Pharmacokinetics distribution volumes

In addition to the possibility of improving therapeutic effects, structural modifications utilizing pharmacokinetic analysis of drug distribution can explain and potentially avoid toxlcitles by selective distribution away from specific tissues. This has been demonstrated in relation to aminoglycoside nephrotoxicity, 5 and accumulation of -adreno-ceptor antagonists in the lungs.However, the full potential for the use of pharmacokinetic distribution volumes in drug development has yet to be realized. 

Usually, one has obtained an estimate for the elimination constant and the distribution volume Vp from a single intravenous injection. These pharmacokinetic parameters, together with the interval between administrations 0 and the single-dose D, then allow us to compute the steady-state peak and trough values. The criterion for an optimal dose regimen depends on the minimum therapeutic concentration (which must be exceeded by and on the maximum safe... 

The three main parameters of clinical pharmacokinetics are clearance, distribution volume, and bioavailability. Clearance is the rate at which the body eliminates a drug. In order to achieve a steady-state concentration, the drug must be given so that the rate of clearance equals the rate of administration. If the drug is given as quickly as it is eliminated, a consistent level in the body will be maintained. 

When a drug is administered intravenously into the circulation the compound undergoes distribution into tissues etc. and clearance. For a drug that undergoes rapid distribution a simple model can explain the three important pharmacokinetic terms volume of distribution, clearance and half-life. 

Pharmacokinetics The volume of distribution of filgrastim averages 150mFkg. Its distribution half-life is 30 minutes, and its elimination half-life is 3 to 4 hours with a clearance of 0.5 to O.TmFmin per kilogram. 

Pharmacokinetics Complete and consistent blocking of the IL-2 receptor is maintained as long as serum basiliximab levels exceed 0.2pg/ml. As concentrations fall below this level, expression of IL-2 receptor returns to pre-therapy values within 1-2 weeks. Basiliximab has a steady-state volume of distribution of 9 liters and total body clearance of 41 ml/h. Its elimination half-life ranges from 7 to 10 days. There is a dose-proportional increase in peak concentration (Cmax) and area under the curve (AUC) up to the highest tested single dose of 60 mg. No clinically relevant influence of body weight or gender on distribution volume or clearance has been observed in adult patients. Elimination... 

The next section is a summary of the bioavailability/pharmacokinetic data and the overall conclusions. The summary should include a table with the following pharmacokinetic parameters peak concentration (Cmax), AUC, time to reach peak concentration (Tmax), elimination constant (kel), distribution volume (Vd), plasma and renal clearance, and urinary excretion. Overall conclusions as well as any unresolved problems should be discussed. 

In the present chapter, we have used an updated version of the VolSurf procedure to exemplify its validity for predicting physicochemical (solubility and log P) and pharmacokinetic properties (volume of distribution and metabolic stability) of drug molecules. 

Pharmacokinetics provides the scientific basis of dose selection, and the process of dose regimen design can be used to illustrate with a single-compartment model the basic concepts of apparent distribution volume (Vd), elimination half-life (b/2) and elimination clearance (CLg). A schematic diagram of this model is shown in Figure 2.4, along with the two primary pharmacokinetic parameters of distribution volume and elimination clearance that characterize it. 

In contrast to elimination clearance, elimination half-life (b 72) is not a primary pharmacokinetic parameter because it is determined by distribution volume as well as by elimination clearance. 

The three estimates of distribution volume that we have encountered have slightly different properties (24). Of the three, Vd(ss) has the strongest physiologic rationale for multicompartment systems of drug distribution. It is independent of the rate of both drug distribution and elimination, and is the volume that is referred to in Equations 3.1 and 3.2. On the other hand, estimates of V ( area) most useful in clinical pharmacokinetics, since it is this volume that links elimination clearance to elimination half-life in the equation... 

FIGURE 30.2 Two-compartment model for peritoneal pharmacokinetics. Drug administered via a catheter is placed in the peritoneal cavity with a distribution volume of VpQ, yielding concentrations within the peritoneum of Cpc- Subsequent transfer betw een the peritoneum and the body compartment is mediated by diffusion with a permeability coefficient—surface area product of PA. CLp is the elimination clearance from the body. Plasma drug concentrations (Cp ) and systemic toxicity are minimized because the distribution volume of the body compartment (Vd) is much greater than VpQ and because CLp prevents complete equilibration of concentrations in the tw o compartments. (Adapted from Dedrick RL et al. Cancer Treat Rep 1978 62 1-11.)... 

Last, population pharmacokinetics of sibrotuzumab, a humanized monoclonal antibody directed against fibroblast activation protein (FAP), which is expressed in the stromal fibroblasts in >90% of malignant epithelial tumors, were analzyed in patients with advanced or metastatic carcinoma after multiple IV infusions of doses ranging from 5 mg/m to a maximum of 100 mg (78). The PK model consisted of two distribution compartments with parallel first-order and Michaelis-Menten elimination pathways from the central compartment. Body weight was significantly correlated with both central and peripheral distribution volumes, the first-order elimination clearance, and ymax of the Michaelis-Menten pathway. Of interest was the observation that body surface area was inferior to body weight as a covariate in explaining interpatient variability. 

Pharmacokinetics. Amiodarone is effective given orally its enormous apparent distribution volume (701/kg) indicates that little remains in the blood. It is stored in fat and many other tissues and the t) of 54 days after multiple dosing signifies slow release from these sites (and slow accumulation to steady state means that a loading dose is necessary, see Table 24.1). The drug is metabolised in the liver and eliminated through the biliary and intestinal tracts. 

Test Items. As a rule, the pharmacokinetic parameters of test substances such as maximum concentration (Cmax) and time to reach maximum concentration (Tmax), area under curve (AUC), elimination half-life, clearance, distribution volume, bioavailability, etc., and pharmacokinetic nonlinearity are studied. The pharmacokinetics of metabolites of the test substance should be examined if necessary. 

Klotz, U. (1976) Pathophysiological and disease-induced changes in drug distribution volume pharmacokinetic implications. Clinical Pharmacokinetics, 1, 204-218. 

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