Plasma elimination profiles, determination

Synthesis of Labeled Neoglycoproteins to Determine Plasma Elimination Profiles... 

When a compound is administered by a route other than intravenously, the plasma level profile will be different, as there will be an absorption phase, and so the profile will be a composite picture of absorption in addition to distribution and elimination (Fig. 3.26). Just as first-order elimination is defined by a rate constant, so also is absorption kab. This can be determined from the profile by the method of residuals. Thus, the straight portion of the semilog plot of plasma level against time is extrapolated to the y axis. Then each of the actual plasma level points, which deviate from this during the absorptive phase, are subtracted from the equivalent time point on the extrapolated line. The differences are then plotted, and a straight line should result. The slope of this line can be used to calculate the absorption rate constant kab (Fig. 3.26). The volume of distribution should not really be determined from the plasma level after oral administration (or other routes except intravenous) as the administered dose may not be the same as the absorbed dose. This may be because of first-pass metabolism (see above), or incomplete absorption, and will be apparent from a comparison of the plasma... 

The pharmacokinetic profile of 2 -MOE partially modified ASOs was similar in mice, rats, dogs, monkeys, and humans in that the drug was cleared within hours from the plasma and distributed to the tissues. Following IV administration, the plasma concentration-time profiles of 2 -MOE partially modified ASO are poly-phasic, characterized by a rapid distribution phase (half-lives of 30-80 min), followed by at least one additional much slower elimination phase with half-lives reported from 10 to 30 days. The recent development of ultrasensitive hybridization ELISA methods have made it possible to follow plasma concentrations for up to three months after dose administration, enabling the investigators to determine terminal plasma elimination half-lives [24, 26, 30, 31]. Representative plasma concentration-time profiles with the rapid distribution phase along the slow terminal elimination phase in monkeys and humans for a 2 -MOE partially modified ASO, ISIS 104838 are shown in Figure 4.2 [26]. 

When a drug is administered as an i.v. bolus, the entire dose of the drug is injected straight into the blood. Therefore, the absorption process is considered to be completed immediately, and the concentration-time profile of fhe drug in plasma will be determined by the rate of distribution and elimination. When the distribution of the drug is very fast, the plasma concentration-time curve is determined only by the elimination rate and shows a mono-exponential (first-order) decline (a theoretical example is shown in Figure 31.7a ... 

When a compound is administered by a route other than intravenously, the plasma level profile will be different as there will be an absorption phase, and so the profile will be a composite picture of absorption in addition to distribution and elimination (figure 3,26). Just as first-order elimination is defined by a rate constant, so also is absorption, ab. This can be determined from the profile by the... 

The elimination process is represented by the elimination rate constant ke, which may be determined from the gradient of the plasma profile (Fig. 3.25). The reasons for the overall process of elimination being first order are that the processes governing it (excretion by various... 

Figure 3.25 Log10 plasma concentration time profile for a foreign compound after intravenous administration. The plasma half-life (fo) and the elimination rate constant (fce ) of the compound can be determined from the graph as shown.

In conclusion, pharmacokinetics is a study of the time course of absorption, distribution, and elimination of a chemical. We use pharmacokinetics as a tool to analyze plasma concentration time profiles after chemical exposure, and it is the derived rates and other parameters that reflect the underlying physiological processes that determine the fate of the chemical. There are numerous software packages available today to accomplish these analyses. The user should, however, be aware of the experimental conditions, the time frame over which the data were collected, and many of the assumptions embedded in the analyses. For example, many of the transport processes described in this chapter may not obey first-order kinetics, and thus may be nonlinear especially at toxicological doses. The reader is advised to consult other texts for more detailed descriptions of these nonlinear interactions and data analyses. 

As stated above, the Vss calculation using Eqs. (5) or (10) is valid only when elimination exclusively occurs from the sampling (plasma/blood) compartment. When some or all elimination occurs from the tissue compartment (Fig. 7.1), the concentration versus time profile will still be characterized by a bi-exponential equation however, the ability of modeling systems to quantify the micro rate constants is lost. That is to say, essentially identical bi-exponential concentration time profiles are possible with and without elimination from the tissue compartment. Therefore, when modeling from a plasma profile only, there is no way of determining if the exit of drug from the body is exclusive to the central compartment. 

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... 

Often the drug effect lags behind the measured plasma concentration-time profile ( hysteresis ), i.e. the same PD measurement corresponds to different measured plasma concentrations. In this case often a hypothetical effect compartment is introduced into the model, where a rate constant keo determines the elimination out of this effect compartment. The concentration-time profile within this effect compartment is now linked to the P D effect model. This allows the description of a time delay between the plasma concentration and the PD (see Fig. 17.7) and again a unique relation between concentration and the observed PD is established. 

We had sought to address two questions (a) what is the elimination half-life of DS-96 in the murine model, and does the tV2 correspond to pharmacodynamic data shown in Fig. 12.19 (b) what is the therapeutic plasma concentration of DS-96 that corresponds to full protection against endotoxemic challenge in mice. DS-96 at a dose of 200 (xg/mouse (8 mg/kg) was administered to CF1 mice via i.p. and i.v. routes. Plasma concentrations of DS-96 were determined by LC-MS/MS using a deuterated DS-96 internal standard (Nguyen et al., 2008 Shrestha et al., 2008). The elimination tV2 in mice is about 400 min (Fig. 12.22), which is consistent with the observed pharmacodynamic (in vivo efficacy) data shown in Fig. 12.19. The observed concentration-versus-time profile of DS-96 in the mouse i.p. model suggests that a plasma concentration of 0.5-1.5 txg/mL corresponds to complete protection by a dose of 200 ng/animal of LPS in the D-galactosamine-primed model of endotoxin-induced lethality. 

The total radioactivity minus the parent compound concentration (determined by the bioanalytical method) in a specimen estimates the amount of metabolites present. If the difference is minimal and does not change over time, the extent of metabolism is low. For plasma or serum specimens, a small difference indicates that metabolites are not present in systemic circulation. For bile or urine specimens, high levels of radioactivity suggest a primary route of elimination for the parent and metabolites. For a drug candidate cleared primarily by metabolism, a preliminary metabolite profile in urine and bile can determine the number of potential metabolites. When the level of a metabolite in a matrix is high, attempts to isolate and identify the metabolite can be undertaken. If sufficient quantities are obtained, the metabolite s pharmacologic and toxicologic... 

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. 

---