Pharmacokinetics steady-state concentrations

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... 

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. 

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 pharmacokinetics of hyperforin have been studied in rats and humans (Biber et ai. 1998). In rats, after a 300 mg/kg orai dose of hypericum extract (WS 5572, containing 5% hyperforin), maximum piasma ieveis of 370 ng/mi (690 nM) are achieved at 3 hours. The haif-iife of hyperforin is 6 hours. Humans given a 300 mg tabiet of hypericum (containing 14.8 mg hyperforin) showed maximum piasma ieveis of 150 ng/mi (280 nM) at 3.5 hours. The haif-iife is 9 hours, and mean residence time is 12 hours. Pharmacokinetics of hyperforin are iinear up to 600 mg, and no accumuiation occurs after repeated doses. By comparison, effective and safe piasma ieveis of paroxetine and fluoxetine vary between 40 and 200 ng/mi (Preskorn 1997). The effective piasma concentration of hyperforin predicted from computer-fit data is approximateiy 97 ng/mi (180 nM), which couid be easiiy monitored (Biber et ai. 1998). There is a iinear correiation between orai dose of hyperforin and piasma ieveis, and steady-state concentrations of 100 ng/mi (180 nM) couid be achieved with three-times-daiiy dosing. 

The pharmacokinetics of ondansetron in man have been determined in healthy volunteers after single and repeat doses [84]. The clinical pharmacokinetics (Table 7.8) showed many similarities with the kinetics in animals, but also some important differences. Elimination is rapid, but less so than in animals. The volume of distribution is similar in animals and man. As in animals, the clearance of ondansetron in man is predominantly by metabolism. However, metabolic clearance in man is considerably lower than in animals, resulting in a lower first-pass metabolism and a significantly greater oral bioavailability of 60 %. Steady-state concentrations of ondansetron are consistent with the single-dose kinetics of the compound and show no evidence of significant accumulation. 

Another problem is the significant inter-species difference observed for these pharmacokinetic steps. Whereas in some species, e.g. in the dog, concentrations above 1 mg g tissue could easily be achieved, this was not the case in others. Unfortunately, humans belong to the group with lowest liver uptake and steady-state concentration, respectively [75]. 

Pharmacokinetics Non-ergot dopamine agonists are rapidly absorbed. The absolute bioavailability is more than 90%. Steady-state concentrations are achieved within 2 days of dosing. Terminal half-life is about 8 hours (about 40 minutes for apomorphine) in young healthy volunteers and about 12 hours in elderly volunteers. Urinary excretion is the major route of elimination. 

Daptomycin pharmacokinetics are nearly linear and time-independent at doses up to 6 mg/kg administered once daily for 7 days. Steady-state concentrations are achieved by the third daily dose. 

Mechanism of Action An antiparkinson agent that stimulates dopamine receptors in the striatum. Therapeutic Effect Relieves signs and symptoms of Parkinson s disease. Pharmacokinetics Rapidly and extensively absorbed after PO administration. Proteinbinding 15%. Widely distributed. Steady-state concentrations achieved within 2 days. Primarily eliminated in urine. Not removed by hemodialysis. Half-life 8 hr (12 hr in patients older than 65 yr). 

Although these preparations are an important addition to the therapeutic armamentarium, particularly for outpatients, they may also occasionally benefit inpatients. It is important to appreciate the different pharmacokinetic properties of long-acting injectable drugs, especially the longer time period (i.e., 3 to 4 months) required to achieve steady-state concentrations, which must be taken into account when titrating dose. 

Estimates of dosing rate and average steady-state concentrations, which may be calculated using clearance, are independent of any specific pharmacokinetic model. In contrast, the determination of maximum and minimum steady-state concentrations requires further assumptions about the pharmacokinetic model. The accumulation factor (equation... 

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular... 

Estimates of dosing rate and average steady-state concentrations, which may be calculated using clearance, are independent of any specific pharmacokinetic model. In contrast, the determination of maximum and minimum steady-state concentrations requires further assumptions about the pharmacokinetic model. The accumulation factor (equation [7]) assumes that the drug follows a one-compartment body model (Figure 3-2 B), and the peak concentration prediction assumes that the absorption rate is much faster than the elimination rate. For the calculation of estimated maximum and minimum concentrations in a clinical situation, these assumptions are usually reasonable. 

Oral verapamil has been shown to increase peak plasma levels, prolong the terminal half-life, and increase the volume of distribution at steady state of doxorubicin (282). Gigante et al. (283) performed similar studies in which the pharmacokinetics of doxorubicin in combination with verapamil given at high doses intravenously were followed for 17 patients with advanced neoplasms. The steady-state concentration and systemic and renal clearances were found to be statistically similar for various doses of verapamil and doxorubicin, and for doxorubicin administered alone. 

After a single oral dose of 12 mg, administered to 10 subjects, peak plasma concentrations of 0.11 to 0.17 pg/ml (mean 0.13) were attained in 1 to 4 hours. Steady-state concentrations of 0.08 to 0.15 (ig/ml (mean 0.12) were measured during dosing of 6 subjects with 9 mg daily (S. A. Kaplan etal., J. Pharmacokinet. Biopharm., 1976,4,1-16). 

Following a single oral dose of 5 mg to 9 subjects, peak plasma concentrations of 0.028 to 0.045 pg/ml (mean 0.04) were attained in 0.5 to 4 hours (D. D. Breimerer a/.,. fir. J. din. Pharmac., 1911, 4, 709-711). Following daily oral doses of 5 mg to 4 subjects, steady-state plasma-nitrazepam concentrations of 0.035 to 0.044 pg/ml (mean 0.04) were reported combined steady-state concentrations of the, 7-amino and 7-acetamido metabolites were in the range 0.018 to 0.053 pg/ml (mean 0.03) (J. Rieder and G. Wendt, Pharmacokinetics and Metabolism of the Hypnotic Nitrazepam, in The Benzodiazepines, S. Garattini, E. Mussini and L. O. Randall (Ed.), New York, Raven Press, 1973, pp. 99-127). 

Sheiner and associates have developed the relationship where the pharmacodynamic model [Eq. (1)] is integrated together with the pharmacokinetic model. This makes possible describing both the steady-state concentration-effect relationship (i.e., EC20, EC50,... 

The interaction of itraconazole 200 mg orally od for 4 days with a single intravenous dose of racemic bupivacaine (0.3 mg /kg given over 60 minutes) has been examined in a placebo-controlled crossover study in 10 healthy volunteers (65). Itraconazole reduced the clearance of i -bupivacaine by 21% and that of 5-bupivacaine by 25%, but had no other significant effects on the pharmacokinetics of the enantiomers. Reduction of bupivacaine clearance by itraconazole is likely to increase steady-state concentrations of bupivacaine enantiomers by 20-25%, and this should be taken into account in the concomitant use of itraconazole and bupivacaine. 

The pharmacokinetic interaction of fluconazole 200 mg/ day with losartan 100 mg/day has been investigated in 32 healthy subjects (25). Fluconazole significantly increased the steady-state concentration of losartan by 66% and inhibited the formation of the active metabolite EXP-3174 by 34%. 

In six patients with severe congestive heart failure and renal insufficiency being treated with continuous veno-venous hemofiltration, the pharmacokinetics of milrinone 0.25 mg/kg/minute by continuous intravenous infusion were different from those that have been previously reported in patients with normal renal function, with a prolonged half-life and a raised mean steady-state concentration, suggestive of reduced clearance (20). The half-hfe of milrinone was 20 hours, compared with reported half-lives of around 3 hours. 

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