Plasma drug concentration topping

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.

Fig. 3. Relationship between total amount of drug in the body, concentration of drug, [D J, in plasma and concentration of unbound drug, tOp], in tissue fluid. Calculated from equations 4, 5 and 10 assumit K = 10, n = 1, P = 5.8 X 10 M, Vp 3 liters. Drug A,...

Figure 10 Plasma concentrations of a drug following a multiple-dosing regimen, of fixed dose and interval, intravenously (top) and orally (bottom). Note that in both cases the area under the plasma concentration-time curve within a dosing interval at plateau is equal to the total area following a single dose. Source From Ref. 1.

Requirements for obtaining in vivo human metabolism information early in the development of an NCE and the opportunity to determine metabolite concentrations at steady state has persuaded several of the pharmaceutical companies to take advantage of the SAD and MAD studies to get a glimpse of the metabolites present in human plasma and urine [24], In SAD studies, urine (0-24 h) and blood samples (3-4 time points) can be collected from placebo- and NCE-dosed healthy volunteers from the top two or three dose groups. Since the volume of plasma samples from FIH studies are limited, one option is to use urine samples (pooled across subjects) to optimize/develop extraction, chromatographic, and MS conditions for metabolite detection activities. Once plasma extraction/reconstitution methods are optimized, pooled plasma from NCE- and placebo-dosed subjects are analyzed. LC-MS profiles of placebo-dosed subjects are used to eliminate matrix ions, dose formulation-related ions, and other background ions so that drug-related ions can be readily identified in the NCE-dosed samples. 

Figure 10.91 Plasma concentrations following three bolus IV injections (top graph) and three first-order absorption drug administrations (bottom graph) are given by the sum of the concentrations associated with each individual dose.

Figure 10.92 Plasma concentrations for drug delivery by both bolus IV injection and IV infusion for a general case (top graph) and for a special case where the bolus IV dose has been designed to be a loading dose for the infusion (bottom graph).

Transporters expressed in the liver and kidney—as well as metabolic enzymes—are key determinants of drug exposure (Figure 2-3, top panel) because they control the total clearance of drugs and thus influence the plasma concentration profiles and subsequent exposure to the toxicological target. 

TOP metabolism is increased by coadministration of inducing drugs. Plasma concentrations are decreased by 50% and TOP doses need to be adjusted. 

Figure 3.16 Ultra-high flow rate LC-MS/MS analysis in about 2.5 min of two candidate drug compounds in plasma. Top, compound 1 at zero concentration, compound II present as SIS bottom, compound I at Ing mL in plasma. The column was 50 X 1mm packed with 30p,m particles. Gradient elution was used at a flow rate of 4mL min. The divert valve was switched from waste to the mass spectrometer one minute after injection. Reproduced from Jemal Rapid Commun. Mass Specirom. (1998) 12, 1389, with permission of John Wiley Sons, Ltd.

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