Pharmacokinetic-dynamic Model Research Articles

Pharmacokinetic and Pharmacodynamic Analysis of Inosine Monophosphate Dehydrogenase Activity in Hematopoietic Cell Transplantation Recipients Treated with Mycophenolate Mofetil

A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplantation (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNCs) at 5 time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic-dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory maximum effect model with an IC50 of 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, nonrelapse mortality, and overall mortality. In conclusion, a pharmacokinetic-dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker.

Population pharmacokinetics and pharmacodynamics in anesthesia, intensive care and pain medicine

Population modeling is a relatively new pharmacological discipline, the development of which has largely been stimulated by the need for accurate models for the pharmacokinetics and dynamics of anesthetic agents. Population-based modeling is now considered superior to older, more traditional modeling methods. Nonlinear mixed-effect modeling - a commonly used population-based modeling approach - estimates intraindividual and interindividual variability, limits the influence of outlying samples and individuals through the use of Bayesian statistical analysis, and provides a potential means of optimizing drug delivery regimens, especially when used to define pharmacokinetic-dynamic models for target-controlled infusion systems. In addition to being used for pharmacokinetic modeling, in which the influence of factors such as age, weight and illness can be studied, it is a powerful tool for the study of the influence of multiple factors on drug pharmacodynamics. Nonlinear mixed-effect population-based modeling has become the gold standard method of pharmacokinetic and pharmacodynamic analysis during new drug development and during subsequent pharmacological studies. Population-based modeling techniques have been applied to numerous aspects of drug delivery in anesthesia, intensive care and pain medicine.

Study of the time course of the clinical effect of propofol compared with the time course of the predicted effect-site concentration: performance of three pharmacokinetic–dynamic models

In the ideal pharmacokinetic-dynamic (PK-PD) model for calculating the predicted effect-site concentration of propofol (Ce(PROP)), for any Ce(PROP), the corresponding hypnotic effect should be constant. We compared three PK-PD models (Marsh PK with Shüttler PD, Schnider PK with fixed ke0, and Schnider PK with Minto PD) in their ability to maintain a constant bispectral index (BIS), while using the respective effect-site-controlled target-controlled infusion (TCI) algorithms. We randomized 60 patients to Group M (Marsh's model with k(e0)=0.26 min(-1)), Group S1 or Group S2 (Schnider's model with a fixed k(e0)=0.456 min(-1) or a k(e0) adapted to a fixed time-to-peak effect=1.6 min, respectively). All patients received propofol at a constant rate until loss of consciousness. The corresponding Ce(PROP), as calculated by the respective models, was set as a target for effect-site-controlled TCI. We observed BIS for 20 min. We hypothesized that BIS remains constant, if Ce(PROP) remains constant over time. All patients in Group M woke up, one in Group S1 and none in Group S2. In Groups S1 and S2, BIS remained constant after 11 min of constant Ce(PROP), at a more pronounced level of hypnotic drug effect than intended. Targeting Ce(PROP) at which patients lose consciousness with effect-site-controlled TCI does not translate into an immediate constant effect.

Early Phase Pharmacokinetics but Not Pharmacodynamics Are Influenced by Propofol Infusion Rate

Conventional compartmental pharmacokinetic models wrongly assume instantaneous drug mixing in the central compartment, resulting in a flawed prediction of drug disposition for the first minutes, and the flaw affects pharmacodynamic modeling. This study examined the influence of the administration rate and other covariates on early phase kinetics and dynamics of propofol by using the enlarged structural pharmacokinetic model. Fifty patients were randomly assigned to one of five groups to receive 1.2 mg/kg propofol given with the rate of 10 to 160 mg . kg(-1). h(-1). Arterial blood samples were taken frequently, especially during the first minute. The authors compared four basic pharmacokinetic models by using presystemic compartments and the time shift of dosing, LAG time. They also examined a sigmoidal maximum possible drug effect pharmacodynamic model. Patient characteristics and dose rate were obtained to test the model structure. Our final pharmacokinetic model includes two conventional compartments enlarged with a LAG time and six presystemic compartments and includes following covariates: dose rate for transit rate constant, age for LAG time, and weight for central distribution volume. However, the equilibration rate constant between central and effect compartments was not influenced by infusion rate. This study found that a combined pharmacokinetic-dynamic model consisting of a two-compartmental model with a LAG time and presystemic compartments and a sigmoidal maximum possible drug effect model accurately described the early phase pharmacology of propofol during infusion rate between 10 and 160 mg . kg(-1). h(-1). The infusion rate has an influence on kinetics, but not dynamics. Age was a covariate for LAG time.

Closed-loop controlled administration of propofol using bispectral analysis.

Ten patients, undergoing elective orthopaedic surgery under spinal anaesthesia, were sedated with propofol using a closed-loop feedback control system. The bispectral index (BIS), a new processed EEG parameter, was used as control variable. Propofol administration was controlled by a patient individualised adaptive model-based controller incorporating target-controlled infusion technology combined with a pharmacokinetic-dynamic model. This feedback control system for propofol administration proved to be adequate and safe. BIS was found to be well suited as control variable.

Advances in pharmacokinetics

Recent advances have been made in the understanding of the pharmaco-kinetics of muscle relaxants by the optimization of pharmacokinetic-dynamic models, thereby improving their description of the time course of action, particularly the onset of neuromuscular block. These models may be implemented in

Adaptive feedback-controlled infusion versus repetitive injections of vecuronium in patients during isoflurane anesthesia

Study Objective: To compare vecuronium requirements using repetitive injections and a model-based, closed-loop, feedback-controlled infusion during isoflurane anesthesia. Design: Randomized open study. Setting: Departments of Anesthesiology and Ear, Nose, and Throat Surgery at a university hospital. Patients: Twenty-two patients of ASA physical status I or ti undergoing elective otolaryngological surgery requiring general anesthesia. Interventions: Vecuronium was used for muscle relaxation. The desired level of neuromuscular transmission was set to 10% of control. All patients received vecuronium 0.08 mglkg for intubation. Thereafter, vecuronium was injected repetitively in 11 patients (Group 1) whenever spontaneous recovery had reached the 10% level. In the other group of 11 patients (Group 2), relaxation was maintained by an adaptive closed-loop feedback system, which was based on a pharmacokinetic-dynamic model. Measurements and Main Results: Neuromuscular transmission was quantified by the evoked electromyogram of the hypothenar muscles. In Group 1, the first repetition of 0.02 mg/kg had to be administered after 27.0 ± 5.5 minutes, followed by repetitions of the same dose every 16.3 ± 3.0 minutes. The induced neuromuscular block ranged from 83% to 100%. The mean vecuronium demand was 0.123 ± 0.018 mg/kg/h. In Group 2, stable relaxation of 90% ± 2% was achieved within 19.2 ± 7.5 minutes after a period of damped oscillations. The mean offset from the target value of 90% blockade was 0.65% ± 0.32%. The average vecuronium requirement was 0.056 ± 0.021 mglkglh during steady state. The difference between the groups in muscle relaxant demand was statistically significant. Conclusion: The model-based adaptive feedback system proved to be useful in maintaining a stable degree of paralysis, adjusting relaxant input to individual demand, and minimizing drug requirement, as compared with repetitive injections.

Angiotensin-converting enzyme inhibitors. Relationship between pharmacodynamics and pharmacokinetics.

The inter-relationship between the pharmacokinetic and pharmacodynamic behaviour of ACE inhibitors is reviewed. First, some of the methods which have been used to assess the pharmacodynamics of ACE inhibitors in humans are presented. They include humoral assays (e.g. ACE activity in plasma, renin activity, etc.), haemodynamic changes (blood pressure, total peripheral resistance, etc.) and agonist challenges (angiotensin I infusions). Subsequently a pharmacokinetic-dynamic model is described, based on biochemical processes obtained after ACE inhibition, which seems to be useful for the interpretation of the complex processes. The various correlations between plasma drug concentration on the one hand and plasma ACE activity, angiotensin II concentration in plasma or blood pressure on the other, are discussed on the basis of this model. From the model obtained it becomes obvious that under many circumstances the release of the inhibitor from ACE binding is the step which in fact determines the pharmacodynamically relevant elimination rate of the drug at low concentrations, whereas at high concentrations the elimination of the drug is mainly dependent on kidney (and/or liver) elimination rate. The dynamic-kinetic correlations are then presented for some ACE inhibitors in various disease states: arterial hypertension, heart failure, old age, renal failure, liver disease. In a final section the kinetic and dynamic relevance of interactions of ACE inhibitors with food and other drugs is described (e.g. prostaglandin inhibitors, diuretics, digoxin and cimetidine). Despite the great body of literature which deals with the kinetic and/or dynamic properties of ACE inhibitors, precise knowledge of the relationship between their kinetic and dynamic behaviour is rather limited and there is a clear need for further studies to elucidate this complex topic, thereby improving therapeutic possibilities with these useful new compounds.