Dose-independent pharmacokinetics

The advantageous effects of liposomal carrier systems include protection of compounds from metabolism or degradation, as well as enhanced cellular uptake. Liposome-mediated delivery of cytotoxic drugs to cells in culture has resulted in improved potency [58,59]. Prolonged release of encapsulated cargo has also been demonstrated [60,61]. More recently, liposomes with extended circulation half-lives and dose-independent pharmacokinetics (Stealth liposomes) [62] have shown promise in delivery of drugs that are normally very rapidly degraded. 

Pharmacokinetic parameters, such as elimination half life (ti/2), the elimination rate constant (K), the apparent volume of distribution (V) and the systemic clearance (Cl) of most drugs are not expected to change when different doses are administered and/or when the drug is administered via different routes as a single or multiple doses. The kinetics of these drugs is described as linear, or dose-independent, pharmacokinetics and is characterized by the first-order process. The term linear simply means that plasma concentration at a given time at steady state and the area under the plasma concentration versus time curve (AUC) will both be directly proportional to the dose administered, as illustrated in Fig. 15.1. 

Figure 15.1 Relationship between the plasma concentration (Cp) at a time at steady state (a) and the area under the plasma concentration versus time (ADC) curve (b) against the administered dose for a drug that exhibits dose-independent pharmacokinetics.

LMWH has greater bioavailability than standard heparin, a longer-lasting effect, and dose-independent clearance pharmacokinetics. The predictable relationship between anticoagulant response and dose allows... 

Tong et al. [65] studied the pharmacokinetics of vigabatrin in rat blood and cerebrospinal fluid (CSF), and the major findings of this study are that (i) the pharmacokinetics of vigabatrin in serum are linear and dose-dependent, while in CSF are dose-independent (ii) vigabatrin is not protein bound in serum (iii) the elimination of vigabatrin from serum is rapid and (vi) vigabatrin is rapidly penetrated the blood-brain barrier (BBB). 

The model independent pharmacokinetic characteristics for XYZ1234 following single dose administration of the different treatments were calculated using non-compartmental procedures. The following table gives the arithmetic means, standard deviations, and coefficients of variation as well as the medians and ranges of the primary pharmacokinetic measure AUCo-co, and of the secondary measures Cm, Cmax and MRT. 

Sulfadimethoxine. The pharmacokinetics of elimination of the intravascularly administered sodium sulfadimethoxine were independent of dose in the range 21 to 55 mg/kg, and the elimination of half life of parent sulfadimethoxine from hemolymph was 77 hours (69). Binding of sulfadimethoxine to hemolymph proteins was dose independent in the range 14 to 203 M-g/ml, and was 53% bound (69). In the intermoult, gonadally regressed lobsters used in the study, there was no sex difference in drug elimination (69). The rate of absorption of orally administered sulfadimethoxine, 42 mg/kg, was... 

When plasma concentration, unbound concentration, the amount of drug and metabolite excreted and so forth all increase in proportion to dose, then the superposition principle applies. This means that concentration over time of a multidose treatment schedule can be calculated as the sum of the concentrations which would be observed from the individual doses were they given alone. For such drugs, the pharmacokinetics are said to be dose-independent or linear. Drugs which do not exhibit dose-proportionality can be difficult to manage. (A notorious example is alcohol.)... 

OxyContin tablets are designed to provide controlled delivery of oxycodone over 12 hours. Oxycodone release from OxyContin tablets is pH-independent. Oxycodone is well absorbed from OxyContin tablets with an oral bioavailability of 60% to 87%. The relative oral bioavailability of OxyContin to immediate-release oral dosage forms is 100%. Steady-state levels are achieved within 24-36 hours in normal volunteers after repeated dosing in pharmacokinetic studies. 

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. 

Daptomycin pharmacokinetics are nearly linear and time-independent at doses up to 6 mg/kg administered once daily for 7 days. Steady-state concentrations are achieved by the third daily dose. 

Pharmacokinetics A study of single IV infusions of 3 to 20 mg/kg in Crohn disease or RA patients showed a linear relationship between the dose and the maximum serum concentration. The volume of distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. The median terminal half-life of infliximab ranged between 8 to 9.5 days. 

The pharmacokinetics of stimulants are characterized by rapid absorption, low plasma protein binding, and quick extracellular metabolism (Patrick et al., 1987). Although some investigators claim that the dose-response relationship is affected by the child s weight, others have shown that individual dose-response stimulant effects are independent of the child s weight (Rapport et al., 1989). 

Pharmacokinetics The bioavaUabUity of subcutaneous interferon beta-lb is 50%. In patients receiving single intravenous Betaseron doses up to 2.0 mg, increases in serum concentrations of interferon beta-lb were dose proportional. Mean serum clearance values ranged from 9.4ml/min per kg to 28.9 ml/minperkg and were independent of dose. Mean terminal elimination half-life values ranged from 8.0 minutes to 4.3 hours and mean steady-state volume of distribution values ranged from 0.25 liter/kg to 2.88 hters/kg. Three-times-a-week intravenous dosing for 2 weeks resulted in no accumulation of interferon beta-lb in the serum of patients. 

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 major metabolic pathway for cisatracurium is Hofmann elimination, although renal and other organ clearance accounts for some elimination. The pharmacokinetics of cisatracurium are independent of dose in healthy adult patients up to doses of 0.2 mg-kg-1 and its elimination half-life is similar to that of atracurium (Table 6.4). In contrast to atracurium, the clearance of cisatracurium is slightly reduced and recoveiy slightly slower in patients with renal failure. Much less laudanosine is produced as a metabolite of cisatracurium as compared with atracurium even when the drug is given by continuous infusion over a prolonged period of time. 

Estimates of dosing rate and average steady-state concentrations, which may be calculated using clearance, are independent of any specific pharmacokinetic model. In contrast, the determination of maximum and minimum steady-state concentrations requires further assumptions about the pharmacokinetic model. The accumulation factor (equation... 

Estimates of dosing rate and average steady-state concentrations, which may be calculated using clearance, are independent of any specific pharmacokinetic model. In contrast, the determination of maximum and minimum steady-state concentrations requires further assumptions about the pharmacokinetic model. The accumulation factor (equation [7]) assumes that the drug follows a one-compartment body model (Figure 3-2 B), and the peak concentration prediction assumes that the absorption rate is much faster than the elimination rate. For the calculation of estimated maximum and minimum concentrations in a clinical situation, these assumptions are usually reasonable. 

The structural submodel describes the central tendency of the time course of the antibody concentrations as a function of the estimated typical pharmacokinetic parameters and independent variables such as the dosing regimen and time. As described in Section 3.9.3, mAbs exhibit several parallel elimination pathways. A population structural submodel to mechanistically cover these aspects is depicted schematically in Fig. 3.14. The principal element in this more sophisticated model is the incorporation of a second elimination pathway as a nonlinear process (Michaelis-Menten kinetics) into the structural model with the additional parameters Vmax, the maximum elimination rate, and km, the concentration at which the elimination rate is 50% of the maximum value. The addition of this second nonlinear elimination process from the peripheral compartment to the linear clearance process usually significantly improves the fit of the model to the data. Total clearance is the sum of both clearance parts. The dependence of total clearance on mAb concentrations is illustrated in Fig. 3.15, using population estimates of the linear (CLl) and nonlinear clearance (CLnl) components. At low concentra-... 

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