Total drug concentration at steady state

Recall that for intravenously administered drug, total drug concentration at steady state is inversely related to hepatic clearance. 

E, hdpatic dXtracHon ratio CIh, hepatic clearance from plasma total drug concentration at steady state concentration of unbound (free) drug at steady state J., reduction t, increase <- , no change. 

A reasonable total phenytoin concentration at steady state is in the middle of the therapeutic range 15 j,gmL . Since unbound drug concentration is equal to the free fraction times the total drug concentration, we define ... 

Changes in average total and free drug concentrations at steady state for an intravenously administered drug... 

The appropriate equation (see also Eq. 11.17 and Eq. 12.19) for average total (bound plus free) plasma drug concentration at steady state is ... 

Table 16.5 The effect of a change in free fraction on average total and free plasma for intravenous administration of the drugs in Table 16.4 drug concentrations at steady state ...

Because the area under the plasma drug concentration-time curve during a dosage interval at steady-state is equal to the total area under the curve after administering a single intravenous dose, the average plasma concentration at steady-state can be estimated from... 

Once the clearance rate for a drug is known, the frequency of dosing may be calculated. It is usually desirable to maintain drug concentrations at a steady-state level within a known therapeutic range. This will be achieved when the rate of drug administration equals the total rate of clearance. 

At steady state, by definition the total drug clearance, or loss, is equal to drug input and plasma concentration oscillates around an average figure. However two situations occur which can provide problems in dosing. 

This physiological approach to defining volume is useful to help explain which drug might be more likely to reside outside the blood based on tissue affinity (fup/ fut), but does not readily lend itself to a calculation because of the difficulty in determining either free or total concentrations in the tissue. A simpler mathematical expression of Vss would be one related to equilibrium conditions achieved with a continuous intravenous (IV) infusion (R0) at steady-state where ... 

The value of Xoo is the maximum total body content of the drug that is reached during a dosing interval at steady state. The maximum concentration is determined by dividing this value by V. The minimum value is given by multiplying either of these maximum values by... 

The ratio of the AUCs of the lactone and total topotecan appears to be relatively constant and averages about 0.3, which means that only 30% of the total drug concentration in the plasma represents the closed-ring lactone form. The distribution volume at steady state is 25-751/m, indicating extensive binding to tissues. Erythrocjdes act as a depot for topotecan (lactone), with steady-state concentrations almost 1.7 times those obtained in plasma. 

If pharmacokinetics are dependent on dose or time, or a slow-release formulation is being studied, it is necessary to examine bioequivalence at steady state. For controlled-release formulations which are intended to produce relatively flat concentration-time profiles, an index of fluctuation is required, for example - Cn,jj])/C. A study at steady state may also be needed if the assay is not sensitive enough to quantify plasma concentrations of drug up to four half-lives after a single dose. Sometimes it is not technically feasible to assay a drug in plasma and it may then the justifiable to compare bioavailability by the total amount of drug excreted in urine, or pharmacodynamic data may be used, but these cases are exceptions. 

Number of subjects with subtherapeutic concentrations after delayed or missed doses quantihed as the percentage of subjects having total drug concentrations lower than 50 mg/L or unbound VPA concentrations less than 5 mg/L. Subtherapeutic subjects at baseline steady state were excluded from poor adherence scenarios. 

Finally, the method used to calculate the volume of distribution may be influenced by renal insufficiency. The three most commonly used volume of distribution terms are volume of the central compartment (Ec), volume of the terminal phase (E, E jea). and volume of distribution at steady state (Eis). The central compartment volume is calculated as the intravenous bolus dose divided by the initial plasma concentration. E for many drugs approximates extracellular fluid volume and thus may be increased or decreased by shifts in this physiologic volume. Renal insufficiency, especially oliguric acute renal failure, is often accompanied by fluid overload and a resultant increased Ec due to reduced renal elimination of water and sodium. Uaiea Or E is Calculated as the total body clearance divided by the terminal elimination rate constant (k or /3). This volume term represents the proportionality constant between plasma concentrations in the terminal elimination phase and the amount of drug remaining in the body. E is affected by both distribution characteristics, as well as by the elimination rate constant. The third volume term, the steady-state volume of distribution (Ess), is calculated as (AUMC x dose)/AUC , where AUMC is the area under the first moment of the concentrationtime curve and AUC is the area under the concentration-time curve... 

The volume of distribution reflects the relationship between the amount of drug in the body at steady state and plasma drug concentration. The volume of distribution is a mathematical concept, which does not necessarily reflect a physiological or real distribution space. This phenomenon can be illustrated by examining the volume of distribution for a number of drugs in Table 7.3. The volume of distribution of some drugs (e.g., chloroquine and digoxin) exceeds total body water (approximately 0.8 L/kg), whereas others (e.g., tolbutamide) are comparable to blood volume (0.08 L/kg). 

At steady state, venlafaxine weakly inhibits the metabolism of risperidone however, this interaction is unlikely to be of clinical significance. Co-administration of milnacipran and levomepromazine increases the milnacipran plasma concentration because of a modification of the apparent total clearance of the drug. 

Steady state the hepatic intrinsic clearance of pravastatin, a substrate for OATP2 and MRP2 (Tokui et al., 1999 Yamazaki et al., 1997), was regulated by the uptake process, followed by rapid metabolism and/or biliary excretion with minimal efflux to the systemic circulation in rats after infusion. The total hepatic elimination rate at steady state exhibited Michaelis-Menton saturation with the drug concentration and the and V ax obtained in rats with different mathematical models (i.e., well stirred, parallel tube, and dispersion models) were comparable with the initial uptake velocity measured from in vitro hepatocytes (Tokui et al., 1999). 

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