scholarly journals Population Pharmacokinetic Parameter Estimates using a Limited Sampling Design: Analysis of Blood Alcohol Levels

2016 ◽  
Vol 16 (0) ◽  
pp. 25-39
Author(s):  
Asuka Nemoto ◽  
Masaaki Matsuura ◽  
Kazue Yamaoka
Keyword(s):  
Pharmacokinetic Parameter ◽  
Sampling Design ◽  
Design Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Blood Alcohol ◽  
Population Pharmacokinetic Parameter ◽  
Limited Sampling ◽  
Blood Alcohol Levels

Development and validation of a pharmacokinetically based fixed dosing scheme for suramin.

1995 ◽  
Vol 13 (9) ◽  
pp. 2187-2195 ◽  
Author(s):  
L M Reyno ◽  
M J Egorin ◽  
M A Eisenberger ◽  
V J Sinibaldi ◽  
E G Zuhowski ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Specific Antigen ◽  
Elevated Serum ◽  
Test Dose ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Dosing Schedule ◽  
Population Pharmacokinetic Parameter ◽  
Hormone Refractory ◽  
Development And Validation

PURPOSE We used population pharmacokinetic-parameter estimates and designed a fixed dosing schedule to maintain plasma suramin concentrations between 100 and 300 micrograms/mL and then evaluated its performance. MATERIALS AND METHODS On day 1, patients received a 200-mg test dose and 1,000-mg/m2 loading dose. On days 2, 3, 4, and 5, patients received 1-hour infusions of 400, 300, 250, and 200 mg/m2, respectively. Subsequent 1-hour infusions of 275 mg/m2 were given on days 8, 11, 15, 19, 22, 29, 36, 43, 50, 57, 67, and 78. Therapy was discontinued for dose-limiting toxicity (DLT) or progressive disease (PD). Patients were to be removed from the fixed dosing schedule if, after day 5, three consecutive peak plasma suramin concentrations were greater than 300 micrograms/mL. RESULTS Forty-two patients, including 40 with hormone-refractory prostate cancer (HRPC), received 700 infusions. Forty patients were assessable for toxicity; 38 were assessable for response. Two patients with preexisting pulmonary disease died early of respiratory insufficiency. Treatment was discontinued in five patients due to DLT and in seven due to PD. No patient had treatment discontinued due to repeated peak plasma suramin concentrations > or = 300 micrograms/mL. The fixed dosing schedule was precise, unbiased, and well tolerated. DLT consisted of grade 4 nephrotoxicity (n = 2), neurotoxicity (n = 2), and corticosteroid-induced psychosis (n = 1). Three patients, who received all 18 doses of suramin per protocol, developed severe, but not dose-limiting, malaise, fatigue, and lethargy. Twenty-four of 36 assessable patients with elevated serum prostate-specific antigen (PSA) levels had a > or = 50% reduction, lasting more than 4 weeks, and 18 had a > or = 75% reduction, lasting more than 4 weeks. Twelve of 23 (52%) symptomatic HRPC patients noted a subjective improvement in pain. There were no measurable responses in four patients with measurable disease. The estimated median survival time in 38 assessable patients with HRPC was 18.8 months. The estimated median time to progression in 35 patients, for whom data were available, was 10.1 months. CONCLUSION This easily implemented schedule allowed suramin to be administered safely as an intermittent bolus injection. Toxicity was manageable and reversible.

Population Pharmacokinetics: Development of a Medical Intensive Care Unit-Specific Gentamicin Dosing Nomogram

1993 ◽  
Vol 27 (2) ◽  
pp. 151-154 ◽  
Author(s):  
Sharon M. Watling ◽  
David F. Kisor
Keyword(s):  
Pharmacokinetic Parameter ◽  
Patient Specific ◽  
Population Pharmacokinetic ◽  
Population Parameter ◽  
Population Pharmacokinetic Parameter ◽  
Actual Patient ◽  
Medical Intensive Care ◽  
Gentamicin Therapy ◽  
Parameter Values ◽  
Dosing Nomogram

Objective This study was designed to develop a population-specific dosing nomogram for gentamicin in medical intensive care unit (MICU) patients using the population pharmacokinetic program nonparametric expectation maximization (NPEM). Design Observational clinical gentamicin dosing data were collected, entered into the USC*PACK database program PASTRX, and downloaded into the population pharmacokinetic program NPEM. NPEM generated population pharmacokinetic parameter values that were used to develop a gentamicin dosing nomogram. The nomogram was tested in the next 15 patients admitted to MICU to determine accuracy. Doses given per the MICU and the Hull-Sarubbi nomograms were compared with doses based on actual patient-specific pharmacokinetic parameter values. Reliability coefficients (intraclass correlation coefficients) were calculated to assess the agreement between observations. Setting Data were gathered from patients receiving gentamicin therapy in the MICU, Presbyterian University Hospital, Pittsburgh. Patients Baseline population pharmacokinetic parameter values were determined in 36 MICU patients receiving gentamicin therapy. Patients with renal failure receiving hemodialysis or another mechanical method of blood clearance or fluid removal were excluded. The population parameter values in the form of a dosing nomogram were then used prospectively to dose gentamicin in 15 patients. Results NPEM generated population parameter values similar to those previously published using the Sawchuk-Zaske method in ICU patients. The mean volume of distribution generated using NPEM was 0.34 ± 0.12 L/kg. The relationship between creatinine clearance (Clcr) and elimination rate constant (Ke) was: Ke = 0.00218 x Clcr + 0.007. The nomogram-derived doses correlated with doses determined by using actual patient-specific pharmacokinetic values (p<0.05). The Hull-Sarubbi derived doses, however, did not correlate with patient-specific doses (p>0.05). Only one patient had a peak concentration <6 mg/L. Two of 15 patients had trough concentrations prior to the first maintenance dose >2 mg/L. Conclusions The use of NPEM to generate population-specific pharmacokinetic parameter values has been previously described. Application of population-specific dosing nomograms can improve initial dosing regimens such that conventional therapeutic concentrations can be achieved early in therapy. This nomogram, however, does not preclude follow-up patient-specific pharmacokinetic analysis.

Blood Alcohol Levels Following Attempted Suicide

1963 ◽  
Vol 24 (1) ◽  
pp. 14-22 ◽  
Author(s):  
I. Pierce James ◽  
D. N. Scott-Orr ◽  
D. H. Curnow
Keyword(s):  
Attempted Suicide ◽  
Blood Alcohol ◽  
Blood Alcohol Levels

High Blood Alcohol Levels in Women

1990 ◽  
Vol 322 (2) ◽  
pp. 95-99 ◽  
Author(s):  
Mario Frezza ◽  
Carlo di Padova ◽  
Gabriele Pozzato ◽  
Maddalena Terpin ◽  
Enrique Baraona ◽  
...  
Keyword(s):  
Blood Alcohol ◽  
Blood Alcohol Levels

Validation of the Alco-Calculator

1975 ◽  
Vol 36 (3) ◽  
pp. 977-978 ◽  
Author(s):  
John V. Compton ◽  
Roger E. Vogler
Keyword(s):  
Confidence Interval ◽  
Blood Alcohol Concentration ◽  
Alcohol Concentration ◽  
Blood Alcohol ◽  
Blood Alcohol Levels

The Alco-calculator was validated by comparing its blood alcohol estimates with actual breath samples (N = 48). The Alco-calculator overestimated the blood alcohol concentration by 20 mg % and showed an accuracy confidence interval of ± 26 mg.% ( p = .95) The utility of the calculator for training in discrimination of blood alcohol levels is discussed.

scholarly journals 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S670-S671
Author(s):  
Ronald G Hall ◽  
Jotam Pasipanodya ◽  
William C Putnam ◽  
John Griswold ◽  
Sharmila Dissanaike ◽  
...  
Keyword(s):  
Human Plasma ◽  
Kidney Injury ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Population Parameter ◽  
Full Thickness ◽  
Severe Burns

Abstract Background Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed. Methods A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested. Results The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B). A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities Summary of pharmacokinetic parameters Conclusion C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities. Disclosures Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support)

scholarly journals Ethanol-Related Behaviors in Mouse Lines Selectively Bred for Drinking to Intoxication

2021 ◽  
Vol 11 (2) ◽  
pp. 189
Author(s):  
Bryan E. Jensen ◽  
Kayla G. Townsley ◽  
Kolter B. Grigsby ◽  
Pamela Metten ◽  
Meher Chand ◽  
...  
Keyword(s):  
Drinking Behavior ◽  
Effective Means ◽  
Fixed Ratio ◽  
Progressive Ratio ◽  
Blood Alcohol ◽  
Drinking Patterns ◽  
Self Administration ◽  
Blood Alcohol Levels ◽  
Drinking In The Dark ◽  
Mouse Lines

Alcohol use disorder (AUD) is a devastating psychiatric disorder that has significant wide-reaching effects on individuals and society. Selectively bred mouse lines are an effective means of exploring the genetic and neuronal mechanisms underlying AUD and such studies are translationally important for identifying treatment options. Here, we report on behavioral characterization of two replicate lines of mice that drink to intoxication, the High Drinking in the Dark (HDID)-1 and -2 mice, which have been selectively bred (20+ generations) for the primary phenotype of reaching high blood alcohol levels (BALs) during the drinking in the dark (DID) task, a binge-like drinking assay. Along with their genetically heterogenous progenitor line, Hs/Npt, we tested these mice on: DID and drinking in the light (DIL); temporal drinking patterns; ethanol sensitivity, through loss of righting reflex (LORR); and operant self-administration, including fixed ratio (FR1), fixed ratio 3:1 (FR3), extinction/reinstatement, and progressive ratio (PR). All mice consumed more ethanol during the dark than the light and both HDID lines consumed more ethanol than Hs/Npt during DIL and DID. In the dark, we found that the HDID lines achieved high blood alcohol levels early into a drinking session, suggesting that they exhibit front loading like drinking behavior in the absence of the chronicity usually required for such behavior. Surprisingly, HDID-1 (female and male) and HDID-2 (male) mice were more sensitive to the intoxicating effects of ethanol during the dark (as determined by LORR), while Hs/Npt (female and male) and HDID-2 (female) mice appeared less sensitive. We observed lower HDID-1 ethanol intake compared to either HDID-2 or Hs/Npt during operant ethanol self-administration. There were no genotype differences for either progressive ratio responding, or cue-induced ethanol reinstatement, though the latter is complicated by a lack of extinguished responding behavior. Taken together, these findings suggest that genes affecting one AUD-related behavior do not necessarily affect other AUD-related behaviors. Moreover, these findings highlight that alcohol-related behaviors can also differ between lines selectively bred for the same phenotype, and even between sexes within those same line.

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