Clearance estimation

An important DMPK property of a NCE is oral bioavailability (F) of the compound in various pre-clinical species.3 The oral bioavailability of a compound is dependent on several factors including intestinal permeability (estimated by the Caco-2 assay) and hepatic clearance (estimated with an in vitro metabolic stability assay).3 30 The metabolic stability assay is typically performed by incubating test compounds in liver microsomes or hepatocytes. The results can provide estimates of in vivo stability in terms of metabolic liabilities.3 8 59 62 Several authors described this assay as an important tool for the rapid assessment of the DMPK properties of NCEs.3 6 8111819 26 44 59 62-65... 

In a first stage, distribution was predicted with tissue composition-based equations and the estimated tissue partition coefficients were combined with clearance estimated by direct scaling of hepatocyte intrinsic clearance in a PBPK model as described earlier. 

Modifications of the EMBT have been described to improve its predictability in drug clearance estimations in cancer patients (Rivory 2000). 

From the standpoint of clinical pharmacology/ the utility of using the Cockcroft and Gault equation/ or other methods/ to estimate creatinine clearance stems from the fact that these estimates can alert healthcare workers to the presence of impaired renal function in patients whose creatinine formation rate is reduced. As discussed in Chapter 5, creatinine clearance estimates also can be used to guide dose adjustment in these patients. 

Vmax and Km for MDZ 1 -liydroxylation. V,nax determined for each biopsy sample was then scaled to the estimated total liver mass and intrinsic clearance estimated as total liver Vmax/Kn- Hepatic clearance then was predicted from Equation 7.6 in Chapter 7. Figure 30.13 compares the observed total elimination clearance with predicted hepatic clearance based on the assumption that the E-hydroxylation pathway accounts for 70% of the substrate loss. The prediction is quite good. The average absolute deviation between the five observed data points and their predicted values is only 28% and the differences are uniformly distributed. 

Kidney size and GFR are roughly proportional to body size. It is conventional therefore to adjust clearance estimates to a standard body surface area (BSA) of 1.73 m, according to the formula devised by Du Bois and Du Bois in 1916"h... 

They observed that the MDRD equation provided more accurate assessment of GFR than either the Cockcroft and Gault equation or measured creatinine clearance. The MDRD formula has several advantages (1) it was developed and validated in a large population, (2) it was developed with a population that included both European-Americans and African-Americans, (3) it does not require patient weight, (4) it was validated against an iothalamate clearance estimate... 

Similar to the techniques used for calculation of chemical disposition parameters, in vivo biotransformation kinetic parameters of a substrate can be estimated from in vitro systems such as microsomes, freshly isolated hepatocytes, fiver slices, and isolated perfused livers (24). Intrinsic clearance or Michaelis-Menten parameters for the whole liver can also be obtained by scaling in vitro parameters based on the cytochrome P450 enzyme content (25-27). These parameters can also be estimated from in vitro data obtained from recombinant human CYP systems, and also through allometric scaling of clearance estimates from animal PBPK models. 

Luke DR, Halstenson CE, Opsahl JA, et al. Validity of creatinine clearance estimates in the assessment of renal function. Clin Pharmacol Ther... 

Davis GA, Chandler MHH. Comparison of creatinine clearance estimation metiiods in patients with trauma. Am J Healtii Syst Pharm 1996 53 1028-1032. 

In the pharmacokinetic arena, there are many cases where the independent variable is measured with error and a classical measurement model is needed. Some examples include in vitro in vivo correlations, such as the relationship between Log P and volume of distribution (Kaul and Ritschel, 1990), in vivo clearance estimates based on in vitro microsomal enzyme studies... 

The well-stirred model therefore allows prediction of in vivo clearance from intrinsic clearance estimates, generated from simple enzyme, sub-cellular or cellular assays. 

The Chion eqnation only provides accnrate clearance estimates if the infnsion rate was constant, serum concentration sample drawings were separated by an interval of at least one half-life, and measurements were performed with a reliable... 

Relationship between Intrinsic Clearance and Organ Clearance Estimation of Permeabihty-Limited Clearance Prediction of Absorption... 

The Monte Carlo based model was built of the clearance between ships and the span. The random variables and their parameters were estimated he the base results obtained in the project The creation of the method of dynamic and probabilistic underkeel clearance estimation [L. Gucma, 2008d]. To build example solution the example bridge on the fairway Szczecin-Swinoujscie with the height above water level of H = 36 m have been chosen. The maximum ship, which can enter to Szczecin now is ship with following parameters L = 160 m, T = 9,15 m, and A = 35 m. The horizontal clearance have been calculated for two ship speeds 8 and 4 kn. Input data to the model one are presented in the Table 1. Monte Carlo simulations... 

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