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- Chermá, Maria D., et al.
(author)
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Methylphenidate for Treating ADHD : A Naturalistic Clinical Study of Methylphenidate Blood Concentrations in Children and Adults With Optimized Dosage.
- 2017
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In: European journal of drug metabolism and pharmacokinetics. - : Springer Science and Business Media LLC. - 0378-7966 .- 2107-0180. ; 42:2, s. 295-307
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Journal article (peer-reviewed)abstract
- BACKGROUND: Methylphenidate (MPH), along with behavioral and psychosocial interventions, is the first-line medication to treat attention-deficit hyperactivity disorder (ADHD) in Sweden. The dose of MPH for good symptom control differs between patients. However, studies of MPH concentration measurement in ADHD treatment are limited.OBJECTIVE: To describe blood and oral fluid (OF) concentrations of MPH after administration of medication in patients with well-adjusted MPH treatment for ADHD, and to identify the most suitable matrix for accurate MPH concentration during treatment.METHODS: Patients were recruited from Child and Adolescent Psychiatry (CAP), General Psychiatry (GP), and the Department of Dependency (DD). Blood and OF samples were collected in the morning before MPH administration as well as 1 and 6 h after administration of the prescribed morning dose of MPH.RESULTS: Fifty-nine patients aged between 9 and 69 years, 76 % males. The daily dose of MPH varied from 18 to 180 mg, but the median daily dose per body weight was similar, approximately 1.0 mg/kg body weight. The median MPH concentration in blood 1 and 6 h after the morning dose was 5.4 and 9.3 ng/mL, respectively. Highly variable OF-to-blood ratios for MPH were found at all time points for all three groups.CONCLUSIONS: Weight is a reliable clinical parameter for optimal dose titration. Otherwise, MPH blood concentration might be used for individual dose optimization and for monitoring of the prescribed dose. Relying only on the outcome in OF cannot be recommended for evaluation of accurate MPH concentrations for treatment monitoring.
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- De Winter, Sabrina, et al.
(author)
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Quantification and Explanation of the Variability of First-Dose Amikacin Concentrations in Critically Ill Patients Admitted to the Emergency Department : A Population Pharmacokinetic Analysis
- 2021
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In: European journal of drug metabolism and pharmacokinetics. - : Springer Nature. - 0378-7966 .- 2107-0180. ; 46, s. 653-663
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Journal article (peer-reviewed)abstract
- Background: There may be a difference between the determinants of amikacin exposure in emergency department (ED) versus intensive care (ICU) patients, and the peak amikacin concentration varies widely between patients. Moreover, when the first dose of antimicrobials is administered to septic patients admitted to the ED, fluid resuscitation and vasopressors have just been initiated. Nevertheless, population pharmacokinetic modelling data for amikacin in ED patients are unavailable.Objective: The aim of this study was to quantify the interindividual variability (IIV) in the pharmacokinetics of amikacin in patients admitted to the ED and to identify the patient characteristics that explain this IIV.Methods: Patients presenting at the ED with severe sepsis or septic shock were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg intravenously. Blood samples were collected at 1, 6 and 24 h after the onset of the first amikacin infusion. Data were analysed using nonlinear mixed-effects modelling.Results: A two-compartment population pharmacokinetic model was developed based on 279 amikacin concentrations from 97 patients. The IIV in clearance (CL) and central distribution volume (V-1) were 71% and 26%, respectively. Body mass index (BMI), serum total protein level, serum sodium level, and fluid balance 24 h after amikacin administration explained 30% of the IIV in V-1, leaving 18% of the IIV unexplained. BMI and creatinine clearance according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 24 h after amikacin administration explained 46% of the IIV in CL, and 39% remained unexplained.Conclusion: The IIV of amikacin pharmacokinetics in ED patients is large. Higher doses may be considered in patients with low serum sodium levels, low total protein levels, or a high fluid balance.
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- Gupta, S, et al.
(author)
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In vitro evidence for auto-induction of artemisinin metabolism in the rat.
- 2001
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In: European journal of drug metabolism and pharmacokinetics. - 0378-7966. ; 26:3, s. 173-8
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Journal article (peer-reviewed)abstract
- Artemisinin disappearance rate was more rapid in incubations with liver microsomes from rats pre-treated with oral artemisinin (60 mg/kg/day for 5 days) compared with microsomes from control animals. A single pathway Michaelis-Menten saturable elimination model was fitted to the concentration-time data of artemisinin incubations by non-linear regression. Model parameters were obtained after fitting results for each animal separately and by pooling data for pre-treated and control animals. Parameter estimates (% coefficient of variation) from fitting the pooled data was maximum velocities (Vmax) = 1.8 (12) mmole/min/mg protein and Michaelis constants (Km) = 20(22) microM for artemisinin pre-treated and Vmax = 0.85 (35) mmole/min/mg protein and Km = 67(52) microM for control animals indicating a 2-fold increase in Vmax and a 3-fold decrease in Km with microsomes from artemisinin pre-treated animals. Estimates of intrinsic clearance in microsomes from the pre-treated animals were 8-fold higher compared with controls. Thus, artemisinin appears to be a potent auto-inducer of drug metabolism in rats as has also been observed in humans. The present findings suggest caution in the interpretation of repeat-dose rat toxicity studies with artemisinin unless its pharmacokinetics are simultaneously monitored, since during multiple administration, the exposure of the drug will not be constant over time.
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- Gupta, S, et al.
(author)
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In vitro evidence for auto-induction of artemisinin metabolism in the rat
- 2001
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In: European journal of drug metabolism and pharmacokinetics. - 0378-7966 .- 2107-0180. ; 26:3, s. 173-178
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Journal article (peer-reviewed)abstract
- Artemisinin disappearance rate was more rapid in incubations with liver microsomes from rats pre-treated with oral artemisinin (60 mg/kg/day for 5 days) compared with microsomes from control animals. A single pathway Michaelis-Menten saturable elimination model was fitted to the concentration-time data of artemisinin incubations by non-linear regression. Model parameters were obtained after fitting results for each animal separately and by pooling data for pre-treated and control animals. Parameter estimates (% coefficient of variation) from fitting the pooled data was maximum velocities (V-max) = 1.8 (12) mmole/min/mg protein and Michaelis constants (K-m) = 20 (22) muM for artemisinin pre-treated and V-max = 0.85 (35) mmole/min/mg protein and K-m = 67 (52) muM for control animals indicating a 2-fold increase in V-max and a 3-fold decrease in Km with microsomes from artemisinin pre-treated animals. Estimates of intrinsic clearance in microsomes from the pre-treated animals were 8-fold higher compared with controls. Thus, artemisinin appears to be a potent auto-inducer of drug metabolism in rats as has also been observed in humans. The present findings suggest caution in the interpretation of repeat-dose rat toxicity studies with artemisinin unless its pharmacokinetics are simultaneously monitored, since during multiple administration, the exposure of the drug will not be constant over time.
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- Jakobsson, Gerd, 1981-, et al.
(author)
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Oxycodone-Related Deaths : The Significance of Pharmacokinetic and Pharmacodynamic Drug Interactions
- 2022
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In: European journal of drug metabolism and pharmacokinetics. - : Springer France. - 0378-7966 .- 2107-0180. ; 47, s. 259-270
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Journal article (peer-reviewed)abstract
- Background and Objectives Oxycodone is frequently prescribed as well as detected in postmortem cases. Concurrent use of pharmacodynamically or pharmacokinetically interacting drugs can cause adverse effects or even fatal intoxication. The aims of this study were to investigate differences in prescriptions for and toxicological findings of pharmacodynamically and pharmacokinetically interacting drugs in fatal oxycodone-related intoxications and other causes of death. We also aimed to investigate the differences in prevalence of oxycodone prescriptions, and the detected postmortem oxycodone concentrations between fatal oxycodone-related intoxications and other causes of death. Methods Forensic autopsy cases (2012-2018) where oxycodone was identified in femoral blood (n = 1236) were included. Medical history and prescription data were retrieved from national databases and linked to the forensic toxicology findings. Results Oxycodone-related deaths were found to have higher blood concentrations of oxycodone (median 0.30 mu g/g vs. 0.05 mu g/g) and were less likely to have a prescription for oxycodone (OR 0.62) compared to nonintoxication deaths. Pharmacodynamically interacting drugs were prescribed in 79% and found in blood in 81% of the cases. Pharmacokinetically interacting drugs were rarely prescribed (1%). Oxycodone-related deaths were more likely to have prescriptions for a pharmacodynamically interacting drug (OR 1.7) and more often have co-findings of one or multiple pharmacodynamically interacting drugs (OR 5.6). Conclusion The results suggest that combined use of oxycodone and pharmacodynamically interacting drugs is associated with oxycodone-related death and that non-medical use of oxycodone is a potential risk factor for oxycodone-related intoxication.
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- Saqlain, Murshid, et al.
(author)
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Investigating Stochastic Differential Equations Modelling for Levodopa Infusion in Patients with Parkinson's Disease
- 2020
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In: European journal of drug metabolism and pharmacokinetics. - : Springer Science and Business Media LLC. - 0378-7966 .- 2107-0180. ; 45:1, s. 41-49
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Journal article (peer-reviewed)abstract
- BACKGROUND AND OBJECTIVES: Levodopa concentration in patients with Parkinson's disease is frequently modelled with ordinary differential equations (ODEs). Here, we investigate a pharmacokinetic model of plasma levodopa concentration in patients with Parkinson's disease by introducing stochasticity to separate the intra-individual variability into measurement and system noise, and to account for auto-correlated errors. We also investigate whether the induced stochasticity provides a better fit than the ODE approach.METHODS: In this study, a system noise variable is added to the pharmacokinetic model for duodenal levodopa/carbidopa gel (LCIG) infusion described by three ODEs through a standard Wiener process, leading to a stochastic differential equations (SDE) model. The R package population stochastic modelling (PSM) was used for model fitting with data from previous studies for modelling plasma levodopa concentration and parameter estimation. First, the diffusion scale parameter (σw), measurement noise variance, and bioavailability are estimated with the SDE model. Second, σw is fixed to certain values from 0 to 1 and bioavailability is estimated. Cross-validation was performed to compare the average root mean square errors (RMSE) of predicted plasma levodopa concentration.RESULTS: Both the ODE and the SDE models estimated bioavailability to be approximately 75%. The SDE model converged at different values of σw that were significantly different from zero. The average RMSE for the ODE model was 0.313, and the lowest average RMSE for the SDE model was 0.297 when σw was fixed to 0.9, and these two values are significantly different.CONCLUSIONS: The SDE model provided a better fit for LCIG plasma levodopa concentration by approximately 5.5% in terms of mean percentage change of RMSE.
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