Biomedical subjects

Meindert Danhof

Publications and source records attributed to Meindert Danhof.

59 records · Page 4Linked to original sources

PubMed2002

Population pharmacokinetic and pharmacodynamic modeling of propofol for long-term sedation in critically ill patients: a comparison between propofol 6% and propofol 1%.

OBJECTIVES: A population pharmacokinetic and pharmacodynamic model of propofol for long-term sedation in critically ill patients is described, because limited information is available in these patients. In the models the influence of time-independent covariates, in particular, the propofol formulation (propofol 6% versus propofol 1%), and of time-dependent covariates was investigated. METHODS: Twenty critically ill, mechanically ventilated patients received propofol formulated as propofol 6% (n = 10) or propofol 1% (n = 10) during a 2- to 5-day period. The level of sedation was assessed with the Ramsay 6-point scale. The data from a short-term sedation study in 24 patients after cardiac surgery were included. Population pharmacokinetic and pharmacodynamic modeling was performed with NONMEM. RESULTS: The pharmacokinetics was adequately described by a 2-compartment model. The propofol formulation was not a significant covariate for the pharmacokinetics, whereas serum triglyceride concentration (TG) and relative body temperature (T(c)) were significant covariates for elimination clearance (CL). The population pharmacokinetic parameters were as follows: CL = 2.2 + 0.27 x T(c) - 0.049 x TG (mean, 2.1 L/min); volume of central compartment, 22.2 L; CL (distribution), 1.5 L/min; and volume of peripheral compartment, 168 L. The addition of other time-independent covariates (long-term versus short-term sedation study, as well as physiologic characteristics) or time-dependent covariates (duration of propofol infusion, additional midazolam rates, and hemodynamic parameters) to the model did not improve the quality of fit. For the pharmacodynamics, the probability that the sedation level was equal to, or more than, a specific score was described with the use of a sigmoid inverse logit of the maximal achievable probability model. The values for the inverse logit of the concentration causing half of the maximal effect for Ramsay sedation scores of 2 through 6 were 0.13 +/- 0.09, 0.31 +/- 0.17, 0.56 +/- 0.24, 0.79 +/- 0.31, and 1.78 +/- 0.65 mg/L, respectively (population mean +/- SE). Interindividual variability was high, with a coefficient of variation of 119% in the 50% effective concentration values. No covariates were identified. CONCLUSIONS: The population models in critically ill patients showed no differences in pharmacokinetics or pharmacodynamics between propofol 6% and propofol 1%. TG and T(c) appeared to be significant covariates for elimination clearance. For the pharmacodynamics, when propofol concentrations were between 0.75 and 1.5 mg/L, Ramsay sedation score 6 was most probable (40%-75%) and the probability for Ramsay sedation score 5 was 20% to 40%. Large pharmacodynamic variabilities were observed.

APACHE↗

PubMed2002

Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats.

The objective of this investigation was to compare the in vivo potency and intrinsic activity of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in rats by pharmacokinetic-pharmacodynamic modeling. Following intravenous administration of buspirone (5 or 15 mg/kg in 15 min) or 1-PP (10 mg/kg in 15 min), the time course of the concentrations in blood were determined in conjunction with the effect on body temperature. The pharmacokinetics of buspirone and 1-PP were analyzed based on a two-compartment model with metabolite formation. Differences in the pharmacokinetics of buspirone and 1-PP were observed with values for clearance of 13.1 and 8.2 ml/min and for terminal elimination half-life of 25 and 79 min, respectively. At least 26% of the administered dose of buspirone was converted into 1-PP. Complex hypothermic effects versus time profiles were observed, which were successfully analyzed on the basis of a physiological indirect response model with set-point control. Both buspirone and 1-PP behaved as partial agonists relative to R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) with values of the intrinsic activity of 0.465 and 0.312, respectively. Differences in the potency were observed with values of 17.6 and 304 ng/ml for buspirone and 1-PP, respectively. The results of this analysis show that buspirone and 1-PP behave as partial 5-hydroxytryptamine(1A) agonists in vivo and that following intravenous administration the amount of 1-PP formed is too small to contribute to the hypothermic effect.

Animals↗

PubMed2002

A competitive interaction model predicts the effect of WAY-100,635 on the time course of R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin-induced hypothermia.

The objective of this investigation was to characterize quantitatively the pharmacodynamic interaction between N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide (WAY-100,635) and R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) in vivo. The 8-OH-DPAT-induced change in body temperature was used as a pharmacodynamic endpoint. Four groups of rats each received 1 mg/kg 8-OH-DPAT in 5 min during computer-controlled infusions of physiological saline or WAY-100,635, targeted at steady-state concentrations of 20, 85, and 170 ng/ml. Body temperature was monitored continuously with a telemetric system, and frequent blood samples were obtained to determine the pharmacokinetics of both drugs. Large differences in pharmacokinetics were observed between WAY-100,635 and R-8-OH-DPAT, reflected in values of the terminal elimination half-life of 33 and 143 min, respectively. Infusion of WAY-100,635 had no influence on the pharmacokinetics of R-8-OH-DPAT. With regard to the pharmacodynamics, clear antagonism of the R-8-OH-DPAT-induced hypothermia was observed. The complex pharmacological effect versus time profiles of R-8-OH-DPAT were analyzed on the basis of an indirect physiological response model with set point control coupled to a competitive interaction model for an agonist and antagonist acting at a common receptor. This model converged, yielding precise estimates of the pharmacodynamic parameters of both WAY-100,635 and R-8-OH-DPAT, which were independent of the infusion rate of WAY-100,635. The estimated in vivo binding constant of WAY-100,635 was 0.98 ng/ml (2.3 nM), which is very similar to the reported value from in vitro receptor binding assays. The findings of this investigation show that, in contrast to earlier reports in the literature, WAY 100,635 behaves as a pure competitive antagonist at the 5-hydroxytryptamine(1A) receptor in vivo.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2002

Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: implications of the barriers between blood and brain.

In the clinical setting, drug concentrations in cerebrospinal fluid (CSF) are sometimes used as a surrogate for drug concentrations at the target site within the brain. However, the brain consists of multiple compartments and many factors are involved in the transport of drugs from plasma into the brain and the distribution within the brain. In particular, active transport processes at the level of the blood-brain barrier and blood-CSF barrier, such as those mediated by P-glycoprotein, may lead to complex relationships between concentrations in plasma, ventricular and lumbar CSF, and other brain compartments. Therefore, CSF concentrations may be difficult to interpret and may have limited value. Pharmacokinetic data obtained by intracerebral microdialysis monitoring may be used instead, providing more valuable information. As non-invasive alternative techniques, positron emission tomography or magnetic resonance spectroscopy may be of added value.

Animals↗

PubMedDate not supplied

Population pharmacokinetic analysis for simultaneous determination of B (max) and K (D) in vivo by positron emission tomography.

PURPOSE: Changes in GABA(A)-receptor density and affinity play an important role in many forms of epilepsy. A novel approach, using positron emission tomography (PET) and [C-11]flumazenil ([C-11]FMZ), was developed for simultaneous estimation of GABA(A)-receptor properties, characterized by B (max) and K (D). PROCEDURES: Following an injection of [C-11]FMZ (dose range: 1-2,000 mug) to 21 rats, concentration time curves of FMZ in brain (using PET) and blood (using HPLC-UV) were analyzed simultaneously using a population pharmacokinetic (PK) model, containing expressions to describe the time course of the plasma concentration (including distribution to the body), the brain distribution, and the specific binding within the brain. RESULTS: Application of this method in control rats resulted in estimates of B (max) and K (D) (14.5 +/- 3.7 ng/ml and 4.68 +/- 1.5 ng/ml, respectively). CONCLUSIONS: The proposed population PK model allowed for simultaneous estimation of B (max) and K (D) for a group of animals using single injection PET experiments per animal.

Animals↗