Pharmacokinetics concentration time

Pharmacokinetic concentration-time curves for a drug and ifs mefabolifes are used to identify primary exposure metrics such as AUC, or which are not time-dependent unlike the sequential measurements of concentration over time. A peak plasma concentration of a drug is often associated with a PD response, especially with an adverse event. There can be large inter-individual variability in the time-to-peak concentration, and closely spaced sampling times are often critical to determining the peak plasma concentration accurately in individual patients because of differences in demographics, disease states, and food effects, if any. All these elements are clearly spelled out in the protocols written to conduct these studies. 

Compound (1) suffered from an unfavorable pharmacokinetic profile when studied in rats. It is cleared very rapidly from rat plasma (half-life, t 2 — 0.4/z) and is poorly bioavailable F — 2%), as reflected by the low plasma concentration (area under the plasma concentration-time curve, AUCo oo = 0.2pMh) following a single oral dose of 25mg/kg in rats [42]. The main challenge was to further optimize this series to obtain NS3 protease inhibitors with low-nanomolar cell-based potency (EC5q< 10 nM) and with an adequate pharmacokinetic profile for oral absorption. 

Also, if conversion of drug to active metabolite shows significant departure from linear pharmacokinetics, it is possible that small differences in the rate of absorption of the parent drug (even within the 80-125% range for log transformed data) could result in clinically significant differences in the concentration/ time profiles for the active metabolite. When reliable data indicate that this situation may exist, a requirement of quantification of active metabolites in a bioequivalency study would seem to be fully justified. 

Coupling with its intravenous pharmacokinetic parameters, the extended CAT model was used to predict the observed plasma concentration-time profiles of cefatrizine at doses of 250, 500, and 1000 mg. The human experimental data from Pfeffer et al. [82] were used for comparison. The predicted peak plasma concentrations and peak times were 4.3, 7.9, and 9.3 qg/mL at 1.6, 1.8, and 2.0 hr, in agreement with the experimental mean peak plasma concentrations of... 

Another method of predicting human pharmacokinetics is physiologically based pharmacokinetics (PB-PK). The normal pharmacokinetic approach is to try to fit the plasma concentration-time curve to a mathematical function with one, two or three compartments, which are really mathematical constructs necessary for curve fitting, and do not necessarily have any physiological correlates. In PB-PK, the model consists of a series of compartments that are taken to actually represent different tissues [75-77] (Fig. 6.3). In order to build the model it is necessary to know the size and perfusion rate of each tissue, the partition coefficient of the compound between each tissue and blood, and the rate of clearance of the compound in each tissue. Although different sources of errors in the models have been... 

Suttee, A. B., Poliack, G. M., Brouwer, K. L., Use of a pharmacokinetic model incorporating discontinuous gastrointestinal absorption to examine the occurrence of double peaks in oral concentration-time... 

Daneshmend [104] measured the serum concentration of miconazole in 11 healthy adult females for 72 h following a single 1200 mg vaginal pessary. The mean peak serum miconazole concentration was 10.4 pg/L and the mean elimination half-life was 56.8 h. The mean area under the serum concentration-time curve was 967 pg/L/h. The calculated mean systemic bioavailability of the vaginal pessary was 1.4%. There was large intersubject variation in serum miconazole pharmacokinetics. This formulation may provide effective single dose treatment for vaginal candidiasis. 

Piel et al. [109] studied the pharmacokinetics of miconazole after intravenous administration to six sheep (4 mg/kg) of three aqueous solutions - a marketed micellar solution containing polyoxyl-35 castor oil was compared with two solutions both containing 50 pM lactic acid and a cyclodextrin derivative (100 pM hydro-xylpropyl-/l-cyclodextrin or 50 pM sulfobutyl ether (SBE7)-/i-cyclodextrin. This work demonstrated that these cyclodextrin derivatives have no effect on the pharmacokinetics of miconazole by comparison with the micellar solution. The plasma concentration-time curves have shown that there is no significant difference between the three solutions. 

Pharmacokinetic parameters such as area under the concentration-time curve (AUC) and maximal plasma concentration can be predictive of treatment outcome when specific ratios of AUC or maximal plasma concentration to the minimum inhibitory concentration (MIC) are achieved. For... 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

Exposure is represented by pharmacokinetic parameters demonstrating the local and systemic burden on the test species with the test compound and/or its metabolites. The area under the matrix level concentration-time curve (AUC) and/or the measurements of matrix concentrations at the expected peak-concentration time Cmax, or at some other selected time C(llme, are the most commonly used parameters. Other parameters might he more appropriate in particular cases. 

Relating the Time-Course of Plasma Concentrations to the Time-Course of Effect A critical decision to be made after the first human study is whether the compound s speed of onset and duration of action are likely to be consistent with the desired clinical response. Speed of onset is clearly of interest for treatments which are taken intermittently for symptoms rehef, for example, acute treatments for migraine, analgesics, or antihistamines for hay fever. Duration of action phase I is particularly important when the therapeutic effect needs to be sustained continuously, such as for anticonvulsants. The first information on the probable time course of action often comes from the plasma pharmacokinetic profile. However, it has become increasingly evident that the kinetic profile alone may be misleading, with the concentration-time and the effect-time curves being substantially different. Some reasons for this, with examples, include... 

Prototype selection is never wisely made based solely on in vitro dissolution data. This is because the resultant plasma concentration-time profiles are dependent not only on this input rate, but also on the pharmacokinetics of the particular drug. This is illustrated in Figure 2. 

Figure 13 Comparison of the mean observed and predicted concentration-time profiles for the three ER formulations, fast ( ), medium (o), and slow ( ), whose dissolution behavior is shown in Figure 3. Pharmacokinetic parameters F= 1, ka = 1000 hr-1, io = 0.17hr 1, V = 114L, fcoi =, coi = 9hr, abs = 96hr. Dosing parameters dose = 10 mg, r = 24hr. IVIVC equation xViVO=Jcvitro (1 1 IVIVC panel a) or 4th order polynomial shown in Figure 11 (panel b). Double Weibull (drug release) parameters for each of the three formulations are listed in Table 2.

Pharmacokinetic Model for Simulation of Concentration-Time Profiles for Orally Administered Extended-Release Dosage Forms... 

Rnally, pharmacokinetic and pharmacokinetic/pharmacodynamic modelling can be used for the purpose of prediction of the concentration-time profile of the drug and drug-carrier conjugate after repeated administration from single dose data, as well as for the prediction of the dose needed to maintain the concentration at the target site within a therapeutic window. 

There are several approaches to pharmacokinetic modelling. These include empirical, compartmental, clearance-based and physiological models. In the latter full physiological models of blood flow to and from all major organs and tissues in the body are considered. Such models can be used to study concentration-time profiles in the individual organs and e. g. in the plasma [57-60]. Further progress in this area may result in better PK predictions in humans [61]... 

Fig. 2.6 Effect of variation in absorption rate on plasma drug concentration. The graph shows simulated plasma concentration-time curves for theophyUine after oral administration, illustrating a 20% difference in Cpmax values resulting from variation in the absorption rate constant. Absorption rate constants top curve 2.2 per h (Cpmax 20 pg/mL) middle curve 1.0 per h (Cptnax 18 M-g/mL) bottom curve 0.7 per h. Note that tmax also changes. The established therapeutic concentration of theophyUin is 10-20 pg/mL. The most rapidly absorbed formulation produces the highest concentration and greatest chance of side effects. Also, the duration for which the plasma concentration is within the therapeutic range also varies. Pharmacokinetic parameters dose, 400 mg bioavaUabiUty, 0.8 volume of distribution, 29 L half-Ufe, 5.5 h.

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. 

Fig. 5.2 Descriptive pharmacokinetic parameters (a) plasma concentration-time plot and (b) semi-logarithmic plot.

By contrast, in the population approach, the raw data set that is analysed consists of concentration-time points (and other necessary data such as demographic information) taken from a large number (up to hundreds to thousands) of patients in Phase 11 and/or Phase 111 trials. The number of plasma samples per subject may be sparse but it is possible to estimate the individual pharmacokinetic characteristics of each subject and hence a measure of the mean parameters and their variability can be assessed. Relationships can be sought between patient characteristics (demographics, chnical status) and pharmacokinetic values is found, its consequence may be examined by looking for altered efficacy or safety which may not be possible in a traditional volunteer study. This might lead to demonstration of a therapeutic concentration range. 

Pharmacokinetic measurements, for example, plasma (serum) half-life, concentration-time curves of parent drug or active metabolite. 

Pharmacokinetics Ticlopidine is rapidly absorbed (more than 80%), with peak plasma levels occurring at approximately 2 hours after dosing, and is extensively metabolized. Administration after meals results in a 20% increase in the area under the plasma concentration-time curve (AUC). Ticlopidine displays nonlinear pharmacokinetics and clearance decreases markedly on repeated dosing. Ticlopidine binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein at concentrations attained with the recommended dose, 15% or less in plasma is bound to this protein. 

Pharmacology Trimetrexate, a 2.4-diaminoquinazoline, nonclassical folate antagonist, is a synthetic inhibitor of the enzyme dihydrofolate reductase. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death. Pharmacokinetics Clearance was 38 15 ml /min/m and volume of distribution at steady state (Vdgs) was 20 8 L/m. The plasma concentration time profile declined... 

However, there is one more relatively recent development in pharmacokinetics, which is important to note. As we went through the measurement of the concentration-time curve for the single intravenous or oral dose, did you consider what the volunteer had to do He or she probably had to be at the laboratory without having had anything to eat, to have a cannula put into one of the forearm veins so that repeated blood samples could be withdrawn at regular intervals - usually up to and beyond 24 hours from dosing. You can see that this would just not be a possible thing to do in a sick child or an elderly patient with a major medical problem. So how do... 

DRUG CONCENTRATION-TIME PROFILES AND BASIC PHARMACOKINETIC PARAMETERS... 

The blood concentration-time profile for a theoretical drug given extravascularly (e.g., orally) is shown in Figure 5.2. Some pharmacokinetic parameters, such as Cmax, T x> area under the curve, and half-life, can be estimated by visual inspection or computation from a con-... 

Phagocytosis rate increase. Polysaccharide fraction of the fruit, administered to adults at a concentration of 10 pg/mL, was active on polymorphonuclear leukocytes k Pharmacokinetics. Hexane extract of the fruit, administered rectally to 12 healthy male adults at a dose of 640 mg, produced bioavailability similar to that observed for the oral formulations. Extract, administered orally to healthy males at a dose of 320 mg (1 X 320 mg capsule, new formulation or 2 X 160 mg, reference preparation) for 1 month, produced a rapid absorption with a peak time (T J of 1.5-1.58 hour and peak plasma level (C J of 2.54-2.67 pg/mL. The area under the curve value ranged from 7.99 to 8.42 pg/hour/mL. The plasma concentration-time profile of both preparation was nearly identical. Both preparations can be considered as bioequivalenp Hexane ex-... 

FIGURE 4.4 A Lithium plasma concentration time profile based on a population pharmacokinetics model (Taright et al., 1994). Closed circles are the actual measured lithium concentrations broken lines represent the therapeutic range (0.6-1.2 mmol/L). B Individualized lithium plasma concentration time profile based on the population model with feedback of measured concentrations (Bayesian recalculation). Closed circles are the measured lithium concentrations. The second part of the curve is the predicted lithium concentration profile after increasing the dose to 1000 mg lithium carbonate twice daily, based on a target of 0.6-1.2 mmol/L (broken lines). 

Sertraline pharmacokinetics were described in 61 children and adolescents (ages 6 to 17) with depression or OCD (Alderman et ah, 1998). Mean area under the plasma concentration-time curve, peak plasma concentration, and elimination half-life for sertraline and des-methylsertraline were similar to previously reported adult values. No differences between children and adolescents were apparent when values were normalized for body weight. 

---