Steady-state drug concentration

In contrast to other protein-bound drugs for which a loading dose is given to achieve rapid steady-state concentrations, a slow and stepwise increase in thyroid hormone replacement therapy is advisable. This is preferred mainly to avoid sudden cardiac adverse effects, especially in older patients with long-standing myxedema. Moreover, since thyroid hormone substitution can change the metabolic clearance of this drug, steady-state concentrations are obtained only after several months (SEDA-6, 363). 

FIGURE 2.23 Schematic diagram showing the routes of possible removal of drug from the receptor compartment. Upon diffusion into the compartment, the drug may be removed by passive adsorption en route. This will cause a constant decrease in the steady-state concentration of the drag at the site of the receptor until the adsorption process is saturated. 

If the entry of a molecule into the body were simply a temporally restricted absorption process, then a steady-state concentration would be achieved given enough time for complete absorption. However, what in fact is observed in drug pharmacokinetics is a complex curve reflecting absorption of the drug into the body and the diminution of the concentration that is absorbed back down to negligible levels. The reason for this complex pattern of rise and fall in... 

If a drug is given repetitively with a constant dose (D) and a constant administration interval (Tau) accumulation occurs until a steady-state concentration (Css) is obtained after 4.32 times the elimination half-life (/ss -4.32 Tl/2). 

In this special case when the time between dosings is equal to the half-life time of the drug, we can deduce that the minimum (steady-state) plasma concentration with repeated dosing is equal to the peak concentration, obtained from a single dose. Under this condition, the corresponding maximum (steady-state) concentration is twice as much as the minimum one. 

In the case of drug administration by an intravenous infusion, the average steady state concentration (Css) is obtained by the equation,... 

When a 100-mg drug is administered, C0 was found to be 10 mcg/mL and half-life of the drug was found to be 4 hours. If the drug was administered q4h, what would be the steady-state concentrations ... 

Calculate the steady-state concentrations of Cmilx, Cmin, and C.. , . after the administration of 500 mg of drug every six hours. C0 of the drug was found to be 25 ng/mL, and the half-life was found to be 2 hours. 

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. 

A single bolus dose administration of 50 mg of a drug showed the following pharmacokinetic parameters C0 = 2.5 mg/mL, and tm = 5.5 hours. If the desired minimum steady-state concentration is 2 mg/mL, calculate the dose that should be administered every six hours, and the expected maximum steady-state concentration with the new dose. 

When a single 250 mg bolus dose of an antibiotic is given, the C0 was found to be 20 ng/mL and the elimination half-life was 5 hours. What would be the dose required to achieve a new minimum steady-state concentration of 10 ng/mL with a dosing interval of 6 hours Also what would be the new maximum steady-state concentration Assume that the drug follows first-order kinetics. 

The rather time- and cost-expensive preparation of primary brain microvessel endothelial cells, as well as the limited number of experiments which can be performed with intact brain capillaries, has led to an attempt to predict the blood-brain barrier permeability of new chemical entities in silico. Artificial neural networks have been developed to predict the ratios of the steady-state concentrations of drugs in the brain to those of the blood from their structural parameters [117, 118]. A summary of the current efforts is given in Chap. 25. Quantitative structure-property relationship models based on in vivo blood-brain permeation data and systematic variable selection methods led to success rates of prediction of over 80% for barrier permeant and nonper-meant compounds, thus offering a tool for virtual screening of substances of interest [119]. 

D. A. Svinarov, C. E. Pippenger, Relationships between Carbamazepine-Diol, Carba-mazepine-Epoxide, and Carbamazepine Total and Free Steady-State Concentrations in Epileptic Patients The Influence of Age, Sex, and Comedication , Ther. Drug Monit. 1996,18, 660 - 665. 

The three main parameters of clinical pharmacokinetics are clearance, distribution volume, and bioavailability. Clearance is the rate at which the body eliminates a drug. In order to achieve a steady-state concentration, the drug must be given so that the rate of clearance equals the rate of administration. If the drug is given as quickly as it is eliminated, a consistent level in the body will be maintained. 

The same relationship to k i and half-life also apply, so that as with intravenous infusion 87.5 % of the final steady state concentration is achieved following administration of the drug for three half-lives. 

If a drug is to be tested in patients who will inevitably be receiving other medications with which the NME is likely to interact, it maybe important to design interaction studies in healthy volim-teers early in ED. This is not merely a matter of whether dosage adjustment may be required. Eor example, the demonstrated ability of a NME to double the concentrations of a standard concomitant therapy due to inhibition of its metabolism may lead to a decision to stop development. The design of such studies will usually involve repeat dosing of one or both drugs to achieve steady-state concentrations. Potential interactions with... 

That blood drug measurements can sometimes provide valuable additional information is, however, not seriously in doubt. For some drugs the intensity of the pharmacological action and severity of side-effects correlates much better with the plasma steady-state concentration than with... 

With some drugs, particularly those with a long half life, a loading dose may be useful in order to achieve a therapeutic level more rapidly. For example, the half-life of phenobarbital in the neonate is long, approximately 120 hours, with steady-state concentrations achieved in two to three weeks. A slowly-infused loading dose can be efficacious in achieving seizure control within minutes, typically followed by maintenance infusion and subsequent transition to oral therapy daily. 

An often-misunderstood principle is that concentration in the blood rises until the rate of absorption equals the rate at which drug is being removed from the body (the so-called peak). This peak does not occur when absorption is complete but rather when the rate of absorption equals the rate of elimination. The time to peak is therefore determined by both absorption and elimination rates in the individual patient. Patients with faster elimination will have earlier peaks than will patients with slower elimination, even when the rate of drug absorption is the same (Fig. 4.2). The extent of absorption is usually expressed as the fraction absorbed or bioavailability. This is an important determinant of drug action. While rate and extent of absorption are related, they are different. In general, the onset and magnitude of effects are related to the rate of absorption, while the average steady state concentrations are related to the extent of absorption. 

Although elimination half-life is usually associated with clearance, it should be noted that this parameter is also influenced by distribution. This concept is important to appreciate when individualizing drug therapy, since it is clearance that determines steady-state concentrations for any given dose absorbed. 

Figure 5.2 Plasma concentration curve of drug after single and repeated administration Csj. nax, maximal steady-state plasma concentration after repeated administration Css av, average steady-state concentration after repeated administration Css mm- minimal steady-state concentration after repeated administration n. maximal plasma concentration after single oral dose t Inax. time to maximal concentration after single oral dose t plasma half-life after single oral dose AUC, area under the concentration vs. time curve...

In summary, both Phase I and Phase II metabolic drug interactions are of clinical relevance because they alto the steady-state concentrations of drugs and thereby attenuate or enhance their pharmacological effects in extreme cases this can either lead to a lack of therapeutic efficacy of a drug or to drug intoxication. The purpose of drug plasma level measurements here is to adjust the dose to suit the new situation. 

---