Pharmacokinetics dose-dependent changes

Paroxetine at low concentration is dependent on CYP 2D6 for its clearance. However, this enzyme is almost completely saturated by paroxetine at low concentrations, which accounts for the nonlinear pharmacokinetics of paroxetine and why its half-life goes from 10 to 20 hours when the dose is advanced from 10 to 20 mg per day. At higher concentrations, paroxetine is most likely dependent on CYP 3A3/4 for its clearance. This dose-dependent change in the clearance of paroxetine probably accounts for the higher incidence of withdrawal reactions with this SSRI than might otherwise be expected for a drug with a half-life of 20 hours at steady-state on 20 mg per day (296, 297). 

If it is possible to acquire an adequate understanding of pharmacokinetics, it may be possible in specific cases to document (1) changing pharmacokinetic patterns with changing dose or (2) pharmacokinetic patterns in the animal species used to develop toxicity data that are substantially different from those seen or expected in humans. Such differences would document that the usual defaults do not hold in those specific cases. The effects of using pharmacokinetic data in the risk assessment process instead of the usual defaults would depend upon what those data actually revealed. 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Nonlinear pharmacokinetics. Nonlinear pharmacokinetics simply means that the relationship between dose and Cp is not directly proportional for all doses. In nonlinear pharmacokinetics, drug concentration does not scale in direct proportion to dose (also known as dose-dependent kinetics). One classic drug example of nonlinear pharmacokinetics is the anticonvulsant drug phenytoin.38 Clinicians have learned to dose pheny-toin carefully in amounts greater than 300 mg/day above this point, most individuals will have dramatically increased phenytoin plasma levels in response to small changes in the input dose. 

A pharmacokinetic (PK) model to describe the relationship between administered dose, route of administration, dosing schedule, and concentrations of the parent drug as well as active metabolites (if necessary) in various body fluids (mainly plasma and urine), lime dependent changes (e.g. decreased clearance due to given treatment) and influence of intrinsic (e.g. influence of creatinine clearance on clearance) and extrinsic factors should also be reflected in the model. 

The pharmacokinetics and pharmacodynamics of recombinant interleukin-2 (IL-2) in patients with human immunodeficiency virus (HIV) infection have been evaluated (75). Patients were administered IL-2 either by continuous infusion or by SC injection for 5 days over multiple cycles. Following repeated injection, soluble IL-2 receptors were substantially but transiently increased. A dose-dependent decrease in area under the concentration-time curve (AUC) between days 1 and 5 was attributed to a receptor-mediated change in clearance. Concentrations were described using an unusual model that employed an indirect stimulatory PD model to link the time-dependent changes of the pharmacokinetics with the change in IL-2 receptor density following repeated administration. 

Pharmacokinetic data are derived from studies of sufficient duration to take into account potential time-dependent changes in pharmacokinetic parameters, which may be detected from toxicokinetic results obtained during the dose-ranging studies. 

In another study the area under the plasma concentration-time curve for prednisolone for the 20 mg dose was 77.89 % of that calculated for the 10 mg dose. This change in area represented an increase in prednisolone clearance from 1,7 ml/min kg to 2.2 ml/min kg when the dose was increased (141). Rose et al. (142) found dose-dependent pharmacokinetics of prednisolone where the plasma half-life increased from 3 to 5 h as the oral dose of prednisone was increased from 5 to 50 mg. Tanner et al (143) reported the pharmacokinetics of prednisolone at different dose levels in 43 subjects. Each subject received only a single dose, 5 - 200 mg of oral prednisolone. Kinetic parameters of oral prednisolone are presented in table 5 and fig. 13 illustrates concentration-time profile of prednisolone. The mean half-life of prednisolone remained fairly constant between 3.4 to 3.8 h. Bioavailability of prednisolone was 98.5 i 4 %. Furthermore as the prednisolone dose increased, the area under the curve increased but not proportionally to the dose, such that a fivefold increase in dose from 20 to 100 mg resulted in only a two-to threefold increase in area under the curve. 

It appears that prednisolone may exhibit dose-dependent pharmacokinetics, so that with increasing dose values volume of distribution, plasma clearance and half-life may increase. It is believed to be related to changes in the plasma protein binding of prednisolone. Prednisolone appears to bind to plasma proteins in a non linear manner over the range of doses used (131). 

At each of these stages, not only do the questions of interest change, but so also does the quality of the information available to answer these questions (Fig. 1 panel b). During target specification, all available pharmacokinetic characteristics are used to build a suitable model (e.g., disposition of the drug after administration of an immediate-release (IR) tablet, oral solution, or intravenous dose dose-proportionality time-dependence metabolism and pharmacological activity of metabolites efficiency of absorption from various sites etc.). However, since no formulations have yet been developed, the in vitro release behavior is unknown, as is the... 

The pharmacokinetic information that can be obtained from the first study in man is dependent on the route of administration. When a drug is given intravenously, its bioavailabihty is 100%, and clearance and volume of distribution can be obtained in addition to half-life. Over a range of doses it can be established whether the area under the plasma concentration-time curve (AUC) increases in proportion to the dose and hence whether the kinetic parameters are independent of dose (see Figure 4.1). When a drug is administered orally, the half-life can still be determined, but only the apparent volume of distribution and clearance can be calculated because bioavailability is unknown. However, if the maximum concentration (Cmax) and AUC increase proportionately with dose, and the half-life is constant, it can usually be assumed that clearance is independent of dose. If, on the other hand, the AUC does not increase in proportion to the dose, this could be the result of a change in bioavailability, clearance or both. 

Finally, developmental differences in pharmacodynamics can be observed in the absence of age-associated changes in the dose versus plasma concentration relationship. Marshall and Kearns demonstrated developmental differences in the pharmacodynamics of cyclosporin. In this study, the IC50 for interleukin-2 (IL-2) expression observed in peripheral blood monocytes obtained from infants less than 12 months of age and exposed in vitro to cyclosporin was approximately 50% of the value observed for older children. In this particular example, the pharmacodynamic differences appeared not to be the consequence of developmental dependence on pharmacokinetics but rather, in the true drug-receptor interaction. 

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