Nonlinear pharmacokinetics

ABORTIVE COMPLEX Nonlinear kinetics of drug bioavailability, PHARMACOKINETICS NONLINEAR LEAST SQUARES ANALYSIS Nonmetal oxides,... 

Nonlinear pharmacokinetics. Nonlinear pharmacokinetics simply means that the relationship between dose and Cp is not directly proportional for all doses. In nonlinear pharmacokinetics, drug concentration does not scale in direct proportion to dose (also known as dose-dependent kinetics). One classic drug example of nonlinear pharmacokinetics is the anticonvulsant drug phenytoin.38 Clinicians have learned to dose pheny-toin carefully in amounts greater than 300 mg/day above this point, most individuals will have dramatically increased phenytoin plasma levels in response to small changes in the input dose. 

Test Items. As a rule, the pharmacokinetic parameters of test substances such as maximum concentration (Cmax) and time to reach maximum concentration (Tmax), area under curve (AUC), elimination half-life, clearance, distribution volume, bioavailability, etc., and pharmacokinetic nonlinearity are studied. The pharmacokinetics of metabolites of the test substance should be examined if necessary. 

The antiepileptic drug phenytoin, an orally available class DB antiarrhythmic, is mainly effective in digitalis-induced arrhythmias. This diug exhibits nonlinear pharmacokinetics and a number of side effects including neuropathy, gingival hypetplasia, hepatitis, immunological disorders and suppression of white blood cells. 

On some occasions, the body does not behave as a single homogeneous compartment, and multicompartment pharmacokinetics are required to describe the time course of drug concentrations. In other instances certain pharmacokinetic processes may not obey first-order kinetics and saturable or nonlinear models may be required. Additionally, advanced pharmacokinetic analyses require the use of various computer programs, such as those listed on the website http //www.boomer.org/pkin/soft.html. 

Studies interested in the determination of macro pharmacokinetic parameters, such as total body clearance or the apparent volume of distribution, can be readily calculated from polyexponential equations such as Eq. (9) without assignment of a specific model structure. Parameters (i.e., Ah Xt) associated with such an equation are initially estimated by the method of residuals followed by nonlinear least squares regression analyses [30],... 

P Veng-Pedersen. Linear and nonlinear systems approach in pharmacokinetics How much do they have to offer I. General considerations. J Pharmacokin Biopharm 16 413-472, 1988. 

PBPK and classical pharmacokinetic models both have valid applications in lead risk assessment. Both approaches can incorporate capacity-limited or nonlinear kinetic behavior in parameter estimates. An advantage of classical pharmacokinetic models is that, because the kinetic characteristics of the compartments of which they are composed are not constrained, a best possible fit to empirical data can be arrived at by varying the values of the parameters (O Flaherty 1987). However, such models are not readily extrapolated to other species because the parameters do not have precise physiological correlates. Compartmental models developed to date also do not simulate changes in bone metabolism, tissue volumes, blood flow rates, and enzyme activities associated with pregnancy, adverse nutritional states, aging, or osteoporotic diseases. Therefore, extrapolation of classical compartmental model simulations... 

The original proposal of the approach, supported by a Monte Carlo simulation study [36], has been further validated with both pre-clinical [38, 39] and clinical studies [40]. It has been shown to be robust and accurate, and is not highly dependent on the models used to fit the data. The method can give poor estimates of absorption or bioavailability in two sets of circumstances (i) when the compound shows nonlinear pharmacokinetics, which may happen when the plasma protein binding is nonlinear, or when the compound has cardiovascular activity that changes blood flow in a concentration-dependent manner or (ii) when the rate of absorption is slow, and hence flip-flop kinetics are observed, i.e., when the apparent terminal half-life is governed by the rate of drug input. 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

In spite of its limitations, the ACAT model combined with modeling of saturable processes has become a powerful tool in the study of oral absorption and pharmacokinetics. To our knowledge, it is the only tool that can translate in vitro data from early drug discovery experiments all the way to plasma concentration profiles and nonlinear dose-relationship predictions. As more experimental data become available, we believe that the model will become more comprehensive and its predictive capabilities will be further enhanced. 

Dosage can be titrated to 12 mg/day with careful monitoring nonlinear pharmacokinetics have been demonstrated. 

AChs are an effective treatment (see Table 71-4). Benztropine has a half-life that allows once- to twice-daily dosing. Dose increases above 6 mg/day must be slow because of nonlinear pharmacokinetics. Trihexyphenidyl, diphenhydramine, and biperiden usually require three-times-daily dosing. Diphenhydramine produces more sedation, but all of the AChs have been abused for euphoriant effects. 

The PBPK model development for a chemical is preceded by the definition of the problem, which in toxicology may often be related to the apparent complex nature of toxicity. Examples of such apparent complex toxic responses include nonlinearity in dose-response, sex and species differences in tissue response, differential response of tissues to chemical exposure, qualitatively and/or quantitatively difference responses for the same cumulative dose administered by different routes and scenarios, and so on. In these instances, PBPK modeling studies can be utilized to evaluate the pharmacokinetic basis of the apparent complex nature of toxicity induced by the chemical. One of the values of PBPK modeling, in fact, is that accurate description of target tissue dose often resolves behavior that appears complex at the administered dose level. 

Ferrero, J.L., Thomas, S.B., Marsh, K.C., Rodrigues, A.D., Uchic, J.T. and Buko, A.M. (2002) Implication of P450-metabolite complex formation in the nonlinear pharmacokinetics and metabolic fate of ( )-(l R, 3R )-3-phenyl-l-[(l, 2, 3, 4 -tetrahydro-5, 6 -methylene-dioxy-l -naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200) in dogs. Drug Metabolism and Disposition, 30 (10), 1094-1101. 

Pharmacokinetic/pharmacodynamic model using nonlinear, mixed-effects model in two compartment, best described time course of concentration strong correlation with creatinine clearance predicted concentration at the efi ect site and in reduction of heart rate during atrial fibrillation using population kinetic approach... 

As mentioned above, bioavailability is the degree to which a drug reaches the intended site of action. The amount of drug that reaches systemic circulation will depend on the processes of absorption, distribution, and biotransformation (when the route of administration exposes the drug to first-pass metabolism). Pharmacokinetics are often linear and when they are nonlinear it is often due to a saturation of protein binding, metabolism, or active renal transport. 

Caffeine pharmacokinetics are nonlinear. For example, when comparing a 500 mg dose to a 250 mg dose, the clearance is reduced and elimination half-life is prolonged with the higher dose (Kaplan et al. 1997). Thus, larger doses prolong the action of the drug. Active metabolites of caffeine are paraxanthine, and to a lesser degree, theobromine, and theophylline. Urinary metabolites are I-methylxanthine, l-methyluric acid, and an acetylated uracil derivative. 

The newer physiologically based pharmacokinetic (PBPK) models take nonlinearity of physiological processes such as chemical metabolism and excretion into consideration. At the high dose levels used in animal experiments, these mechanisms become saturated with the result that the tissues may be exposed to a different composition of pure compound and metabolites than at the low dose levels encountered in real-life human exposure. 

Pharmacokinetics Ticlopidine is rapidly absorbed (more than 80%), with peak plasma levels occurring at approximately 2 hours after dosing, and is extensively metabolized. Administration after meals results in a 20% increase in the area under the plasma concentration-time curve (AUC). Ticlopidine displays nonlinear pharmacokinetics and clearance decreases markedly on repeated dosing. Ticlopidine binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein at concentrations attained with the recommended dose, 15% or less in plasma is bound to this protein. 

Absorption/Distribution - Propafenone is nearly completely absorbed after oral administration with peak plasma levels occurring approximately 3.5 hours after administration. It exhibits extensive first-pass metabolism resulting in a dose-dependent and dosage-form-dependent absolute bioavailability. Propafenone follows a nonlinear pharmacokinetic disposition presumably due to saturation of first-pass hepatic metabolism as the liver is exposed to higher concentrations of propafenone and shows a very high degree of interindividual variability. 

Metabolism/Excretion - There are 2 genetically determined patterns of propafenone metabolism. In more than 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life of 2 to 10 hours. These patients metabolize propafenone into two active metabolites 5-hydroxypropafenone and N-depropylpropafenone. They both are usually present in concentrations less than 20% of propafenone. The saturable hydroxylation pathway is responsible for the nonlinear pharmacokinetic disposition. 

Other barbiturates are also used as anticonvulsants. See Sedatives/Hvonotics section. Exhibits dose-dependent, nonlinear pharmacokinetics. 

The pharmacokinetics of voriconazole are nonlinear because of the saturation of its metabolism. The interindividual variability of voriconazole pharmacokinetics is high. 

Theoretical depiction of phenytoin concentrations achieved following various doses of the antiepileptic phenytoin. Shaded area indicates the therapeutic range of phenytoin concentrations below 10 (xg/mL, results in subtherapeutic effect above 20 (xg/mL, results in toxicity. Within the therapeutic range, a relatively small increase in dose results in a greater than proportional increase in concentration, suggesting nonlinear pharmacokinetics. 

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