cardiovascular disease in South Asian women is increasing, both in native and migrant populations. The reasons for this finding may be in part related to changes in lifestyle and alterations in cultural behavior. Methods: We studied 301 healthy women (average age 28) recently migrated to the United States from the South Asian countries of India, Bangladesh, Pakistan, and Sri Lanka within 3 months of the time of arrival and at 3 years (31– 41 months) following their arrival. A questionnaire regarding activities pertaining to diet, physical activity, and socioeconomic status was performed. Measurements included changes in blood pressure (BP), total body weight, lipids, glucose, and determinations of high sensitivity CRP (hsCRP) and adiponectin from frozen serum specimen at these time points. Results: In this diverse population, subjects reported an increase in food intake (including added salt and fat quantities) and no overall change in physical activity. Accordingly, there was a significant increase in total body weight after a 3 year period (119.7±14.4 to 127.9±15.3 pounds, p<0.005). There was a significant increase in serum LDL cholesterol (103.8±17.6 to 111.0±15.9 mg/dl, p=0.018), triglycerides (136.1±25.3 to 157.5±20.0 mg/dl, p=0.023), and glycosylated hemoglobin (4.9±0.7 to 5.3±0.6%, p=0.029). Moreover, the prevalence of diabetes mellitus (fasting glucose>125 mg/dl) increased from 3.3 to 9.7% in the 3-year follow-up period. There was an increase in serum hsCRP (1.80±0.19 to 2.05±0.18 mg/l, p=0.010) and a decrease in serum adiponectin (10.8±0.9 to 9.5±1.0 mg/l, p=0.022) in these subjects. Conclusions: The population of South Asian women is at increased risk for cardiovascular disease and diabetes mellitus. Changes in lifestyle, including dietary intake and physical activity, affect parameters that may be crucial in the pathogenesis of these disease states.

Sulfamethazine Water Medication Pharmacokinetics and Contamination in a Commercial Pig Production Unit

2008 ◽  
Vol 71 (3) ◽  
pp. 584-589 ◽  
Author(s):  
SHARON E. MASON ◽  
RONALD E. BAYNES ◽  
JENNIFER L. BUUR ◽  
JIM E. RIVIERE ◽  
GLEN W. ALMOND
Keyword(s):  
Plasma Levels ◽  
Pharmacokinetic Model ◽  
The United States ◽  
Volume Of Distribution ◽  
Model Parameters ◽  
Physiologically Based Pharmacokinetic Model ◽  
Swine Industry ◽  
Initial Exposure ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Sulfamethazine is often used to treat disease in the swine industry. Sulfamethazine is available as water or feed medication and historically (over the past 40 years) has been associated with residue violations in both the United States and Europe. Despite sulfamethazine's approval for use as a water medication, little research on the pharmacokinetics of the water formulation is available. Therefore, a pilot study was performed to determine the plasma levels of an approved sulfamethazine water medication. Plasma levels in pigs treated with an oral bolus (250 mg/kg), which is equivalent to the total drug consumed within a 24-h period, achieved therapeutic concentrations (50 μg/ml). Noncompartmental-based pharmacokinetic model parameters for clearance, half-life, and volume of distribution were consistent with previously published values in swine. However, the above treatment resulted in exposure of pen mates to sulfamethazine at levels currently above tolerance (0.1 ppm). Using a physiologically based pharmacokinetic model, the treatment dose simulation was compared with observed plasma levels of treated pigs. Flexibility of the physiologically based pharmacokinetic model also allowed simulation of control-pig plasma levels to estimate contamination exposure. A simulated exposure to 0.15 mg/kg twice within approximately 8 h resulted in detectable levels of sulfamethazine in the control pigs. After initial exposure, a much lower dose of 0.059 mg/kg maintained the contamination levels above tolerance for at least 3 days. These results are of concern for producers and veterinarians, because in commercial farms, the entire barn is often treated, and environmental contamination could result in residues of an unknown duration.

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