Elimination clearance and

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. 

For drugs with a linear disposition, the clearance, the generalized elimination clearance, and the distribution clearance are simply related by... 

The effect of hemofiltration on drug elimination can be estimated from serum creatinine (SCr), age, and the MDRD-2 formula to predict the combined effect of filtration rate (eGFR = GFRresidual + HFR) on drug clearance and drug half-life during hemofiltration. 

The area under the PCP concentration-time curve (AUC) from the time of antibody administration to the last measured concentration (Cn) was determined by the trapezoidal rule. The remaining area from Cn to time infinity was calculated by dividing Cn by the terminal elimination rate constant. By using dose, AUC, and the terminal elimination rate constant, we were able to calculate the terminal elimination half-life, systemic clearance, and the volume of distribution. Renal clearance was determined from the total amount of PCP appearing in the urine, divided by AUC. Unbound clearances were calculated based on unbound concentrations of PCP. The control values are from studies performed in our laboratory on dogs administered similar radioactive doses (i.e., 2.4 to 6.5 pg of PCP) (Woodworth et al., in press). Only one of the dogs (dog C) was used in both studies. 

In patients who have failed initial therapy (i.e., salvage), liposomal amphotericin products, itraconazole, or the echinocandin caspofungin can be used. Itraconazole has a response rate of approximately 40%.100 Oral itraconazole exhibits erratic absorption the IV formulation is suspended in cyclodextrin, which is eliminated renally, and thus IV itraconazole should be avoided in patients with a creatinine clearance of less than 30 mL/minute (0.29 mL/s m2).103 Itraconazole also has negative inotropic cardiac effects and increases the serum concentrations of medications (e.g., cyclophosphamide, etopo-side, calcineurin inhibitors, and sirolimus). 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

Only a subset of the parameter values in the O Flaherfy model require inputs from the user to simulate blood and tissue lead concentrations. Lead-related parameters for which values can be entered into the model include fractional absorption from the gastrointestinal tract partition coefficients for lead in nonbone tissues and in the surface region of bone maximum capacity and half-saturation concentration for capacity-limited binding in the erythrocyte elimination clearance fractional clearance of lead from plasma into forming bone and the restricted permeability coefficients for lead diffusion within bone, from plasma into bone, and from bone into plasma (O Flaherty 1991a). 

Mihaly et al. [127] examined the pharmacokinetics of primaquine in healthy volunteers who received single oral doses of 15, 30, and 45 mg of the drug, on separate occasions. Each subject received an intravenous tracer dose of 14C-prima-quine (7.5 pCi), simultaneously with 45 mg oral dose. Absorption of primaquine was virtually complete with a mean absorption bioavailability of 0.96. Elimination half-life, oral clearance, and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size or route of administration. 

Renal elimination of unchanged drug accounts for 66% of drug clearance, and the dose should be adjusted for impaired renal function. The role of therapeutic drag monitoring is unknown. It has linear pharmacokinetics and is metabolized in blood by nonhepatic enzymatic hydrolysis. 

TABLE 77-3 Relationship between Creatinine Clearance and Total-Body Clearance and Terminal Elimination Rate Constant of Selected Drugs ... 

T or si Free fraction of highly plasma protein-bound drugs si Clearance and T t1/2 for some oxidatively metabolized drugs si Clearance and T t1/2 for drugs with high hepatic extraction ratios si Clearance and T t 2 for renally eliminated drugs and active metabolites... 

The absorption of inhaled -hexane has been investigated in six healthy male volunteers (Veulemans et al. 1982). Three different trials were performed on each volunteer 4-hour exposure at 102 ppm -hexane 4-hour exposure at 204 ppm, and exposure during exercise on a stationary bicycle ergometer at 102 ppm. Each trial was done at least two weeks apart. Lung clearance (from alveolar air to blood) and retention were calculated from -hexane concentrations in inhaled and expired air. After exposure, /7-hcxane in exhaled air was measured for up to 4 hours to determine respiratory elimination. Retention of -hexane (calculated from lung clearance and respiratory minute volume) was approximately 20-25%... 

The term clearance is used here in the sense of total body clearance and is analogous to the term renal clearance. The body as a whole is regarded as acting as a xenobiotic-eliminating system, where the rate of elimination divided by the average plasma concentration of the compound is the total body clearance. Here clearance is calculated (25) by dividing the administered dose of the substance by the area under the plasma concentrationtime curve produced by that dose. This pharmacokinetic parameter, as well as others presented in this publication, was calculated by the use of the MLAB on-line computer system established at the National Institutes of Health by Knott and Reece (26). Similar to t the total clearance is a composite of the individual clearances of the material by the various tissues of the body. 

Half-lives estimated after the administration of vinblastine to patients were 4 min, 1.6 hr, and 25 hr, indicating rapid distribution of the drug to most tissues, relatively rapid clearance, and a subsequent slow terminal elimination process. The distribution and initial clearance phase for vincristine are kinetically comparable to those observed for vinblastine half-lives for these phases have been reported to be 4 min and 2.3 hr in studies with vincristine. The terminal elimination phase for vincristine has been reported to be three to four times longer than that estimated for vinblastine, and the slow elimination of vincristine from susceptible neuronal tissue has been suggested to play a role in the neurotoxicity commonly observed in clinical settings with vincristine but not with vinblastine 51). 

Figure 13.1. Compartmental model based on clearance and volume (Section 13.2.4.1). The drug is administered at a rate Ri into the central compartment, which is characterized by a volume of distribution K. The drug is transported to and from the peripheral compartment with inter-compartmental clearance CL12 and CL21, respectively (usually it is assumed that there is no net transport between the two compartments if the concentrations in both compartments are equal in this case CL21 = CLi2)- The peripheral compartment is characterized by a volume of distribution 1 2-Elimination may take place from both compartments and is characterized by clearance CL o and CL20, respectively.

Walton et al. (2004) determined the extent of interspecies differences in the internal dose of compounds, which are eliminated primarily by renal excretion in humans. Renal excretion was also the main route of elimination in the test species for most of the compounds. Interspecies differences were apparent for both the mechanism of renal excretion (glomemlar filtration, tubular secretion, and/or reabsorption), and the extent of plasma protein binding. Both of these may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which were eliminated unchanged by both humans and the test species, the average difference in the internal dose between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats, and 13 for mice. This suggests that for renal excretion the differences between humans and the rat, and especially the mouse, may exceed the fourfold default factor for toxicokinetics. 

Abbreviations include t elimination half-life Cl, total plasma clearance and Clj-enab renal clearance. Data expressed as mean values (from James et al., 1998). 

A single study in humans reports clearance and elimination by gender for... 

The blood concentrations, time-courses, and half-lives (1,2-1.4 h) of 2-PAM and toxogonin are similar in humans,but toxogonin has a smaller volume of distribution than 2-PAM (174 vs. 795 ml/kg) and a smaller renal elimination (clearance, 133 vs. 717 ml/min). The smaller volume of distribution and slower clearance Imply different distribution and handling of the two oximes. They also imply that, if toxogonin and 2-PAM were given In equimolar concentrations, the toxogonin plasma concentration would be greater than that of 2-PAM. 

Pharmacokinetics According to the product label, the pharmacokinetics of eptihbatide are linear and dose proportional. Plasma elimination half-life is approximately 2.5 hours. The extent of eptihbatide binding to human plasma protein is about 25% its mean volume of distribution is 185mPkg. Clearance in patients with coronary artery disease is 55-58 ml/kg per hour. Clinical studies have included 2418 patients with serum creatinine between 1.0 and 2.0mg/dl without dose adjustment. No data are available in patients with more severe degrees of renal impairment, but plasma eptihbatide levels are expected to be higher in such patients. Patients in clinical studies were older than the subjects in clinical pharmacology studies, and they had lower total body eptihbatide clearance and higher eptihbatide plasma levels. Men and women showed no important differences in the pharmacokinetics of eptihbatide. 

Clearance (Cl) and volumes of distribution (VD) are fundamental concepts in pharmacokinetics. Clearance is defined as the volume of plasma or blood cleared of the drug per unit time, and has the dimensions of volume per unit time (e.g. mL-min-1 or L-h-1). An alternative, and theoretically more useful, definition is the rate of drug elimination per unit drug concentration, and equals the product of the elimination constant and the volume of the compartment. The clearance from the central compartment is thus VVklO. Since e0=l, at t=0 equation 1 reduces to C(0)=A+B+C, which is the initial concentration in VI. Hence, Vl=Dose/(A+B-i-C). The clearance between compartments in one direction must equal the clearance in the reverse direction, i.e. Vl.K12=V2-k21 and VVkl3=V3-k31. This enables us to calculate V2 and V3. 

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