Maximum plasma concentration determination

Pharmacokinetic studies in pigs following a single oral administration of 20 mg kitasamycin/kg bw showed that the drug was rapidly absorbed and distributed in the body. A maximum plasma concentration of 4.5 ppm was attained within 0.5 h, the half-life in plasma being 0.7 h. Highest tissue residue concentrations (21 ppm) were detected in kidney within 1-2 h. The ratio of the maximum concentrations determined in kidney to that in liver was around 3 2. 

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed [33] and validated for the determination of donepezil in human plasma samples. Diphenhydramine was used as the IS. The collision-induced transition m/z 380 > 91 was used to analyze donepezil in selected reaction monitoring mode. The signal intensity of the m/z 380 —> 91 transition was found to relate linearly with donepezil concentrations in plasma from 0.1 to 20.0 ng/ml. The lower limit of quantification of the LC/MS/MS method was 0.1 ng/ml. The intra- and inter-day precisions were below 10.2% and the accuracy was between 2.3% and +2.8%. The validated LC/MS/MS method was applied to a pharmacokinetic study in which healthy Chinese volunteers each received a single oral dose of 5 mg donepezil hydrochloride. The non-compartmental pharmacokinetic model was used to fit the donepezil plasma concentration-time curve. Maximum plasma concentration was... 

Figure 16 Changes to pharmacokinetic parameters over 13-week dosing regimen. (A) Maximum plasma concentration (Cmax) of DFP determined after single doses of 10, 30, or 100 mg/kg of DFP compared to the Cmax after 13 weeks of dosing. (B) AUC after a single dose of 10, 30, or 100 mg/kg of DFP compared with the Cmax after 13 weeks of dosing. Abbreviations DFP, [(5,5-dimethyl-3-(2-propoxy)-4-(4-methanesulfonylphenyl)-2(5//)-furanone)J AUC, area under the plasma concentrationtime curve. Source From Ref. 64.

An indication of the rate of drug absorption can be obtained from the peak (maximum) plasma concentration (Cmax) and the time taken to reach the peak concentration (fmjx), based on the measured plasma concentration-time data. However, the blood sampling times determine how well the peak is defined and, in particular, fmax. Both Cmax and tm3LX may be influenced by the rate of drug elimination, while Cmax is also affected by the extent of absorption. The term Cmax/ AUC, where AUC is area under the curve from time zero to infinity or to the limit of quantification (LOQ) of the analytical method, provides additional information on the rate of absorption. This term, which is expressed in units of reciprocal time (h ), can easily be calculated. In spite of the imprecision of the estimation provided by Cmax, it generally suffices for clinical purposes. 

Several different suppository formulations were evaluated in monkeys to determine the formulation that maximized bioavailahility and reduced first-pass metabolism of THC by the fiver (Mattes et al. 1993, 1994) THC-hemisuccinate provided the highest bioavailahility of 13.5%. Brenneisen et al. evaluated plasma THC concentrations in two patients who were prescribed THC hemisuccinate suppositories or Marinol for spasticity (Brenneisen et al. 1996). THC did not accumulate in the blood following 10 to 15 mg daily doses. THC concentrations peaked within 1 to 8 h after oral administration and ranged between 2.1 and 16.9 ng/ml. Rectal administration of 2.5 to 5 mg THC produced maximum plasma concentrations of... 

GHB exhibits zero-order (constant rate) elimination kinetics after an intravenous dose. Since GHB exhibits zero-order kinetics, it has no true half-life. The time required to eliminate half of a given dose increases as the dose increases. A daily therapeutic dose of 25 mg kg has an apparent half-life of about 30 min in humans, as determined in alcohol dependent patients under GHB treatment (Ferrara et al., 1992). In contrast, an apparent half-life of 1-2 h was observed in dogs when they were given high intravenous doses of GHB. In humans it has been documented that there is increased rate of absorption if GHB is administered on an empty stomach, resulting in a reduced time to reach the maximum plasma concentration of GHB (Borgen et al., 2001). 

Unlike the one-compartment first-order absorption model, the time hax of the maximum plasma concentration (Cmax) cannot be written in a solved equation form. Thus determination of hax and C ax for this model requires a trial-and-error approach in which a time (<) is guessed and the plasma concentration (Cp) is calculated repeatedly until the C ax and hax are identified. 

Clearly, to be able to apply this approach in projects at an early stage, a validation is necessary that convinces the teams that this data will be useful. To this end, dose, C ax (maximum plasma concentration), and C ,i (minimum plasma concentration, at 12 h time point) data from a number of AZ CD compounds (22 compounds in total, comprising 4 acids, 6 bases, 11 neutrals, and 1 zwitterion) that have entered phase I clinical trials, usually across a number of dose levels, were collated. Human dose predictions (eD2M values) for this compound data set were also undertaken, using the models and inputs described above, while in vitro clearance was described by CLm, data determined in human hepatocytes. All clinically utilized human doses were then normalized in two ways. 

Age does not significantly affect plasma concentrations or disposition of ibuprofen however, investigators have determined that the onset of antipyresis and maximum antipyretic effect is greater in children less than one year old as compared to children older than 6 years [43]. The authors hypothesized that this accelerated response was related to the greater relative body surface area of the young child. It should be noted that cystic fibrosis patients do have a higher clearance of ibuprofen [43a]. 

This information may affect selection criteria for the study population and the choice of tests in addition to routine safety monitoring, and will certainly determine the starting dose, range of doses, maximum exposure and dose increments to be studied. Pharmacokinetics in man may be quite different from those in animal species so that plasma and, if possible, tissue concentrations are generally more important than dose. One exception to this may be hepatotox-icity resulting from exposure of the liver to portal blood drug concentrations, when the oral dose administered to the animals may be more relevant than the systemic plasma concentrations, which reflect first-pass metabolism as well as absorption. 

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. 

Pharmacokinetic studies with sheep treated with the recommended dosage showed that praziquantel was rapidly absorbed, peak plasma concentration being reached within 2 h of dosing (72). A half-life of 4.2 h was determined and excretion from plasma was rapid, 98% being excreted within 72 h. At 8 h posttreatment, the maximum levels present in liver, kidneys, muscle, and fat were 2.87, 2.55, 0.19, and 0.1,3 ppb, respectively, of praziquantel equivalents. At 24 h post-... 

The usual daily dose ranges of antidepressants are shown in Table 30-4. Doses are almost always determined empirically the patient s acceptance of adverse effects is the usual limiting factor. Tolerance to some of the objectionable effects may develop, so that the usual pattern of treatment has been to start with small doses, increasing either to a predetermined daily dose, or to one that produces relief of depression, or to the maximum tolerated dose (except in the case of nortriptyline, which loses efficacy at plasma concentrations over 150 ng/mL). 

---