Plasma concentration, pharmacokinetics analysis

If the unbound drug concentrations in plasma are higher than their K values on the transporters, then transporter function may be significantly affected [106], Following a pharmacokinetic analysis of the effect of probenecid on the hepatobiliary excretion of methotrexate, it has been shown the extent of an in vivo drug-drug interaction can be quantitatively predicted from the kinetic parameters for transport across the sinusoidal and bile canalicular membranes determined in vitro [107]. 

No modern studies of the human pharmacokinetics of LSD have been done, largely because human experimentation has virtually stopped. An older study that used a spectrofluorometric technique for measuring plasma concentrations of LSD was done in humans given doses of 2 Mg/kg i.v. After equilibration had occurred in about 30 min, the plasma level was between 6 and 7 ng/ml. Subsequently, plasma levels gradually fell until only a small amount of LSD was present after 8 hr. The half-life of the drug in humans was calculated to be 175 min (2). Subsequent pharmacokinetic analysis of these data indicated that plasma concentrations of LSD were explained by a two-compartment open model. Performance scores were highly correlated with concentration in the tissue (outer) compartment, which was calculated at 11.5% of body weight. The new estimation of half-life for loss of LSD from plasma, based on this model, was 103 min (47). 

Pharmacokinetic data reported thus far show dose-proportional exposure with a short half-life of ca. 2 h. Exposure in patients receiving 250 mg/day of CP-724714 reportedly exceeds the plasma levels required for efficacy in precHnical tiunor xenograft models (50 to 60% TGI). However, robust efficacy (stasis or minor regression) in mouse models was only achieved at doses resulting in plasma exposures 40% higher than those observed in humans. From a kinetic standpoint, it appears that within 3 h, plasma concentrations in hiunans of CP-724714 fall below the levels required for pErbB knockdown in mouse models. This analysis, of course, neglects free fraction differences that may exist between species and the differential levels of active metabohtes. Enrollment in this trial continues at the 250 mg/tid dosing level. 

It is possible to predict what happens to Vd when fu or fur changes as a result of physiological or disease processes in the body that change plasma and/or tissue protein concentrations. For example, Vd can increase with increased unbound toxicant in plasma or with a decrease in unbound toxicant tissue concentrations. The preceding equation explains why because of both plasma and tissue binding, some Vd values rarely correspond to a real volume such as plasma volume, extracellular space, or total body water. Finally interspecies differences in Vd values can be due to differences in body composition of body fat and protein, organ size, and blood flow as alluded to earlier in this section. The reader should also be aware that in addition to Vd, there are volumes of distribution that can be obtained from pharmacokinetic analysis of a given data set. These include the volume of distribution at steady state (Vd]SS), volume of the central compartment (Vc), and the volume of distribution that is operative over the elimination phase (Vd ea). The reader is advised to consult other relevant texts for a more detailed description of these parameters and when it is appropriate to use these parameters. 

Objective The objective of this analysis was to develop a population pharmacokinetic model for NS2330 and its major metabolite Ml, based on data from a 14-week proof of concept study in Alzheimer s disease patients, including a screening for covariates that might influence the pharmacokinetic characteristics of the drug and/or its metabolite. Subsequently, several simulations should be performed to assess the influence of the covariates on the plasma concentration-time profiles of NS2330 and its metabolite. 

The primary analysis examined pharmacokinetic parameters calculated from plasma concentrations of CYS-conjugated XYZ1234 using non-compartmental techniques. The secondary analysis examined the pharmacokinetic parameters of unconjugated XYZ1234. 

NAPA concentrations in erythrocytes were 1.5 times as high as in plasma/ and this preferential distribution of drug into red blood cells enhanced drug removal by hemodialysis. Unfortunately/ most hemodialysis studies have not incorporated the full range of readily available measurements in an integrated pharmacokinetic analysis. 

No change, often based on steady-state plasma concentration rather than full pharmacokinetic analysis. 

Pai, S.M. Shukla, U.A. Grasela, T.H. Knupp, C.A. Dolin, R. Valentine, F.T. McLaren, C. Liebman, H.A. Martin, R.R. Pittman, K.A. Barbhaiya, R.H. Population pharmacokinetic analysis of didanosine (2, 3 -dideoxyino-sine) plasma concentration obtained in phase I clinical trials in patients with AIDS or AIDS-related complex. J. Clin. Pharmacol. Ther. 1995, 52, 164—169. 

Metabolism and elimination Plasma concentrations of alosetron increase proportionality with increasing single oral doses up to 8 mg and more than proportionately at a single oral dose of 16 mg. Twice-daily oral dosing of alosetron does not result in accumulation. The terminal elimination half-life of alosetron is 1.5h (plasma clearance is 600 ml min ). Population pharmacokinetic analysis in IBS patients confirmed that alosetron clearance is minimally influenced by doses up to 8 mg. 

Pharmacokinetic analysis revealed R115777 to be rapidly absorbed with peak plasma concentrations being reached by 3 to 4 h and steady state levels after 3 days. The degree of bioavailability and the steady state levels attained were sufficient pharmacologically for antitumor effects as predicted by preclinical experiments. The drug exhibits biphasic elimination with half-lives of 4 h and 16 h. 

When the drug is administered as an intravenous bolus dose, the total areas under the curves can be calculated from the coefficients and exponents of the equation describing the disposition curve and obtained by compartmental pharmacokinetic analysis of the plasma concentration-time data. 

Stage 1 Pharmacokinetic (PK) data from the healthy subject studies (studies 1 and 2) were analyzed using the statistical moments analysis approach. From the results of the analysis, peak concentration (Cmax) and area under the plasma concentration curve (AUC) were selected for exploring the relationship between exposure and safety data (biomarker elevation). 

PHARMACOKINETICS The area under the plasma concentration-time curve (AUC) was identified, in a preliminary analysis, as the important exposure covariate that was predictive of the safety biomarker outcome. Consequently, it became necessary to compare the distributions of AUC values across studies and dosage regimens. Figure 47.8 illustrates distributions of the exposure parameter AUC across studies. It is evident that AUC values are higher in diseased subjects than in healthy volunteer subjects at the same dose level. To adjust for the difference between the two subpopulations, an indicator function was introduced in a first-order regression model to better characterize the dose-exposure data. Let y be the response variable (i.e., AUC), X is a predictor variable, P is the regression coefficient on x, and e is the error term, which is normally distributed with a mean of zero and variance cP. Thus,... 

An integrated summary and analysis is to be provided on all data that pertain to dose-response or drug candidate plasma concentration-response relationships of effectiveness and thus to contribute to dose selection, dosing interval, and dosage duration. Relevant data from nonclinical and clinical studies should be referenced and, where appropriate, summarized to illustrate further and describe these relationships. Any identified deviations (e.g., nonlinearity of pharmacokinetics, delayed effects, tolerance, enzyme induction) from relatively simple relationships should be discussed. Also, any evidence of differences in the relationships that result from the age, gender, race, disease status, or other factors of the patients should be described. How the potential for these deviations and differences were evaluated, even if no differences were found, should be described. 

HI-6 was administrated to rats in dose 36,0 mg/kg b.w. ( l,0xl0-4 M/kg b.w.), Diazepam - 2,5 mg/kg and Scopolamine - 0,5 mg/kg, b.w. administrated i.m. Rats intoxicated with 1,5 LD50 soman (70 pg/b.w., i.m.) were treated 1 min later with drug combination. A HPLC-method for analysis of HI-6 was used. Time-related plasma concentrations were fitted to one-compartment pharmacokinetic model. The result of plasma concentrations are presented in Figure 8 and pharmacokinetics parameters on Table 7. 

---