Plasma concentration profile

The CAT model estimates not only the extent of drug absorption, but also the rate of drug absorption that makes it possible to couple the CAT model to pharmacokinetic models to estimate plasma concentration profiles. The CAT model has been used to estimate the rate of absorption for saturable and region-depen-dent drugs, such as cefatrizine [67], In this case, the model simultaneously considers passive diffusion, saturable absorption, GI degradation, and transit. The mass balance equation, Eq. (51), needs to be rewritten to include all these processes ... 

The ACAT model is loosely based on the work of Amidon and Yu who found that seven equal transit time compartments are required to represent the observed cumulative frequency distribution for small intestine transit times [4], Their original compartmental absorption and transit (CAT) model was able to explain the oral plasma concentration profiles of atenolol [21]. 

In spite of its limitations, the ACAT model combined with modeling of saturable processes has become a powerful tool in the study of oral absorption and pharmacokinetics. To our knowledge, it is the only tool that can translate in vitro data from early drug discovery experiments all the way to plasma concentration profiles and nonlinear dose-relationship predictions. As more experimental data become available, we believe that the model will become more comprehensive and its predictive capabilities will be further enhanced. 

Time profiles in vitro and in vivo represent distribution functions in a mathematical and statistical sense. For example, a release profile Fj)(t) in vitro expresses the distribution of drug released at time t the corresponding probability distribution function (PDF) profile fo(t) characterizes the rate of release. Similarly, a plasma concentration profile fp(t) represents the distribution of drug in the plasma at any time t, i.e., absorbed but not yet eliminated its cumulative distribution function (CDF) equivalent FP(t) represents the drug absorbed and already eliminated. 

For (differential) plasma concentration profiles, the initial slope fo is frequently used as metric reflecting the rate of absorption. Again, it must be realized that this metric is affected by extent as well as by rate. Only when extent is proven as complete, may the initial slope be used as measure of rate of the input. 

For the comparison of two differential plasma concentration profiles R(t) and T(t), Rescigno (18) proposed a dimensionless index of bioequivalence ... 

In order to obtain an in vitro-in vivo relationship two sets of data are needed. The first set is the in vivo data, usually entire blood/plasma concentration profiles or a pharmacokinetic metric derived from plasma concentration profile (e.g., cmax, tmax, AUC, % absorbed). The second data set is the in vitro data (e.g., drug release using an appropriate dissolution test). A mathematical model describing the relationship between these data sets is then developed. Fairly obvious, the in vivo data are fixed. However, the in vitro drug-release profile is often adjusted by changing the dissolution testing conditions to determine which match the computed in vivo-release profiles the best, i.e., results in the highest correlation coefficient. 

Sawamoto T, Haruta S, Kurosaki Y, Higaki K, Kimura T (1997) Prediction of the plasma concentration profiles of orally administered drugs in rat on the basis of gastrointestinal transit kinetics and absorbability. J. Pharm. Pharmacol. 49 450-457. 

N. Inotsume, J. Fujii, M. Nakano, Plasma Concentration Profile of Diazepam After Oral Administration of the Open-Ring Form of Diazepam to Man , Chem. Pharm. Bull. 1986, 34, 937 - 940. 

Fig. 2.4 Plasma concentration profile observed after intravenous infusion.

When oral doses are administered far apart in time they behave independently. This is usually not the desired profile if we assume that a certain concentration is needed to maintain efficacy and if a certain concentration is exceeded side-effects will occur. Giving doses of the drug sufficiently close together so that the following doses are administered prior to the full elimination of the preceding dose means that some accumulation will occur, moreover a smoothing out of the plasma concentration profile will occur. This is illustrated in Figure 2.7. 

Fig. 2.7 Plasma concentration profile for multiple oral dose administration.

Fig. 4.1 Plasma concentration profiles after doubling doses showing (a) proportional increase with dose,...

The study should provide unique information on the plasma-concentration profiles of parent drug and metabolite. The rates and extended excretion in urine, faeces and, if appropriate, expired air can be defined. 

Lipophilic drug molecules are absorbed across the nasal epithelium by passive transcellular diffusion. For small, unionized molecules, this provides a rapid efficient transport mechanism, often resulting in plasma concentration profiles resembling that of intravenous injection and bioavailabilities of up to 100%. 

Solutions (lavages) and foams are liquid preparations. The foams differ from the solutions in the presence of a suitable propellant, in the formulation, and the type of container, a pressurized delivery device. Plasma concentration profiles obtained after solution administration are characterized by a burst effect followed by a rapid decrease below therapeutic levels, due to the low residence time of the formulation in the vaginal cavity. Such preparations are designed to achieve a local effect particularly in case of inflammations or infections caused by bacteria or yeasts (anaerobic bacteria or Candida species). Nonoxynol-9 (N-9) foam is used as a contraceptive and against sexually transmitted diseases [19]. 

To demonstrate equivalence in plasma concentration profiles, rate and extent of availability must be assessed and compared. The parameters Cmax and AUC are typically used here, and they are regarded as surrogate markers for clinical safety and efficacy. If they are too much higher in the new drug formulation N, they could lead to unwanted side effects. On the other hand, if they are too much lower, the new formulation may be less effective in treating the condition. The definition of too much in this context is not simple, and we will not discuss the details here (see Patterson and Jones, 2006, for more details). 

Figure 5. Predicted plasma concentration profile for the transdermal delivery of propranolol.

Figure 7. Simulation of the plasma concentration profile for a hydrophilic drug with two penetration enhancers PE1 and PE2 compared to a control.

Plasma concentration profiles after buccal administration of the saturated drug solution varied considerably between animals but the overall time dependency was similar (Figure 4). Plasma levels increased rapidly after application of the solution onto the mucosa to produce relatively constant concentrations in the range 1500-8000 ng/ml after 2 h. Following removal of the solution the drug exhibited the expected decline in plasma concentrations at a rate comparable to that observed in the intravenous bolus study. 

Using this method we were able to obtain plasma concentration profiles from humans who had smoked cigarettes dosed at 88 yg THC/kg. Thirty minutes after smoking the concentration ranged from 5 to 35 ng/ml with an average of 17 ng/ml (4). These values were similar to the concentration range reported by Agurell (5). ... 

FIGURE 2 (a) Schematic picture of blood plasma concentration profile after administra-... 

Albertsson-Wikland K, Rosberg S, Libre E, Lundberg LO, Groth T. Growth hormone secretory rates in children as estimated by deconvolution analysis of 24-h plasma concentration profiles. Am J Physiol 1989 257 E809-14. 

Once the physicochemical and biopharmaceutical properties of the drug are determined and the desired plasma concentration profile is defined, the pharmaceutical scientist can select and develop an efficacious dosage form by utilizing a formulation approach, a prodrug approach, a device approach, or an alternative administration route approach. 

Fig. 6 Cross-sectional view of a unit of Transderm-Nitro system, showing various structural components, and plasma concentration profiles of nitroglycerin in 14 human volunteers, each receiving one unit of Transderm-Nitro system (20 cm, with a delivery rate of lOmg/day) for 24h. (From RefsJ l)...

Fig. 5 Rabbit plasma concentration profiles of norethin-drone following the intravenous administration of a single dose (solution). Also shown is the intravaginal absorption of ethynodiol diacetate from a solution dose and from a vaginal delivery device. (From Ref. l)...

A recently developed unfolding GRDF formulation of L-Dopa showed, in a Beagle dogs model, a remarkable extension in the length of the absorption phase in comparison to non-GRDF, which led to flatter plasma concentration profile as shown in Fig. 1... 

Fig. 5 Calculation of the input (absorption curve) from a plasma concentration profile.

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