Pharmacokinetic interactions simulation

R., Hauck, W.W. et al., An individual bioequivalence criterion regnlatory considerations, Stat. Med. 19, 2821-2842, 2000 Meyer, M.C., United States Food and Drug Administration requirements for approval of generic drug products, J. Clin. Psychiatry 62 (Suppl. 5), 4-9, 2001 Temple, R., Policy developments in regulatory approval, Stat. Med. 21, 2939-3048, 2002 Gould, A.L, Substantial evidence of effect, J. Biopharm. Stat. 12, 53-77, 2002 Chen, M.L., Panhard, X., and Mentre, F, Evaluation by simulation of tests based on nonlinear mixed-effects models in pharmacokinetic interaction and bioequivalence cross-over clinical trials, Stat. Med. 24,1509-1524,2005 Bolton, S., Bioequivalence studies for levothy-roxine, AAPS J. 7, E47-E53, 2005. 

Dickins, M., Galetin, A. and Proctor, N. (2007) Modelling and simulation of pharmacokinetic aspects of cytochrome P450-based metabolic dmd-drug interactions, in Comprehensive Medicinal Chemistry II, vol. 5 (eds J.B. Taylor and D.J. Triggle), Elsevier Ltd, Oxford,... 

Tardif et al. (1992, 1993 a, 1997) have developed a physiologically based toxicokinetic model for toluene in rats (and humans—see Section 4.1.1). They determined the conditions under which interaction between toluene and xylene(s) occurred during inhalation exposure, leading to increased blood concentrations of these solvents, and decreased levels of the hippurates in urine. Similar metabolic interactions have been observed for toluene and benzene in rats (Purcell et al., 1990) toluene inhibited benzene metabolism more effectively than the reverse. Tardif et al. (1997) also studied the exposure of rats (and humans) to mixtures of toluene, we/a-xylene and ethylbenzene, using their physiologically based pharmacokinetic model the mutual inhibition constants for their metabolism were used for simulation of the human situation. 

Tardif et al. (1997) developed a physiologically based pharmacokinetic model for zneio-xylene in rats and humans. They also simulated interactions between weto-xylene, toluene and ethylbenzene, and showed that for exposures at air concentrations remaining within the permissible range for a mixture, biologically significant interactions at the pharmacokinetic level would not occur. 

A simulation model describes the temporal variation of a system in terms of the processes and interactions that are presumed to be at work. In connection with the development of new medicines, the model combines a pharmacokinetic description of the absorption, distribution, metabolism, and excretion of the medicine, with a detailed representation of the mechanisms responsible for its function and for the development of side-effects or possible synergetic interactions with other medicines [16]. 

PURPOSE AND RATIONALE Pharmacokinetic/pharmacodynamic modeling and subsequent simulations may be applied to answer key questions during the drug development process. This example shows that a PK/PD approach could be used to determine whether reduction in exposure of a given drug by 25 % due to an interacting variable results in any clinically relevant effect. 

For noncancer effects the use of PBTD models has elucidated the fundamental mechanisms of toxicological interactions. Such mechanistic knowledge linked with Monte Carlo simulations has initially been employed in in silico toxicology to develop models that predict the toxicity of mixtures in time. The combination of PBTK/TD models for individual compounds with binary PBTK/TD models can be achieved by incorporating key mechanistic knowledge on metabolism inhibitions and interactions through shared enzyme pathways. Simulations of such models can then be compared to experimental data and allow conclusions to be reached about their pharmacokinetics and the likelihood of effects being dose additive. 

Sale, M. Sadler, B.M. Stein, D.S. Pharmacokinetic modeling and simulations of interaction of amprenavir and... 

A pharmacokinetic model has been developed to describe the interaction of amprenavir with ritonavir (6). A two-compartment linear model with first-order absorption fitted the amprenavir data best, while a one-compartment model best described the ritonavir data. Inhibition of the ehmination of amprenavir by ritonavir was modelled with an Emax inhibition model. Simulation of drug regimens based on the model suggested that in patients who fail to respond to a traditional amprenavir regimen, amprenavir 600 mg plus ritonavir 100 mg bd would produce similar Cmii, ICso ratios to amprenavir 1200 mg bd alone. 

Kato M, TachibanaT, Ito K, etal. Evaluation of methods for predicting drug-drug interactions by Monte Carlo simulation. Drug Metab Pharmacokinet. 2003,18 121-127. 

Data describing the interaction of 2-butoxyethanol or 2-butoxyethanol acetate with other chemicals are scarce. Simulations of human pharmacokinetics of co-exposure to ethanol (0.1% in the blood) during an 8-hour exposure to 20 ppm 2-butoxyethanol with no exercise predict that the arterial levels of 2-butoxyethanol will be elevated as a result of a decrease in elimination rate (Johanson 1986, 1991a Johanson and Naslund 1988). Because the increase in 2-butoxyethanol is due to decreased elimination and not increased uptake, the rise and fall of blood concentrations of 2-butoxyethanol are slower in the ethanol co-administration model than in the increased workload model. A study in rats indicated that co-administration of ethanol and 2-butoxyethanol resulted in a higher blood level and a prolonged blood... 

Figure 7.23 Scatter plots and box and whiskers plots of true clearance against the EBE for clearance using FOCE with interaction. A total of 250 or 75 subjects were simulated with each subject having either 2, 4, or 8 samples collected. In this example, all pharmacokinetic parameters had 40% CV whereas residual error had a 10% CV. A 2-compartment model was fit to the data with all pharmacokinetic parameters treated as log-normal random effects and residual error modeled using an additive and proportional error model where the additive component was fixed to 0.00001 (ng / mL)2 to avoid infinite objective functions. Solid line is the line of unity.

The first simulation is to show how half-life, a pharmacokinetic parameter physicians are particularly interested in, varies as function of patient covariates. Many times when a modeler shows nonscientists an equation, some of them cannot understand how the variables interact or how the dependent variable might change when the one of the predictor variables is... 

No clinically relevant effects were found in interaction studies in which sertraline was given with a single intravenous dose of diazepam. One in vitro study in human liver microsomes suggested that sertraline inhibits the metabolism of alprazolam, whereas another suggested no interaction occurred. In vivo studies largely demonstrate a lack of interaction. For example, a pharmacokinetic study in 10 healthy subjects found that sertraline 50 to 150 mg daily had no effect on the pharmacokinetics of alprazolam, although some small decreases in a driving simulation score were seen at the 100- and 150-mg doses of sertraline. Similarly, sertraline 50 mg daily had no effect on the pharmacokinetics of alprazolam 1 mg daily in 12 healthy subjects, after 2 weeks of concurrent use. ... 

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