Plasma concentration analysis

Kurowski M, Arslan A MoeckJinghoff C, Sa er W, Hill A. Effects of ritonavir on saquinavir plasma concentration analysis of 271 patients in routine clinical practice (P261 A). AIDS (2000) 14 (Suppl 4), 591. 

The simplest toxicokinetic analysis involves measurement of the plasma concentrations of a chemical at several time points after the administration of... 

The quantities AUMC and AUSC can be regarded as the first and second statistical moments of the plasma concentration curve. These two moments have an equivalent in descriptive statistics, where they define the mean and variance, respectively, in the case of a stochastic distribution of frequencies (Section 3.2). From the above considerations it appears that the statistical moment method strongly depends on numerical integration of the plasma concentration curve Cp(r) and its product with t and (r-MRT). Multiplication by t and (r-MRT) tends to amplify the errors in the plasma concentration Cp(r) at larger values of t. As a consequence, the estimation of the statistical moments critically depends on the precision of the measurement process that is used in the determination of the plasma concentration values. This contrasts with compartmental analysis, where the parameters of the model are estimated by means of least squares regression. 

Compartmental analysis is the most widely used method of analysis for systems that can be modeled by means of linear differential equations with constant coefficients. The assumption of linearity can be tested in pharmaeokinetic studies, for example by comparing the plasma concentration curves obtained at different dose levels. If the curves are found to be reasonably parallel, then the assumption of linearity holds over the dose range that has been studied. The advantage of linear... 

The principle of ICP-AES is that atoms (or sometimes ions) are thermally excited, in a plasma torch, to higher energy levels, these atoms or ions then relax back to lower electronic energy levels by emitting radiation in the UV-visible region. The emitted radiation is detected and used to determine which elements are present, and their concentration. Analysis of organometallic and inorganic additives, based on the ICP-AES determination of specific metal ions, is routinely undertaken. 

From such rat neuropharmacokinetic studies, in which animals (N = 2/ time point, >2 doses) are euthanized at specific time points postdose for plasma, CSF, and brain collection for compound concentration analysis, composite neuromatrix-specific compound concentration-time curves are generated (Figure 2). 

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). 

The apparent retinal influx clearance,. Kin,retina expressed as mL/(min g retina), of the test substrate labeled with either [3 H] or [14C] from the circulating blood to the retina is determined by integration plot analysis. In brief, rats are anesthetized, followed by injection of the test substrate (e.g., an [3H]-labeled compound, about 10 /u.Ci/head) into the femoral vein. After collection of plasma samples, rats are decapitated and the retinas removed. The retinas are dissolved in 2 N NaOH and subsequently neutralized with 2 N HC1. The radioactivity of retinal cell lysates is measured by liquid scintillation spectrometry. As an index of the retinal distribution characteristics of the radiolabeled test substrate, the apparent retina-to-plasma concentration ratio (Vd) as a function of time is used. This ratio [Vd(Q] (mL/g retina) is defined as the amount of [3H] per gram retina divided by that per milliliter plasma, calculated over the time-period of the experiment. The Kjn,retina can be described by the following relationship ... 

Bioavailability of human insulin assessed from pharmacological data. After extravascu-lar administration only the time course governs the observed pharmacological effects. The pharmacological data was translated into theoretical plasma-concentration data using the PK/PD model. The results of the PK/PD analysis indicate that the doses administered can be accurately predicted from pharmacological data... 

Responses in the dopamine system are more complex (see chapter by Balfour, this volume). Repeated nicotine injections resulted in enhanced extracellular DA levels in the NAc (Benwell and Balfour 1992, 1997), but not in the striatum (Benwell and Balfour 1997). Analysis of the precise placement of dialysis probes has revealed differential responses to drugs of abuse, including nicotine, between the NAc core (ventral striatum) and shell (Di Chiara 2002 Balfour 2004 Wonnacott et al. 2005 see chapter by Balfour, this volume). Moreover, the sensitised neurotransmitter responses observed in the hippocampus and NAc were markedly attenuated if rats received a constant infusion of a low level of nicotine (Benwell and Balfour 1997). Thus, transient peaks of nicotine appear capable of sensitising some brain pathways with respect to catecholamine release, but the responses may be mitigated by lower sustained plasma concentrations, possibly due to desensitisation. The extent that presynaptic nAChRs contribute to this process in vivo is unclear presynaptic a7 nAChRs on glutamatergic afferents to the VTA merit attention as potential mediators of sensitisation (see Sect. 2.2.2). 

Figure 2.4. In vivo measurement of blood-brain barrier (BBB) permeability, (a) Internal carotid artery perfusion technique (i) in the rat. Other branches of the carotid artery are ligated or electrically coagulated (o, occipital artery p, pterygopalatine artery). The external carotid artery (e) is cannulated and the common carotid artery (c) ligated. Perfusion time may range from 15 s to 10 min, depending on the test substance. It is necessary to subtract the intravascular volume, Vo, from (apparent volume of distribution), to obtain true uptake values and this may be achieved by inclusion of a vascular marker in the perfusate, for example labelled albumin. Time-dependent analysis of results in estimates of the unidirectional brain influx constant Ki (pi min which is equivalent within certain constraints to the PS product. BBB permeability surface area product PS can be calculated from the increase in the apparent volume of distribution Vd over time. Capillary depletion, i.e. separation of the vascular elements from the homogenate by density centrifugation, can discriminate capillary uptake from transcytosis. (b) i.v. bolus kinetics. The PS product is calculated from the brain concentration at the sampling time, T, and the area under the plasma concentration-time curve, AUC.

Here Cbrain is the brain concentration after correction for intravascular content, and AUC is determined between time 0 and the final sampling time. Two assumptions must hold when interpreting the evaluation in the simple form described above (1) the brain uptake of the compound is linear, meaning is dose independent, and (2) the analysis is performed within a time-frame where the efflux from tissue is negligible (tissue concentrations are sufficiently low compared to plasma concentrations). Violation of these assumptions requires adjustments in experimental design and evaluation. For example, nonlinear kinetics may be accounted for by incorporation of a MichaeUs-Menten term, while efflux can be treated by compartmental analysis [46]. 

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. 

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