Pharmacokinetics infusion rate constant

Figure 19.5 Physiological pharmacokinetic model for hepatic uptake of drug constantly infused in the isolated rat liver perfusion system. Q, flow rate (mL/min) Cb, inflow concentration (pg/mL) Cs, sinusoidal concentration (pg/mL) Vs, sinusoidal volume (mL) X, binding constant (pg) Xm, maximum binding amount (pg) K, binding constant (mL/pg) kmt, internalization rate constant (min-1).

In contrast to noncompartmental analysis, in compartmental analysis a decision on the number of compartments must be made. For mAbs, the standard compartment model is illustrated in Fig. 3.11. It comprises two compartments, the central and peripheral compartment, with volumes VI and V2, respectively. Both compartments exchange antibody molecules with specific first-order rate constants. The input into (if IV infusion) and elimination from the central compartment are zero-order and first-order processes, respectively. Hence, this disposition model characterizes linear pharmacokinetics. For each compartment a differential equation describing the change in antibody amount per time can be established. For... 

Reaction rate parameters required for the distributed pharmacokinetic model generally come from independent experimental data. One source is the analysis of rates of metabolism of cells grown in culture. However, the parameters from this source are potentially subject to considerable artifact, since cofactors and cellular interactions may be absent in vitro that are present in vivo. Published enzyme activities are a second source, but these are even more subject to artifact. A third source is previous compartmental analysis of a tissue dosed uniformly by intravenous infusion. If a compartment in such a study can be closely identified with the organ or tissue later considered in distributed pharmacokinetic analysis, then its compartmental clearance constant can often be used to derive the required metabolic rate constant. 

FIGURE 1.1 The three most commonly used pharmacokinetic models in explaining the pharmacokinetic behavior of drugs. The symbols C, P, S, and D represent central, peripheral, shallow, and deep compartments, whereas the first-order rate constants, symbolized by k j, represent drug transport from compartment i to compartment j. ka, and kd represent a bolus rV dose, the absorption rate constant, and constant rate infusion, respectively. 

Sanders, A. B., and Moore, J. G. Intragastric pH and pharmacokinetics of intravenous ranitidine during sinusoidal and constant-rate infusions. Chronobiol. Int. 8 267—276, 1991. 

Pharmacokinetic information gained following single-dose administration can be used to help predict the likely events following chronic dosing, either as a constant-rate infusion or multiple dosing, which often involves giving a fixed dose at set time intervals. 

Fentanyl (0.001 mg/kg i.v.) can be used with xylazine (0.44 mg/kg i.v.) for anesthetic premedication. Fentanyl is sometimes used as an anesthetic adjunct during inhalation anesthesia to improve analgesia. The pharmacokinetics of fentanyl make it ideal for administration by constant rate infusion and it can be administered intra-operatively at a rate of 0.001-0.004 mg/kg/h after a 0.001 mg/kg loading dose. To prevent excitement or locomotory stimulation in recovery, the infusion should be discontinued 30 min prior to recovery or the horse should be sedated with xylazine (0.1 mg/kg i.v.) prior to recovery. 

The pharmacokinetic parameters for propofol in the horse are derived from a study of propofol and ketamine constant rate infusion (Nolan et al... 

Diltiazem was shown to exhibit dose dependent (30 mg - 120 mg administrated orally, three times a day) nonlinear pharmacokinetics (43) when administered to healthy individuals. The nonlinearity of diltiazem area under the curve (AUC) is a result of dose dependent first pass metabolism and is not reflected in the elimination half-life which is the same regardless of dose. The mean apparent oral clearance (44) and half-life of diltiazem following chronic oral therapy was 20.9 mL/min/kg and 3.5 hours, respectively. After a constant rate infusion, diltiazem was also shown to exhibit (45) nonlinear pharmacokinetics. After IV administration the following pharmacokinetic parameters were determined in healthy male volunteers the elimination t-1/2 (40) was 11.2 hours and the total clearance was 11.5 mL/min/kg. Diltiazem elimination is affected by liver damage (46) but not by kidney failure. 

Several publications have demonstrated circadian variation in the pharmacokinetics and pharmacodynamics of 5-fluorouracil (5-FU) during constant infusions of varying rates typically infused over 5-14 days (55-57). The maximum and minimum concentrations each day based on cosinor analysis occurred at approximately 0100-0400 and 1300 hours, respectively. Dehydropyrimidine dehydrogenase (DPD) is primarily responsible for the metabolism of 5-FU and demonstrates circadian variation in activity with its maximum and minimum activity based on cosinor analysis occurring at 0100 and 1300 hours, respectively. Some patients demonstrated an inverse relationship to the plasma 5-FU concentration (55). This appeared to increase the tolerance to 5-FU side effects between OOOOh and 0400h (58, 59). 

Peptide and protein drugs requiring an IV route of administration may also be given as a constant rate infusion. Pharmacokinetic data from experiments designed to achieve a steady-state plasma concentration (C ) allow for the direct calculation of drug clearance according to the equation ... 

For the pharmacokinetics of rhG-CSF in humans, it has been reported that the absorption and clearance of rhG-CSF follow first-order kinetics without any apparent concentration dependence [114], When rhG-CSF was administered by 24-h constant i.v. infusion at a dose level of 20pg/kg, the mean serum concentration achieved 48ng/mL. Constant i.v. infusion for 11 to 20 days produced steady-state serum concentrations over the infusion period. Subcutaneous administration of rhG-CSF at doses of 3.45 and 11.5pg/kg resulted in peak serum concentrations of 4 and 49ng/mL, respectively. The mean value of volume of distribution was 150mL/kg. The elimination half-life was 3.5h after either i.v. routes or s.c. routes, with a clearance rate of 0.5-0.7 mL/min/kg. The administration of a daily dose for 14 consecutive days did not affect the half-life. 

Fig. 9.37. Plots of drug concentration ([jg/mL ) and drug concentration x time ((jg/ml /hr o) versus time during and after 1 hour of a constant-rate infusion. The area under the concentration versus time plot to infinity is AUC the area under the concentration x time versus time plot to infinity is AUMC. (From Gibaldi M. Biopharmaceutics and Clinical Pharmacokinetics, 4th Ed. Philadelphia Lea and Febiger, 1991 with permission.)...

Chiou, W. L., Gadalla, M. A., and Peng, G. W., Method for the rapid estimation of the total body drug clearance and adjustment of dosage regimens in patients during a constant-rate intravenous infusion, J. Pharmacokinet. Biopharm., 6(2) 135-151, 1978. 

Bidgood TL, Papich MG, Plasma and interstitial fluid pharmacokinetics of enrofloxacin, its metabolite ciprofloxacin, and marbofloxacin after oral administration and a constant rate intravenous infusion in dogs, J. Vet. Pharmacol. Ther. 2005 28 329-341. 

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