Rowland and Tozer method

The Rowland and Tozer method allows the elimination half life and elimination rate constant to be calculated for an administered drug by using plasma concentration-time data obtained during the infusion period (i.e. plasma concentration values in the post-infusion period are not required). 

Plot the difference between the steady-state plasma concentration and the observed plasma concentration in Table 10.4 (i.e. (Cp)ss — (Cp)obs) versus time on semilogarithmic paper (values 

The elimination half life and elimination rate constant are calculated by the methods described above. Please note that this method will yield an accurate estimate of parameters provided that the 

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Figure 10.20 Rowland and Tozer method. Data from Table 10.4 is plotted. (Cp)ss - (Cp)obs/ the difference between plasma concentration at steady state and that observed during the infusion, fi/2, half life of drug K, elimination constant. See text for further details.

In dmg discovery, preliminary PK studies are usually conducted in rodents to evaluate the extent of dmg exposure in vivo. This is commonly followed by PK studies in larger animals such as dog or monkey to better characterize the PK profile of the compound and to support safety studies. Pharmacokinetic scaling (also called allometry) is a discipline that is used to predict human PK profiles using preclinical data and is widely used in predicting the dmg human half-life, dose, and extent of absorption. Accurate prediction of a human PK profile is imperative to minimize dmg failure in development due to poor PK attributes. A detailed description of methods in predicting human PK is beyond the scope of this chapter but can be found in many excellent reviews (Obach et al., 1997 Miners et al., 2004 Poggesi, 2004 Raunio et al., 2004 Thomas et al., 2006 Hurst et al., 2007). A more in-depth discussion of various PK concepts and their applications can be found in various references (Gibaldi and Perrier, 1982 Rowland and Tozer, 1995 Hurst et al., 2007). 

If specific literature recommendations and/or the relationship of kinetic parameters to CLcr are not available, then one can estimate the kinetic parameters of the patient with the method of Rowland and Tozer, provided you know the fraction of the drug that is eliminated renaUy unchanged (f ) in subjects with normal renal function. This approach assumes that the change in CL and k are proportional to CLcr, that renal disease does not alter the drug s metabolism, that the metabolites if formed are inactive and nontoxic, that the drug obeys first-order (linear) kinetic principles, and that it is adequately described by a one-compartment model. If these assumptions are true, then the kinetic parameter/dosage adjustment factor (Q) can be calculated as ... 

Regardless of whether the data are analysed by a compartmental or non-compartmental method, the duration of blood sampling and the limit of quantification of the analytical method used to measure the drug concentration are important features of the pharmacokinetic study. The MRT, after an intravenous bolus dose of a drug can be estimated from either plasma drug concentration or urinary excretion data (Rowland Tozer, 1989). 

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