Dose-linear kinetics

After the administration of a drug, its concentration in plasma rises, reaches a peak, and then declines gradually to the starting level, due to the processes of distribution and elimination (p. 46). Plasma concentration at a given point in time depends on the dose administered. Many drugs exhibit a linear relationship between plasma concentration and dose within the therapeutic range (dose-linear kinetics (A) note different scales on ordinate). However, the same does not apply to drugs whose elimination processes are already sufficiently activated at therapeutic plasma levels so as to preclude further proportional increases in the rate of elimination when the concentration is increased further. Under these conditions, a smaller proportion of the dose administered is eliminated per unit of time. 

The time course of the effect and of the concentration in plasma are not identical, because the concentration-effect relationships obeys a hyperbolic function (B cf. also p. 54). This means that the time course of the effect exhibits dose dependence also in the presence of dose-linear kinetics (C). 

In particular, high-dose data usually cannot identify a threshold. A threshold is a dose or exposure below which there is no effect. It is often assumed that there is no threshold for an end point, like a gene mutation, that may involve one molecule of the toxicant and one target molecule in such a case, the dose-response relationship would be linear at low doses. If the observed relationship is linear over the dose range studied and if the fitted line is extrapolated to no effect (or the background frequency of effects) at zero dose, linear kinetics with no threshold are likely. But data are usually not clear. Even such a large carcinogenesis study as the EDqi study conducted by... 

Figure 7.16 represents plasma concentration versus time data following the administration of three different doses of a drug via identical formulation and identical dosage form. Since the only difference here is the dose administered, it is reflected in peak plasma concentration and in (AUC)o. Please note that these differences result only from differences in the administered dose (linear kinetics). Also, please note that peak time remains unaffected. 

This situation does not qualify for use of the high dose equation (Eq. 15.15). Neither are the plasma drug concentrations obtained small enough to warrant use of the low dose (linear kinetic) equation (Eq. 15.13). This leaves the requirement to use the general equation for Michaelis-Menten elimination kinetics (Eq. 15.14) ... 

The major metabolic pathways of the TCAs are demethylation, hydroxyla-tion, and glucuronide conjugation. Metabolism of the TCAs appears to be linear within the usual dosage range, but dose-related kinetics cannot be ruled out in the elderly. 

Upon the administration of 1 gram of an aminoglycoside every 12 hours, the Cmj v, was found to be 8 mcg/mL. The plasma concentration at time zero was 63 mcg/mL and elimination rate constant was 0.14 hour 1. If it is desired to increase the Cmin ss to 10 mcg/mL, what should be the dose of the drug, and the new Cmax ss Assume that the drug follows linear kinetics. 

When a single 25-mg bolus dose of an antibiotic is given, the C0 was found to be 2.5 mcg/mL and the elimination half-life was 2.5 hours. What would be the dose required to achieve a new minimum steady-state concentration of 0.45 mcg/mL with a dosing interval of 6 hours Also what would be the new maximum steady-state concentration Assume that the antibiotic follows linear kinetics ... 

Intravenous bolus dose of a 500-mg dose of an antibiotic every six hours in a patient produces minimum steady-state concentration of 10 meg/ mL. If the desired minimum steady-state concentration in this patient is 16 mcg/mL, calculate the size of dose needed to change this concentration. Assume that the drug follows linear kinetics. 

Milnacipran is also a dual-action antidepressant which, like venlafaxine, has been shown to be more effective than the SSRIs in the treatment of severe, hospitalized and suicidally depressed patients. At lower therapeutic doses, milnacipran blocks the noradrenaline transporters and therefore resembles the NRI antidepressants. Higher doses result in the serotonergic component becoming apparent (i.e. an SSRI-like action). The main problem with milnacipram appears to be its lack of linear kinetics with some evidence that it has a U-shaped dose-response curve (Figure 7.3). 

The mechanism of action of this benzamide compoimd is not entirely understood but it has been shown to inhibit HDAC and cellular proUferation. It displays linear kinetics and is rapidly absorbed after oral administration. The main dose limiting toxicity (DLT) reported was thrombocytopenia with the MTD at 8 mg/m /day, although other toxicities Uke nausea, vomiting, diarrhea and fatigue were seen [136]. One partial response was seen in the 53 patients evaluated. 

Zolpidem is rapidly absorbed and has a quick onset of hypnotic action. Bioavailability is 70 percent following oral administration and the drug demonstrates linear kinetics in the therapeutic dose range. Peak plasma concentration is reached at 0.5 and 3 hours. The elimination half-life is short. It is 92% plasma protein bound and is metabolised in liver to inactive metabolites. It is eliminated in the urine and in the faeces. 

A placebo-controlled, randomized clinical trial with monitoring of hypericin and pseudohypericin plasma concentrations was performed to evaluate the increase in dermal photosensitivity in humans after application of high doses of SJW extract (Table 2) (73). The study was divided into a single-dose and a multiple-dose part. In the single dose crossover study, each of the 13 volunteers received either placebo or 900, 1800, or 3600 mg of the SJW extract LI 160. Maximum total hypericin plasma concentrations were observed about four hours after dosage and were 0, 28, 61, and 159ng/mL, respectively. Pharmacokinetic parameters had a dose relationship that appeared to follow linear kinetics (73). 

Non-linear pharmacokinetics are much less common than linear kinetics. They occur when drug concentrations are sufficiently high to saturate the ability of the liver enzymes to metabolise the drug. This occurs with ethanol, therapeutic concentrations of phenytoin and salicylates, or when high doses of barbiturates are used for cerebral protection. The kinetics of conventional doses of thiopentone are linear. With non-linear pharmacokinetics, the amount of drug eliminated per unit time is constant rather than a constant fraction of the amount in the body, as is the case for the linear situation. Non-linear kinetics are also referred to as zero order or saturation kinetics. The rate of drug decline is governed by the Michaelis-Menton equation ... 

Tiagabine is 90-100% bioavailable, has linear kinetics, and is highly protein-bound. The half-life is 5-8 hours and decreases in the presence of enzyme-inducing drugs. Food decreases the peak plasma concentration but not the area under the concentration curve (see Chapter 3). Hepatic impairment causes a slight decrease in clearance (and may necessitate a lower dose), but the drug does not cause inhibition or induction of hepatic... 

Peak plasma concentrations are reached within 2 to 3 h after oral dosing. Diflunisal is heavily bound to plasma protein (>99 %), has a long elimination half-life (8-12 h) and non-linear kinetics. Hence, it is used with an initial loading dose (1000 mg) and a lower maintenance dose (500-1000 mg/day). Diflusinal is excreted as glucuronide in the urine. 

Most anticonvulsants have linear elimination kinetics, which means that an increase in the dose of drug administered leads to a proportional increase in the blood concentration and pharmacological activity. However, diphenylhydantoin and valproate are exceptions the former does not follow linear kinetics so that the blood concentration is not directly related to the dose administered, while valproate is highly bound to serum proteins so that the total blood concentration may not directly reflect the quantity of drug available to the brain. 

Thus, for a dosing interval of 24 h and a half-life close to 24 h, the predicted accumulation factor is 2, close to the observed value found in this study. This is a good indication for linear kinetic behavior of XYZ1234 between single and repeated dosing. 

Since clozapine may be the gold standard and the last resort in the treatment of refractory schizophrenia, the authors of a review aimed to discover whether a trial with clozapine is adequate (15). The results favored the approach of increasing the clozapine plasma concentration in treatment-refractory schizophrenic patients who do not respond to an initial low-to-medium dose. Some patients, especially young male smokers, will need dosages over 900 mg/day, and the addition of low-dose fluvoxamine while closely monitoring clozapine concentrations can help to reduce the large number of tablets required, since fluvoxamine increases the clozapine plasma concentration 2- to 3-fold, maximally 5-fold, and reduces N-desmethylclozapine concentrations the combination can lead to non-linear kinetics of clozapine. 

Paclitaxel has non-linear kinetics peak plasma concentrations and drug exposure increase disproportionately with increasing doses and the pharmacokinetics depend on the schedule of administration. Saturation is reached with high-dose short infusions (4). Paclitaxel has been reported to follow both biphasic (5) and triphasic models (6). The half-life has been estimated at 6-13 hours after intravenous administration (7). 

AUC is a frequency distribution of the number of molecules within the body versus time. When measured out to infinity (< ), the AUC value (AUCo a) represents the total drug exposure. Its value is unaffected by the rate of absorption (assuming linear kinetics) but is affected by dose, clearance and bioavailability. Bioavailability is calculated by comparing the total amount of drug in the body (AUC) following administration by a non-i.v. route with that obtained following i.v. administration (100%), corrected for dose. 

These linear kinetic models and diffusion models of skin absorption kinetics have a number of features in common they are subject to similar constraints and have a similar theoretical basis. The kinetic models, however, are more versatile and are potentially powerful predictive tools used to simulate various aspects of percutaneous absorption. Techniques for simulating multiple-dose behavior evaporation, cutaneous metabolism, microbial degradation, and other surface-loss processes dermal risk assessment transdermal drug delivery and vehicle effects have all been described. Recently, more sophisticated approaches involving physiologically relevant perfusion-limited models for simulating skin absorption pharmacokinetics have been described. These advanced models provide the conceptual framework from which experiments may be designed to simultaneously assess the role of the cutaneous vasculature and cutaneous metabolism in percutaneous absorption. 

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