Multiple-dosing factor

Any of these compartmental equations can be used to determine serum concentrations after multiple doses. The multiple-dosing factor (1 -e nKr y( i g-Kr where n is the number of doses, K is the appropriate rate constant, and r is the dosage interval, is simply multiplied by each exponential term in the equation, substituting the rate constant of each... 

At steady state, the number of doses becomes large, e approaches zero, and the multiple-dosing factor equals 1/(1 -Therefore, the steady-state versions of the equations are simpler than their multiple-dose counterparts ... 

As in any safety evaluation, the planned work should be related to the intended use and treatment of humans, for example one dose in a few gravely ill patients or multiple doses of the entire healthy community as prophylaxis against a trivial condition. Contrast, say, what might be appropriate for tumor necrosis factor, as in an experimental trial in a few sufferers from late-stage cancer, with the requirements... 

The progressive increase of chemical and/or metabolites in the body. Accumulation is influenced by the dosing interval and half-life of the chemical. The process can be characterized by an accumulation factor, which is the ratio of the plasma concentration at steady state to that following the first dose in a multiple dosing regimen. 

Three thousand individual volunteer exposures to LSD took place under the supervision of Dr. Van Sim before 1961 (his own estimate, according to his summary report). Adding up the numbers given for the separate tests, this estimate appears to have been inflated by at least a factor of two. It is hard to be precise because the records are incomplete, and some volunteers received multiple doses. 

Renwick and Lazarus (1998) analyzed the default UF for human variability based on the evaluation of an extensive database in relation to a subdivision of the 10-fold factor due to variability in toxicokinetics and toxicodynamics, as well as the adequacy of the 10-fold factor. Papers giving kinetic data were selected on the basis of the quality and/or size of the study, the interest of the results, and the physiological/metabolic process determining the kinetic parameter. Papers giving dynamic data were selected on the basis of the adequate separation of variability due to kinetics and dynamics. The data on kinetics and dynamics were tabulated, the coefficients of variation were averaged for different studies which measured a common endpoint, or for multiple doses which measured the same endpoint. 

Calculated volume based on the 9.5 ml multiple-dose vial (10,000 anti-Factor Xa units/mL). ... 

The pharmacokinetics of a drug can also determine the frequency of monitoring. Many believe that TDM requires frequent blood drawings, primarily based on the experience with lithium. However, this drug is relatively unique in that its levels are determined by multiple independent factors. Thus, the plasma level of lithium is not solely a function of the dose and of renal status, but also of fluid and salt intake and output, which can vary independent of dose. 

The statistical submodel characterizes the pharmacokinetic variability of the mAb and includes the influence of random - that is, not quantifiable or uncontrollable factors. If multiple doses of the antibody are administered, then three hierarchical components of random variability can be defined inter-individual variability inter-occasional variability and residual variability. Inter-individual variability quantifies the unexplained difference of the pharmacokinetic parameters between individuals. If data are available from different administrations to one patient, inter-occasional variability can be estimated as random variation of a pharmacokinetic parameter (for example, CL) between the different administration periods. For mAbs, this was first introduced in sibrotuzumab data analysis. In order to individualize therapy based on concentration measurements, it is a prerequisite that inter-occasional variability (variability within one patient at multiple administrations) is lower than inter-individual variability (variability between patients). Residual variability accounts for model misspecification, errors in documentation of the dosage regimen or blood sampling time points, assay variability, and other sources of error. 

The pharmacokinetic evaluation of biopharmaceuticals is generally simplified by the usual metabolism of products to small peptides and to amino acids, and thus classical biotransformation and metabolism studies are rarely necessary. Routine studies to assess mass balance are not useful. However, both single- and multiple-dose toxicokinetic data are essential in safety pharmacology asessments, and these can be complicated by two factors (1) biphasic clearance with a saturable, initial, receptor-dependent clearance phase, which may cause nonlinearity in dose-exposure relationships and doseresponses [14] and (2) antibody production against an antigenic biopharmaceutical that can alter clearance or activity in more chronic repeat-dose safety studies in the preclinical model. 

Single-dose and steady-state multiple-dose plasma-level-vs.-time profiles of tolrestat, an aldose reductase inhibitor, were compared. The terminal exponential-phase half-life was 31.6 hours at the conclusion of multiple-dose therapy administered at a 12-hour dosing interval. However, there was little apparent increase in plasma concentrations with repetitive dosing, and the cumulation factor, based... 

Dose-response models describe a cause-effect relationship. There are a wide range of mathematical models that have been used for this purpose. The complexity of a dose-response model can range from a simple one-parameter equation to complex multicompartment pharmacokinetic/pharmacodynamic models. Many dose-response models, including most cancer risk assessment models, are population models that predict the frequency of a disease in a population. Such dose-response models typically employ one or more frequency distributions as part of the equation. Dose-response may also operate at an individual level and predict the severity of a health outcome as a function of dose. Particularly complex dose-response models may model both severity of outcome and population variability, and perhaps even recognize the influence of multiple causal factors. 

Many injections are formulated as aqueous solutions, with Water for Injections as the vehicle. Their formulation depends upon several factors including the aqueous solubility of the active ingredient, the dose, its thermal stability, the route of administration, and whether the product is to be offered as a multiple-dose product (i.e. with doses removed on different occasions) or as a single-dose form (as the term suggests, only one dose per container). Most injections are prepared as a single-dose form but this is mandatory for certain routes, e.g. spinal injections where the intrathecal route is used, and large volume intravenous infusions. Multiple-dose... 

Multiple risk factors for aminoglycoside nephrotoxicity have been identified. These relate to aminoglycoside dosing, synergistic toxicity in combination with other drugs, and predisposing conditions in the patient (Table 46-2). These risk factors have been consistently identified in all investigations and the reader is referred to in-depth reviews on this issue. ... 

Another factor associated with the adverse effects of oxybutynin IR, especially in older patients, is the transient high peak serum oxybutynin plasma concentration and area under the plasma concentration-versus-time curve (AUC), which is twofold higher in elderly patients than in younger adults, after both single and multiple doses. Oxybutynin IR is best tolerated when the dose is gradually escalated from no more than 2.5 mg twice daily to start, to 2.5 mg three times daily after... 

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