Plasma-drug concentration/time curve

Bioavailability is the amount of drug in a formulation that is released and becomes available for absorption or the amount of the drug absorbed after oral administration compared to the amount absorbed after intravenous administration (bioavailability - 100%), judged from areas remaining under plasma drug concentration-time curves. 

Three correlation levels have been defined and categorized in descending order of the ability of the correlation to reflect the entire plasma drug concentration-time curve that will result from administration of a dosage form. The relationship of the entire in vitro dissolution curve to the entire plasma level curve defines the correlation. 

The Drug Delivery Index (DDI) ahows a quantification of the reduction in the drug dose and the systemic exposure observed after drug release specificahy to the colon [37]. It may be calculated using AUC (Area l/nder the plasma drug concentration-time Curve) data or drug concentrations in blood and colonic tissues under steady-state conditions ... 

In the case of metoprolol succinate and metoprolol fumarate, the maximum drug concentration in the plasma( max) and the area under the plasma drug concentration-time curve were statistically equivalent, based on a 90% conLdence interval (Sandberg et al., 1993). With fenoprdffcQmthe following administration of its calcium salt was reached somewhat later thaCmjpassociated with the sodium form (Rubin et al., 1971). This was attributed to the slower dissolution rate for the calcium salt in acidic pH. Bioavailability and the measured distribution and elimination parameters, however, were reported to be similar. 

Cl plasma concentration at time zero fi/2a, distribution half-life f1/2jg, elimination half-life Kej, elimination rate constant from central compartment Ki2/.K2i, transfer rate constant between peripheral and central compartments AUC(o ), total area under plasma drug concentration time curve Vd(area> apparent volume of distribution GB, total body clearance. 

Should an early decision be made to develop the eutomer, then the drug development program would be the same as for conventional NCEs, with the possible exception that assessment of in vitro and/or in vivo chiral inversion may be desirable. However, if development continues with the racemate, time, cost, and staff resource commitments become magnified. For example, a very important variable to consider is spedes differences in enantiomer exposure. Appropriate toxicokinetic studies are advisable in order to assure that, at toxicological doses, the animal species tested have attained suffident plasma concentrations of each enantiomer to support clinical evaluation at therapeutic doses in humans. The enantiomeric ratio (based on maximum drug concentrations fCmax] and/or area under the plasma drug concentration-time curve [ALJC]) should be evaluated, and... 

This may be concentration and drug dependent. t = Increase = decrease — = no effect, k, = absorption rate constant = time AUC = area under the plasma drug concentration time curve. for peak drug concentration in plasma ... 

The mean in vitro dissolution time is compared to either the mean residence time or the mean in vivo dissolution time. Level B correlation, like Level A correlation, uses all of the in vitro and in vivo data but is not considered to be a point-to-point correlation and does not uniquely reflect the actual in vivo plasma level curve, since several different in vivo plasma level-time curves will produce similar residence times. A Level C correlation is the weakest IVIVC and establishes a single point relationship between a dissolution parameter (e.g., time for 50% of drug to dissolve, or percent drug dissolved in two hours, etc.) and a pharmacokinetic parameter (e.g., AUC, Cmax, Tmax). Level C correlation does not reflect the complete shape of the plasma drug concentration-time curve of dissolution profile. 

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... 

AUC total area under the plasma drug concentration-time curve (from... 

Fig. 2.3 Application of the trapezoidal rule for estimating area under the curve (AUC). The observed (measured) plasma drug concentration-time data are plotted on arithmetic coordinates. Total area under the curve is obtained by adding together areas of the trapezoids, the triangle from time zero to the first measured datum point and the calculated area under the extrapolated (terminal) portion of the curve, Cp yka, where Cp(n is the last measured datum point and kd is the apparent first-order disposition rate constant. The sample collection times and duration of sampling determine how well and/or completely the curve is defined.

Residue concentrations and their depletion profiles are inevitably linked to administered dose of an antimicrobial drug, albeit in a possibly complex and tissue dependent manner. This is illustrated first by the equation linking, for a systemically administered drug, dose to area under the plasma/blood concentration-time curve ... 

Area under the Curve (AUC) refers to the area under the curve in a plasma concentration-time curve. It is directly proportional to the amount of drug which has appeared in the blood ( central compartment ), irrespective of the route of administration and the rate at which the drug enters. The bioavailability of an orally administered drug can be determined by comparing the AUCs following oral and intravenous administration. 

The significance of P-gp, however, in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in knockout mice that do not have intestinal P-gp. The gene responsible for producing that protein has been knocked out of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) of the anticancer drug paclitaxel (Taxol) compared to the control animals [54]. Another line of evidence is the recent report... 

Pharmacokinetic concentration-time curves for a drug and ifs mefabolifes are used to identify primary exposure metrics such as AUC, or which are not time-dependent unlike the sequential measurements of concentration over time. A peak plasma concentration of a drug is often associated with a PD response, especially with an adverse event. There can be large inter-individual variability in the time-to-peak concentration, and closely spaced sampling times are often critical to determining the peak plasma concentration accurately in individual patients because of differences in demographics, disease states, and food effects, if any. All these elements are clearly spelled out in the protocols written to conduct these studies. 

The area under the plasma-concentration time curve, the AUC, is a useful parameter in defining fhe overall body exposure to a drug this parameter integrates the concentration-over-time fimction ... 

In calves and cows at high dose levels (100 SDM mg/kg), a biphasic elimination SDM plasma concentration-time curve was observed with a steady state plasma SCH2OH concentration resulting from the capacity limited hydroxylation of SDM into the latter. The drug concentrations in the milk reflected those in plasma. 

In the horse, hydroxylation is more important than acetylation as a metabolic pathway, with hydroxylation at the 5 position being dominant over hydroxylation of the 6-methyl group. Low percentages of metabolites are present in plasma, for N -SDM, 0.6 to 0.9 % for SCH2OH, 0.38 to 0.71 % and for SOH, 0.38 to 6.7 %. The plasma concentration-time curves of the metabolites run parallel to that of SDM. The elimination half-life of sulfadimidine varies between 5 and 14 h. The main metabolite in urine, accounting for 50 % of the drugs present (Table III), is the SOH and its glucuronide. 

Fig. 2.6 Effect of variation in absorption rate on plasma drug concentration. The graph shows simulated plasma concentration-time curves for theophyUine after oral administration, illustrating a 20% difference in Cpmax values resulting from variation in the absorption rate constant. Absorption rate constants top curve 2.2 per h (Cpmax 20 pg/mL) middle curve 1.0 per h (Cptnax 18 M-g/mL) bottom curve 0.7 per h. Note that tmax also changes. The established therapeutic concentration of theophyUin is 10-20 pg/mL. The most rapidly absorbed formulation produces the highest concentration and greatest chance of side effects. Also, the duration for which the plasma concentration is within the therapeutic range also varies. Pharmacokinetic parameters dose, 400 mg bioavaUabiUty, 0.8 volume of distribution, 29 L half-Ufe, 5.5 h.

The pharmacokinetic information that can be obtained from the first study in man is dependent on the route of administration. When a drug is given intravenously, its bioavailabihty is 100%, and clearance and volume of distribution can be obtained in addition to half-life. Over a range of doses it can be established whether the area under the plasma concentration-time curve (AUC) increases in proportion to the dose and hence whether the kinetic parameters are independent of dose (see Figure 4.1). When a drug is administered orally, the half-life can still be determined, but only the apparent volume of distribution and clearance can be calculated because bioavailability is unknown. However, if the maximum concentration (Cmax) and AUC increase proportionately with dose, and the half-life is constant, it can usually be assumed that clearance is independent of dose. If, on the other hand, the AUC does not increase in proportion to the dose, this could be the result of a change in bioavailability, clearance or both. 

Pharmacokinetic measurements, for example, plasma (serum) half-life, concentration-time curves of parent drug or active metabolite. 

---