Clinical pharmacokinetics of valproic acid in children with seizures. Plasma concentration data analysis by the Bayesian method.

Abstract Background The aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies. Methods We conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens. Results Plasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95–5.92] L h− 1 and central volume of distribution of 4.29 [1.81–7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7–25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall. Conclusion A dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude.

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Valproic Acid Plasma Concentration Decreases in a Dose-Independent Manner Following Administration of Meropenem: A Retrospective Study

The Journal of Clinical Pharmacology ◽

10.1177/0091270009334377 ◽

2009 ◽

Vol 49 (11) ◽

pp. 1363-1369 ◽

Cited By ~ 37

Author(s):

Simon Haroutiunian ◽

Yael Ratz ◽

Bella Rabinovich ◽

Miriam Adam ◽

Amnon Hoffman

Keyword(s):

Valproic Acid ◽

Retrospective Study ◽

Plasma Concentration ◽

Independent Manner

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A Numerical Bayesian Approach to Spatial Data Analysis

Calcutta Statistical Association Bulletin ◽

10.1177/0008068319970305 ◽

1997 ◽

Vol 47 (3-4) ◽

pp. 181-198

Author(s):

Indranil Mukherjee ◽

Himadri Ghosh ◽

Aditya Chatterjee

Keyword(s):

Data Analysis ◽

Gibbs Sampling ◽

Bayesian Approach ◽

Spatial Data ◽

Bayesian Method ◽

Spatial Data Analysis ◽

Scientific Investigations ◽

Sampling Approach

Investigators in diverse fields of scientific investigations (specially the geo-statisticians) have long been concerned with the so called Regionalised Variable (ReV) or variables whose values are in some way related to their positions in space. In such situations it becomes sometimes necessary to estimate the values for certain measures based on the ReV over some suitable blocking or redivision of the space. In thls paper we deliniate a numerical Bayesian method based on the Gibbs sampling approach towards solving this class of problems whlch is capable of being tuned to various situations arising in the geological and other investigations dealing with ReVs. The paper deals with the problem of estimating the volume of an accumulation, from a data comprising of heights of the accumulation at random points, in some details and also reports the results of a few numerical applications of the methodology developed.

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Are Plasma Concentration Values Necessary for Pharmacodynamic Modeling of Muscle Relaxants?

Anesthesiology ◽

10.1097/00000542-199703000-00008 ◽

1997 ◽

Vol 86 (3) ◽

pp. 567-575 ◽

Cited By ~ 19

Author(s):

Dennis M. Fisher ◽

Peter M. C. Wright

Keyword(s):

Plasma Concentration ◽

Traditional Approach ◽

Muscle Relaxants ◽

Adductor Pollicis ◽

Pharmacodynamic Modeling ◽

Concentration Data ◽

Mechanical Responses ◽

Drug Concentrations ◽

Train Of Four ◽

The Hill

Background The traditional approach to pharmacokinetic/ pharmacodynamic modeling of muscle relaxants requires sampling of plasma to determine drug concentrations. The authors recently proposed that certain pharmacodynamic characteristics (IR50, the steady-state infusion rate to maintain 50% twitch depression; keo, the rate constant for equilibration between plasma concentration and effect; and gamma, the Hill factor describing sigmoidicity of the concentration-effect relation) could be estimated without plasma concentration data. Here estimates for IR50, keo, and gamma determined with and without plasma concentration data are compared. Methods Six volunteers were given 15-60 micrograms/kg vecuronium on each of two occasions during anesthesia with propofol. Mechanical responses to train-of-four stimulation were measured at the adductor pollicis and at the laryngeal adductors. Various pharmacokinetic models accounting for the presence and potency of vecuronium's 3-desacetyl metabolite and a sigmoid e-max pharmacodynamic model were fit to the resulting plasma concentration and effect (adductor pollicis and laryngeal adductors) data to determine IR50 keo, and gamma for each effect. One model related dose to effect without plasma concentration data. Results Values for IR50(adductor pollicis), IR50(laryngeal adductors), gamma (adductor pollicis), and gamma (laryngeal adductors) were similar when determined with and without plasma concentration values. Values for keo (adductor pollicis) and keo (laryngeal adductors) were larger when determined without plasma concentration values compared with those determined with these values; however, the ratio of keo (adductor pollicis) to keo(laryngeal adductors) was similar when determined with and without plasma concentration values. Conclusions Certain pharmacodynamic parameters were estimated accurately in the absence of plasma concentration values. This suggests limited utility for plasma concentration data under conditions similar to those of the present study.

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Levetiracetam compared to valproic acid: Plasma concentration levels, adverse effects and interactions in aneurysmal subarachnoid hemorrhage

Clinical Neurology and Neurosurgery ◽

10.1016/j.clineuro.2011.05.007 ◽

2011 ◽

Vol 113 (8) ◽

pp. 644-648 ◽

Cited By ~ 14

Author(s):

S. Mink ◽

C. Muroi ◽

M. Seule ◽

M. Bjeljac ◽

E. Keller

Keyword(s):

Valproic Acid ◽

Subarachnoid Hemorrhage ◽

Plasma Concentration ◽

Adverse Effects ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Concentration Levels

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Clinical Rules for Phenytoin Dosing

Annals of Pharmacotherapy ◽

10.1177/106002809302701001 ◽

1993 ◽

Vol 27 (10) ◽

pp. 1169-1173 ◽

Cited By ~ 10

Author(s):

Michael D. Privitera

Keyword(s):

Plasma Concentration ◽

Plasma Concentrations ◽

Test Group ◽

Patient Data ◽

Pharmacokinetic Parameters ◽

Concentration Data ◽

Simple Method ◽

Actual Patient ◽

Initial Plasma ◽

Clinical Rules

OBJECTIVE: To develop simple clinical rules for dosing phenytoin (PHT) using computer simulations, then to test the rules for accuracy and safety on actual patient data. DESIGN: Patients with steady-state PHT plasma concentrations at least two different PHT doses were identified from three separate sources of patient data. A computerized dosing program calculated pharmacokinetic parameters using Bayesian methodology, then predicted how many patients were likely to reach potentially toxic PHT plasma concentrations when their daily dosage was increased by 30, 50, or 100 mg. Dosing rules were developed to allow fewer than ten percent of resultant plasma concentrations to exceed 25 μg/mL. The dosing rules then were tested on dose/plasma concentration data from a separate group of patients. SETTING: All patients were being treated by neurologists either as outpatients or inpatients. PATIENTS: All patients were adults with epilepsy being treated with PHT; none had clinically significant renal or hepatic disease. Patients for the computer simulation were from three sources: (1) patients who had an initial PHT plasma concentration <10 μg/mL and required a dosage increase; (2) patients admitted to the hospital for PHT intoxication; and (3) patients who required consultations specifically for PHT dosing. Patients on whom the dosing rules were tested were part of a prospective, randomized trial of antiepileptic drug safety and efficacy. MAIN OUTCOME MEASURES: Successful dosing rules allowing fewer than ten percent of resulting plasma concentrations in the test group to exceed 25 μg/mL. RESULTS: The simulations used 167 actual dose/plasma concentration pairs from 45 patients. The resulting dosing rules were: increase the dosage by 100 mg/d if the initial plasma concentration was <7 μg/mL; increase the dosage by 50 mg/d if the initial plasma concentration is 7 to <12 μg/mL; increase the dosage by 30 mg/d if the initial plasma concentration is ≥12 μg/mL. The rules were tested on 129 50- or 100-mg dosage increases in 77 patients. All 53 dosage increases that were within the dosing rules produced plasma concentrations <25 μg/mL, whereas 36 percent (27 of 74) of the dosage increases that exceeded the dosing rules produced plasma concentrations >25 μg/mL. CONCLUSIONS: The proposed dosing rules are a simple method for clinicians to estimate PHT dosage changes and appear to be safe and accurate when applied retrospectively to actual patient data.

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