Steady-state plasma concentration estimating

In practice, one will seek to obtain an estimate of the elimination constant kp and the plasma volume of distribution Vp by means of a single intravenous injection. These pharmacokinetic parameters are then used in the determination of the required dose D in the reservoir and the input rate constant k (i.e. the drip rate or the pump flow) in order to obtain an optimal steady state plasma concentration... 

Absorption-The oral bioavailability at steady-state is estimated to be 15% and 19% for 7.5 and 15 mg tablets, respectively. Peak plasma concentrations are reached approximately 7 hours after multiple dosing, and steady-state plasma concentrations are achieved by the sixth day of dosing. 

Human clinical studies Plasma levels of hyperforin were followed for 24 hours in two studies with healthy volunteers after administration of film-coated tablets containing 300 mg SJW extract representing 14.8 mg hyperforin (Table 2) (72). In the first crossover study, six male volunteers received 300, 600, or 1200 mg of a SJW extract preparation (WS 5572, Dr. Willmar Schwabe Arzneimittel, Karlsruhe, Germany) after a 10-hour fasting time. Maximum plasma levels of 150 ng/mL (approximately 280 nM) were reached after 3.5 hours after intake of 300 mg SJW extract. Half-life and MRT were 9 and 12 hours, respectively. Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. In a repeated dose study with seven healthy volunteers, no accumulation of hyperforin in plasma was observed after intake of 900mg/day SJW extract for seven days. The estimated steady-state plasma concentrations of hyperforin after intake of 3 x 300mg/day was approximately 100 ng/mL (approximately 180 nM) (Table 2) (72). 

Direct evidence that irreversible inhibition is the principle mechanism underlying in vivo drug-drug interactions (DDIs) is often lacking because of the requirement for either direct tissue sampling to reveal inactivated enzyme or in vivo inhibition of activity after drug is essentially eliminated from the body. Nevertheless the steady-state plasma concentrations of several clinically important CYP inhibitors are well below the in vitro estimated competitive inhibition constant, Kv This suggests that competitive inhibition is unlikely to occur in vivo, yet these compounds inhibit CYP activity in a time and concentration-dependant manner when cDNA-expressed CYPs or HLMs are used as an enzyme... 

Kinetic parameters were estimated in nonsmokers and smokers to help elucidate the quantitative ascorbate metabolism in humans. This approach allows calculation of turnover rates at different levels of steady state intakes of ascorbate. Metabolic and renal turnovers were calculated separately. At plasma levels above about 0.7 mg/100 mL the renal elimination increased sharply and the metabolic turnover showed a saturation at a plasma level corresponding to a total turnover of about 60 mg/d. At the tested levels of intake of ascorbic acid the calculated total pool size increased to a level reached at a steady state plasma concentration achieved at an intake of about 90 mg/d. At intakes of this magnitude the absorption is substantially less than 100%. A daily intake of 100 mg of ascorbate for larger populations should be attained. Similar experiments with smokers showed an increase in the metabolic turnover corresponding to a demand of 140 mg/d to reach a similar stage. 

Unlike the estimates of dosage rates and average steady-state plasma concentrations, which may be determined independently of any pharmacokinetic model in that systemic clearance is the only pharmacokinetic parameter used, the prediction of peak and trough steady-state concentrations requires pharmacokinetic compartmental model assumptions. It is assumed that, (i) drug disposition can be adequately described by a one-compartment pharmacokinetic model, (ii) disposition is independent of dose (i.e. linear pharmacokinetics apply), and (iii) the absorption rate is much faster than the rate of elimination of the drug, which is always valid when the drug is administered intravenously. For clinical applications, these assumptions are reasonable. 

This continuous infusion method can also be employed without urine collection, and plasma clearance is then calculated as CL = infusion rate/Css. Requirements of this method include steady-state plasma concentrations and accmate measmement of infusate concentrations. Plasma clearance can also be determined following a singledose intravenous injection with multiple samples of blood taken to estimate the area under the curve (AUCo oo)- Here clearance is calculated as CL = dose/AUC. These plasma clearance methods commonly yield clearance values 10% to 15% higher than urine collection methods. ... 

Plasma samples for PK analysis by a one-compartment IV infusion model can be collected either during the infusion period and/or during the postinfusion period. However, plasma samples from the postexposure period are easier to analyze by standard PK methods. PK parameters can be estimated from plasma concentration data collected during the infusion period only if the infusion is continued long enough (T > 7 ty eiim) to provide a reasonable estimate for the steady-state plasma concentration (Q ). 

Thus all the basic model parameters for the one-compartment IV infusion model can be determined from a linear regression analysis of measured infusion period plasma concentration data as long as an estimate of the steady-state plasma concentration can be made. 

To construct such a plot and estimate the values of Michaelis-Menten parameters (i.e. i/max andlCni)/ one needs at least two sets (three or four is ideal) of doses along with their corresponding steady state plasma concentration values. 

Example estimation of dosing rate (R) and steady-state plasma concentration (Cp), for phenytoin from Michaelis-Menten parameters... 

If the Michaelis-Menten parameters are known in a patient or are reported in the literature, the dosing rate necessary to obtain a desired steady-state plasma concentration can be estimated. 

Forexample, forphenytoin, the estimated value of Km and V max are 6.5 mgL and 548mgday, respectively. It is desired to obtain a steady-state plasma concentration of 15mgL. The dosing rate can be determined from Eq. 15.8 ... 

The choice of steady-state plasma concentrations (Cmax, Cave, and Ctrough) or the concentration in hepatic circulation (Chept inlet,max) of the inhibitor as an estimate of the concentration at the active site of the enzyme (hepatic intracellular concentration). The Chept inlet,max is estimated using Cmax and the rate of absorption after oral administration [Eq. (4.10)]. The DDI may be under- or overpredicted if the drugs are substrates of hepatic transporters (efflux or uptake), show poor membrane permeability, and/or are prone to rapid metabolism. 

Oxymorphone ER has an absolute bioavailability of approximately 10%. This bioavailability is thought to be primarily due to pre-systemic (first pass) metabolism in the liver [ 1 ]. Oxymorphone ER has a mean steady-state plasma concentration which linearly increases with dose [1]. The time to maximum concentration is estimated to be 25-90 minutes for all doses. Oxymorphone ER has a mean t, of9.35-11.30 hours for doses of 5-40... 

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... 

The bioavailability of indapamide is not significantly reduced when taken with food or antacids. Steady-state blood concentrations of indapamide appear to be independent of body weight. The volume of distribution for indapamide has been estimated from blood concentrations to be 25 to 27 L. The volume of distribution estimated from plasma concentrations was 110 L (26). 

As shown above, early/late sampling will require the use of equations to adjust observed high and low concentrations to achieve more accurate estimates of the "peak" and trough concentrations. Early/late sampling will also have ramifications for the equations used to for solve for the apparent volume of distribution and the elimination rate constant by using two steady-state plasma drug concentrations sampled after a multiple intravenous infusion. Table 14.4 summarizes these equations. 

Estimation of the potency can be made in a several ways and will be highly dependent on the nature of the target. If a purified system is used it is normal to correct for the effect of plasma protein binding (which can be measured directly in human plasma) as it is usual for the effect to be proportional to the unbound concentration [82]. This can be used to set a value for the minimum plasma concentration at steady state. 

The plasma concentration at when divided by the dose gives an estimate of distribution volume that can be used to calculate dosing for fast equilibrating drug, in particular, such as anesthetics. This distribution volume term often proves more useful than the traditional central volume of distribution or the steady-state distribution volume. 

Distribution - The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses. Varying degrees of hepatic and renal insufficiency do not affect the protein... 

The clinical development stage comprises three distinct components or phases (I, II, and III), and culminates in the filing of the NDA/MAA. Each phase involves process scale-up, pharmacokinetics, drug delivery, and drug safety activities. During phase I clinical development, the compound s safety and pharmacokinetic profile is defined. The determination of maximum concentration at steady state (Cmax), area under the plasma concentration time curve (AUC), elimination half-life, volume of distribution, clearance and excretion, and potential for drug accumulation is made in addition to studies that provide estimates of efficacious doses. Dose levels typically... 

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