Concentration time course

Ishihara, N. and Urushiyana, K., Longitudinal study of workers exposed to mercury vapor at low concentration Time course of inorganic and organic mercury concentration in urine, Toxicology and Applied Pharmacology, 155, 161-168, 1994. 

HU is an inhibitor of ribonucleotide reductase, a rate-limiting enzyme which catalyzes the conversion of ribonucleotides into deoxyribonucleotides. HU is thus a cytotoxic agent as it has the ability to inhibit DNA synthesis. Consequently, H U can affect only cells that are actively synthesizing DNA and, therefore, a drug of S-phase cell-cycle specific. Moreover, HU-mediated inhibition of ribonucleotide reductase is reversible, implying that the action of HU will exhibit a relatively straight forward concentration-time course dependence [2—4-]. 

Figure 5.9. The concentration-time course of (a) naproxen and (b) captopril in the kidney after intravenous injection of the parent drug or the drug-lysozyme (LZM) conjugate. Values are given as means + SEM.

Toxicokinetic studies are designed to obtain species-, dose-, and route-dependent data on the concentration-time course of the parent compound and its metabolites, e.g., in blood, urine, feces, and exhaled air. From these data toxicokinetic parameters can be derived by appropriate techniques. The information, which can be taken from in vivojex vivo toxicokinetic studies is (EC 2003) ... 

If after single dose administration, the blood samples are not collected at time intervals, which allow for a description of the whole plasma concentration time course, including the absorption, distribution, and elimination phase, the information obtained is limited. In particular, data should be available in the hrst hours after administration to cover the absorption phase. If measurements of the parent compound and its metabolite(s) are made in this period, this will allow assessment of an extensive first pass effect, i.e., when a substance after oral administration is transported via the portal vein to the liver where metabolism takes place before the substance enters the systemic circulation. 

Fig. 2a,b. Principle of integral and differential measurement of reaction kinetics a concentration-time course b rate-time course. Symbols indicate initial and final concentrations in parallel integral measurements. Corresponding curves use same dashes... 

Cladribine, or 2-chlorodeoxyadenosine, is resistant to adenosine deaminase and after intracellular phosphorylation by deoxycytidine kinase, it is incorporated into DNA. It is considered the drug of choice in hairy cell leukemia because of high activity combined with acceptable toxicity. Cladribine shows variable oral absorbtion and is usually administered intravenously. Its concentration-time course is biphasic with plasma half-lives of 35 minutes and 6.7 hours. Excretion is primarily by the kidneys. Its most prominent dose-limiting toxicity is myelosup-pression. 

The blood concentrations, time-courses, and half-lives (1,2-1.4 h) of 2-PAM and toxogonin are similar in humans,but toxogonin has a smaller volume of distribution than 2-PAM (174 vs. 795 ml/kg) and a smaller renal elimination (clearance, 133 vs. 717 ml/min). The smaller volume of distribution and slower clearance Imply different distribution and handling of the two oximes. They also imply that, if toxogonin and 2-PAM were given In equimolar concentrations, the toxogonin plasma concentration would be greater than that of 2-PAM. 

FIGURE B-2 Time course for VOC concentrations in blood after a bolus dose. Arrows indicate two of the many time points when a biomonitoring sample may be taken. Without prior knowledge, a useful screening approach is to assume that the sample was taken at the 5-hour arrow, well after the peak blood concentration. If that assumption is used across the population, a pharmacokinetic model can yield reasonably conservative bounding estimates of exposure dose. (Many exposure events might occur in a single day that could affect the concentration-time course of the VOCs in blood.)... 

The PPK approach estimates the joint distribution of population specific pharmacokinetic model parameters for a given drug. Fixed effect parameters quantify the relationship e.g. of clearance to individual physiology like function of liver, kidney, or heart. The volume of distribution is typically related to body size. Random effect parameters quantify the inter-subject variability which remains after the fixed effects have been taken into account. Then the observed concentrations will still be randomly distributed around the concentration time course predicted by the model for an individual subject. This last error term called residual variability... 

Concentration time courses can be simulated by the model and the demographic parameters for different dose regiments. The final administration of the drug has to be adjusted so that e.g. 95% of the target population falls into the therapeutic window. If sub-populations differ too much, adjusted administration regiments have to be considered. 

Simulations of the concentration time course under steady state conditions as predicted by the model for a 500 mg twice daily dose regimen are shown in Figure 4. The broad line corresponds to the typical male and... 

Fig. 1. Individual concentration time courses. CONC creatinine clearance, PRED model predictions for the population with r = 0, IPRE model predictions for the individual subject with random q j, CLcr creatinine clearance in L/h is calculated as left hand scale 10/4...

Fig. 4. Simulations of the concentration time course under steady state conditions as predicted by the model (C) for a 500 mg twice daily dose regimen. The broad line corresponds to the typical male (CLCR = 72.53 ml/min LBM = 57.63 kg) and female (58.32 ml/min 43.12 kg) patients. All other lines are calculated using only CL and V pairs of the 95% contour line of their joint probability of occurrence as shown in Figure 3 as ellipses. The horizontal solid line marks the MIC of 2mg/L...

To ensure interchangeability, the multisource product must be therapeutically equivalent to the comparator product. Types of in vivo bioequivalence studies include pharmacokinetic studies, pharmacodynamic studies and comparative clinical trials. Direct practical demonstration of therapeutic equivalence in a clinical study usually requires large numbers of patients. Such studies in humans can be financially daunting, are often unnecessary and may be unethical. For these reasons the science of bioequivalence testing has been developed over the last 40 years. According to the tenets of this science, therapeutic equivalence can be assured when the multisource product is both pharmaceutically equivalent/alternative and bioequivalent. Assuming that in the same subject an essentially similar plasma concentration time course will result in essentially similar concentrations at the site(s) of action and thus an essentially similar therapeutic outcome, pharmacokinetic data may be used instead of therapeutic results. In selected cases, in vitro comparison of dissolution profile of the multisource product with that of the comparator product, or dissolution studies, may be sufficient to provide indication of equivalence. 

The rate and extent to which the active moiety is absorbed from a pharmaceutical dosage form and becomes available at the site(s) of action. Reliable measurements of drug concentrations at the site(s) of action are usually not possible. The substance in the general circulation, however, is considered to be in equilibrium with the substance at the site(s) of action. Bioavailability can be therefore defined as the rate and extent to which the active pharmaceutical ingredient or active moiety is absorbed from a pharmaceutical dosage form and becomes available in the general circulation. Based on pharmacokinetic and clinical considerations it is generally accepted that in the same subject an essentially similar plasma concentration time course will result in an essentially similar concentration time course at the site(s) of action. 

Fig. 1. Principle of calculation of genotype-based dose adjustments based on differences in pharmacokinetic parameters, such as clearance and area under the curve. The theoretic dosages for genetic subgroups of poor (PMs), intermediate (IMs), extensive (RMs), and ultrarapid metabolizers (UMs) are depicted as schematic genotype-specific dosages to obtain equal plasma concentration time courses. C, concentration T, time. (From Kirchheiner J, Nickchcn K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004 9(5) 442-73 with permission.)...

The same extract was given to healthy volunteers as film-coated tablets in single doses of 300, 600 and 1200 mg. Mean Cmax concentrations of 153, 302 and 437 ng/ml were observed after 3 h (Table 4). The lag time of absorption was about 1.5 h. Terminal half-life (t p) and mean residence time (MRT) were 9 and 12 h, respectively. Pharmacokinetics were linear up to 600 mg, at 1200 mg lower Cmax and AUC values were observed as were expected from a linear function. The plasma concentration time course could be described by an open two-compartment model, with a distribution half-life (imo) of about 2.7 h. 

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