Maximum plasma concentration Cmax

Most physicians will be familiar with the basic shape of a plasma concentration-time curve following oral or intravenous administration, and they are likely to be familiar with, or at least readily imderstand, the simple terms that relate to this shape. Such terms - (1) maximum plasma concentration (Cmax). (2) time to maximum plasma concentration (fmax), (3) area under the plasma concentration-time curve (AUC) and (4) half-life (fi/2) - are illustrated in Figure 5.2. 

HIV-infected patients administered saquinavir mesylate (600 mg 3 times daily) had area under the curve (ADC) and maximum plasma concentration (Cmax) values approximately 2 to 2.5 times those observed in healthy... 

Absorption/Distribution Following oral administration to HIV-infected patients, the mean absolute bioavailability of zalcitabine was greater than 80%. The absorption rate of a 1.5 mg oral dose was reduced when administered with food. This resulted in a 39% decrease in mean maximum plasma concentrations (Cmax) 25.2 to 15.5 ng/mL, and a 2-fold increase in time to achieve Cmaxfro mean of 0.8 hours under fasting conditions to 1.6 hours when the drug was given with food. The extent of absorption was decreased by 14% (from 72 to 62 ng h/mL). 

Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia after ima-tinib treatment and for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. The overall mean terminal half-life of dasatinib is 3-5 hours. Adverse events included mild to moderate diarrhea, peripheral edema, and headache. Neutropenia and myelosuppression were common toxic effects. 

Zopiclone is available as a racemic mixture. Zopiclone, 7.5 mg administered orally at nighttime, is rapidly absorbed. It has a bioavailability of approximately 75 % and a time of occurrence of maximum plasma concentration (Cmax) of 1.6 hours [22, 23], The compound undergoes oxidation to the N-oxide metabolite, which is pharmacologically active, and demethylation to the inactive N-demethyl-zopiclone (Tab. 2). The elimination half-life (ti/2) of zopiclone and its active metabolite ranges from 3.5 to 6.0 h [24],... 

As noted in 320.24, several in vivo and in vitro methods can be used to measure product quality BA and establish BE. In descending order of preference, these include pharmacokinetic, pharmacodynamic, clinical, and in vitro studies. These general approaches are discussed in the following sections of this guidance. Product qualities BA and BE frequently rely on pharmacokinetic measures such as area under the curve (AUC) and maximum plasma concentration (Cmax) that are reflective of systemic exposure. 

Figure 16 Changes to pharmacokinetic parameters over 13-week dosing regimen. (A) Maximum plasma concentration (Cmax) of DFP determined after single doses of 10, 30, or 100 mg/kg of DFP compared to the Cmax after 13 weeks of dosing. (B) AUC after a single dose of 10, 30, or 100 mg/kg of DFP compared with the Cmax after 13 weeks of dosing. Abbreviations DFP, [(5,5-dimethyl-3-(2-propoxy)-4-(4-methanesulfonylphenyl)-2(5//)-furanone)J AUC, area under the plasma concentrationtime curve. Source From Ref. 64.

In humans, the mean maximum plasma concentration (Cmax) is 79 ng/mL and the time to achieve Cmax was 2.67 h after a single 3-h infusion of decitabine (1) at 15 mg/m2. At this dose, the volume of distribution at steady state is 148 mL/kg, and the total plasma clearance is 122 L/kg/m2. The terminal half-life is approximately 35 min as decitabine (1) is primarily metabolized in the liver by cytidine deaminase to yield noncytotoxic 5-aza-2 -deoxyuridine. Urinary excretion of unchanged decitabine (1) is low (0.01-0.9% of total dose).13... 

The intake of a high fat meal before or at dosing lowered the maximum plasma concentration (Cmax) and increased the absorption time (tmax). 

L-Dopa is a prodrug of dopamine and is known as the drug of choice for the treatment of Parkinson s disease. L-Dopa has a narrow absorption window and is actively absorbed from the upper part of the small intestine. The large fluctuations in L-Dopa plasma concentration cause severe side effects. Hence, there is a PK rationale to elevate the extent of absorption while minimizing the maximum plasma concentration (Cmax) obtained, following oral administration of a sustained release (SR) formulation of L-Dopa. 

An indication of the rate of drug absorption can be obtained from the peak (maximum) plasma concentration (Cmax) and the time taken to reach the peak concentration (fmjx), based on the measured plasma concentration-time data. However, the blood sampling times determine how well the peak is defined and, in particular, fmax. Both Cmax and tm3LX may be influenced by the rate of drug elimination, while Cmax is also affected by the extent of absorption. The term Cmax/ AUC, where AUC is area under the curve from time zero to infinity or to the limit of quantification (LOQ) of the analytical method, provides additional information on the rate of absorption. This term, which is expressed in units of reciprocal time (h ), can easily be calculated. In spite of the imprecision of the estimation provided by Cmax, it generally suffices for clinical purposes. 

Provide confidence that the pharmacological model will predict efficacy in humans. If a drag is effective in therapeutic models using different species and these animals receive equivalent exposures (as measured by the maximum plasma concentration, Cmax, or area under the plasma concentration curve, AUC), then the clinician can choose a dose for trials with confidence. 

As far as the rate component of bioavailability is concerned, it is estimated by two parameters, Cmax and tmax. The maximum plasma concentration (Cmax) is related to (a) total plasma clearance (b) the fraction of dose that reaches the general circulation without being metabolized (c) the rate of absorption and (d) the rates of distribution and elimination. The time to reach Cmax (tmax) depends on (a) the rate of absorption and (b) the rates of distribution and elimination. 

The most widely used technique for the evaluation of hERG channel interaction is the voltage clamp. A detailed description of the experimental setup has been described elsewhere [119]. The hERG interaction is measured and reported as the % inhibition of the hERG current compared to the vehicle control at various concentrations of the NCE. The concentration that inhibits 50% (IC50) is calculated, whenever possible. The concentrations of NCE used in the assay are carefully selected based on the expected maximum plasma concentration (Cmax) at the pharmacologically active dose (usually based on studies in animal models) and the human plasma protein binding for the NCE. 

The median maximum plasma concentrations (Cmax) in (g/L for the respective doses are as follows ... 

The standard bioavailability variables after a single-dose administration are the maximum plasma concentration (Cmax), the time to reach Cmax (fmax) and the area under the plasma concentration—time curve from time zero to infinity (AUC). 

Unlike the one-compartment first-order absorption model, the time hax of the maximum plasma concentration (Cmax) cannot be written in a solved equation form. Thus determination of hax and C ax for this model requires a trial-and-error approach in which a time (<) is guessed and the plasma concentration (Cp) is calculated repeatedly until the C ax and hax are identified. 

Abbreviations [I], inhibitor concentration C ax, maximum plasma concentration Cmax,fu, maximum free plasma concentration /max, maximum portal vein concentration /max,fu, maximum free portal vein concentration PBPK, physiologically-based pharmacokinetics. 

It has been suggested [60,61] that the rate of input of chiral drugs after the oral administration may affect the stereoselectivity in their pharmacokinetics. Simulations [60] have shown that drugs with Michaelis-Menten type first-pass metabolism whose input rate approaches the maximum rate of metabolism (Fmax) of the enantiomers are most susceptible to this phenomenon. A study [151] in isolated perfused rat livers demonstrated that when the input rate of racemic verapamil was doubled, the stereoselectivity in the outlet concentration of the drug was lost. In humans, Karim and Piergies [152] showed that the R S plasma concentration ratios of verapamil at maximum plasma concentration (Cmax) were formulation dependent a sustained release formulation resulted in lower total concentrations at time to reach C ax ( max), associated with higher R S ratios, when compared with an immediate release formulation (Fig. 8). Similar input rate-dependent stereoselective pharmacokinetics of verapamil have also been suggested by others [146,153]. 

Ideally, observational time periods are defined based on the pharmacokinetic (PK) properties of the test article with at least one time point approximating the time at which the maximum plasma concentration (Cmax) occurs. Subsequent time points typically span 24 h or longer depending on the duration of the drug s half life. 

In a detailed clinical study, it was demonstrated that both enantiomers of fexofenadine possess equal potency but differ in selected pharmacokinetic parameters [10]. A 63 37 steady-state ratio of f -(-f)-l and 5-(—)-l was observed in plasma and this remained constant across time and dosing. In a later study, it was found that the AUC and the maximum plasma concentration (Cmax) of f -(-f)-l were significantly greater than those of the 5-(—)-enantiomer [11]. Furthermore, plasma and renal clearance of oral 5-(—)-fexofenadine were both significantly greater than for the f -(-i-)-enantiomer. 

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