Area under the plasma concentration-time curve

Compound (1) suffered from an unfavorable pharmacokinetic profile when studied in rats. It is cleared very rapidly from rat plasma (half-life, t 2 — 0.4/z) and is poorly bioavailable F — 2%), as reflected by the low plasma concentration (area under the plasma concentration-time curve, AUCo oo = 0.2pMh) following a single oral dose of 25mg/kg in rats [42]. The main challenge was to further optimize this series to obtain NS3 protease inhibitors with low-nanomolar cell-based potency (EC5q< 10 nM) and with an adequate pharmacokinetic profile for oral absorption. 

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... 

AUMC = area under the first-moment curve for tissue i AUMCP = area under the first-moment curve for plasma AUCP = area under the plasma concentration-time curve... 

Area under the plasma concentration-time curve... 

Area under the (plasma concentration-time) curve... 

Quantitative assessment of the extent of absorption (absolute bioavailability) is most rigorously obtained by comparison of the areas under the plasma concentration-time curves (after adjusting for dose) following IV and oral administration. However, even after oral administration alone some idea of absorption or bioavailability can be obtained in the following ways ... 

If the apparent plasma clearance (dose/area under the plasma concentration-time curve, equivalent to true clearance/fraction of dose absorbed) gives an implausibly high value of clearance (e.g., greater than hepatic and renal plasma flow), it is likely the bioavailability is low. However, this could be due to presystemic metabolism in addition to low absorption. 

Figure 2.4. In vivo measurement of blood-brain barrier (BBB) permeability, (a) Internal carotid artery perfusion technique (i) in the rat. Other branches of the carotid artery are ligated or electrically coagulated (o, occipital artery p, pterygopalatine artery). The external carotid artery (e) is cannulated and the common carotid artery (c) ligated. Perfusion time may range from 15 s to 10 min, depending on the test substance. It is necessary to subtract the intravascular volume, Vo, from (apparent volume of distribution), to obtain true uptake values and this may be achieved by inclusion of a vascular marker in the perfusate, for example labelled albumin. Time-dependent analysis of results in estimates of the unidirectional brain influx constant Ki (pi min which is equivalent within certain constraints to the PS product. BBB permeability surface area product PS can be calculated from the increase in the apparent volume of distribution Vd over time. Capillary depletion, i.e. separation of the vascular elements from the homogenate by density centrifugation, can discriminate capillary uptake from transcytosis. (b) i.v. bolus kinetics. The PS product is calculated from the brain concentration at the sampling time, T, and the area under the plasma concentration-time curve, AUC.

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. 

Most physicians will be familiar with the basic shape of a plasma concentration-time curve following oral or intravenous administration, and they are likely to be familiar with, or at least readily imderstand, the simple terms that relate to this shape. Such terms - (1) maximum plasma concentration (Cmax). (2) time to maximum plasma concentration (fmax), (3) area under the plasma concentration-time curve (AUC) and (4) half-life (fi/2) - are illustrated in Figure 5.2. 

Pharmacokinetics Ticlopidine is rapidly absorbed (more than 80%), with peak plasma levels occurring at approximately 2 hours after dosing, and is extensively metabolized. Administration after meals results in a 20% increase in the area under the plasma concentration-time curve (AUC). Ticlopidine displays nonlinear pharmacokinetics and clearance decreases markedly on repeated dosing. Ticlopidine binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein at concentrations attained with the recommended dose, 15% or less in plasma is bound to this protein. 

Coadministration with food has no significant effect on the peak plasma concentration and the area under the plasma concentration time curve of oseltamivir carboxylate. 

In the past the results of toxicology studies were interpreted and extrapolated to the human situation on the basis of the dose/kg or dose/m. However, it has long been recognized that measuring the plasma concentration of the compound and its metabolites often provides a better indication of exposure, and therefore this has become mandatory. The area under the plasma concentration-time curve (AUC) and... 

Indinavir was rapidly absorbed in the fasted state, with a time to peak plasma concentration of 0.8 0.3 hours (mean S.D.) (n=l 1). A greater than dose-proportional increase in indinavir plasma concentrations was observed over the 200-1000 mg dose range. At a dosing regimen of 800 mg every 8 hours, the steady-state area under the plasma concentration time curve (AUC) was 30,691 11,407 nM-hour (n=16), peak plasma concentration was 12,617 4037 nM (n=16), and plasma concentration eight hours post dose (trough) was 251 178 nM... 

Sertraline pharmacokinetics were described in 61 children and adolescents (ages 6 to 17) with depression or OCD (Alderman et ah, 1998). Mean area under the plasma concentration-time curve, peak plasma concentration, and elimination half-life for sertraline and des-methylsertraline were similar to previously reported adult values. No differences between children and adolescents were apparent when values were normalized for body weight. 

Abbreviations AUC, area under the plasma concentration-time curve CYP, cytochrome P450 HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A. 

Kita et al. [154] have undertaken a study to help predict the optimal dosage of omeprazole for extensive metabolizers in the anti-H. pylori therapy. Seven healthy Japanese subjects, classified based on the CYP2C19 genotype into extensive metabolizers (n = 4) and poor metabolizers (ft = 3), participated in this study. Each subject received a single oral dose of omeprazole 20, 40, and 80 mg, with at least a 1-week washout period between each dose. Plasma concentrations of omeprazole and its two metabolites were monitored for 12 h after each dose of medication. After each dose was administered, the pharmacokinetic profiles of omeprazole and its two metabolites were significantly different between extensive metabolizers and poor metabolizers. The area under the plasma concentration-time curve of omeprazole in extensive metabolziers was disproportionally increased 3.2- or 19.2-fold with dose escalation from 20 to 40 to 80 mg omeprazole, respectively. In contrast, the area under the plasma concentration-time curve of omeprazole was proportionally increased with the higher dose in poor metabolizers. The area under the plasma concentration-time curve of omeprazole after 20 mg administration to poor metabolizers was almost equal to the area under the plasma concentration-time curve in extensive metabolizers after 80 mg administration. The recommended dose of omeprazole for extensive metabolizers is a maximum of 80 mg x 2/day based on pharmacokinetic considerations. 

The pharmaceutical and biological availability of eight commercial furose-mide preparations was compared including two products with modified release properties [67], an enteric-coated tablet and a sustained-release preparation, in the form of a capsule containing diffusion pellets [28], A correlation between the rate of dissolution of different techniques and the area under the plasma concentration time curve was documented. The sustained-release preparation and the enteric-coated formulation clearly showed different pharmacokinetic behavior compared with conventional tablets. Although the literature mentions the maximal absorption at pH 5.5, the modified release formulations only showed a relative bioavailability of 80%. 

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... 

---