Linear dosing profile

Studies of the pharmacokinetics of this deHvery system in two animal models have been reported in the Hterature. After iajection of these microspheres at three doses, leuproHde concentrations were sustained for over four weeks foUowing an initial burst (116). The results iadicated that linear pharmacokinetic profiles in absorption, distribution, metaboHsm, and excretion were achieved at doses of 3 to 15 mg/kg using the dmg loaded microspheres in once-a-month repeated injections. 

The toxic effects model uses concentration-time profiles from the respiratory and skin protection models as input to estimate casualty probabilities. Two approaches are available a simple linear dose-effect model as incorporated in RAP and a more elaborate non-linear response model, based on the Toxic Load approach. The latter provides a better description of toxic effects for agents that show significant deviations of simple Haber s law behaviour (i.e. toxic responses only depend on the concentration-time product and not on each quantity separately). 

Using the sensitive quantitative LC-MS/MS method described above, linear PK profiles between clinical dosing and microdosing were obtained. Furthermore, Yamane et al. (2007) demonstrated that concentrations in human plasma after an oral dose of 100 pig is quantifiable using LC-ESI-MS/MS (Fig. 1.6), similar to what can be achieved using AMS (Chapter 2). 

Fig. 1 Hypothetical dose-effect and dose toxicity curves for cytotoxic (A) and non-cytotoxic, molecularly targeted anticancer agents (B). The cytotoxic agents are known for their dose-dependent toxicity, which closely follows the dose-effect curve. Non-cytotoxic agents, on the other hand, could have a linear dose toxicity relationship similar to the cytotoxic agents (I) or a non-linear profile with dose toxicity curve lower than the dose-effect curve (II). MTD represents the maximum tolerated dose for the cytotoxic agent. Modified from Hoekstra et al. [8]...

The bio availability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in three divided doses, respectively. The bioavailability is not dose-proportional (as the dose is increased, bioavailability decreases). In contrast, pregabalin offers a more linear pharmacokinetic profile over gabapentin and a consistent >90% bioavailability. Pregabalin may result in a shorter course of titration and quicker response in clinical application. 

Linear (solid line), exponential (dotted line) and quadratic (dashed line) dosing profiles. 

The residue depletion profiles of closantel in cattle and swine are almost similar. Highest concentrations of closantel are seen in kidney, whereas the depletion of closantel from all edible tissues is very slow over the first 28 days of withdrawal. Within animal species, the parenteral and the oral routes of adminis-fration yield comparable residue concentrations provided that the oral dose is twice the parenteral dose. A dose linearity is also observed for residue concentrations in tissues doubling the dose for a particular route of administration doubles the residue level. 

A purely hydrophilic matrix of hypromellose prolongs the release of tramadol from Tramal long (Fig. 3) developed by Gruenenthal. The tablets have the same dimensions, resulting in an identical release profile for all dosages (100, 150, 200 mg, see Fig. 4). For a titrated effect linear pharmacokinetics on increasing doses produce dose-proportional blood levels at any time. External influences, such as pH value, mechanical stress, surface-active... 

Various PK parameters such as CL, Vd, F%, MRT, and T /2 can be determined using noncompartmental methods. These methods are based on the empirical determination of AUC and AUMC described above. Unlike compartmental models (see below), these calculation methods can be applied to any other models provided that the drug follows linear PK. However, a limitation of the noncompartmental method is that it cannot be used for the simulation of different plasma concentration-time profiles when there are alterations in dosing regimen or multiple dosing regimens are used. 

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