Time to maximum plasma concentration

Some idea of the rate of absorption can be obtained from examination of the plasma concentration-time profile. It should be remembered, however, that the time to maximum plasma concentration Y ) is not when absorption is complete but when the rates of drug absorption and elimination are equal. Thus two drugs with the same absorption rate will differ in /max if elimination rates differ. Assessment of the rate of absorption can also be confounded by complex or slow drug distribution. For example, the calcium-channel blocker amlodipine has a much later /max than other similar drugs. This is not due to slow absorption but to partitioning in the liver membrane with slow redistribution. A quantitative assessment of the rate of absorption can be obtained by deconvolution of plasma profiles following IV and oral administration. 

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. 

Absorption - Nalmefene is completely bioavailable following IM or subcutaneous administration. Nalmefene will be administered primarily as an IV bolus however, it can be given IM or subcutaneous if venous access cannot be established. While the time to maximum plasma concentration was 2.3 hours following IM and 1.5 hours following subcutaneous administrations, therapeutic plasma concentrations are likely to be reached within 5 to 15 minutes after a 1 mg dose in an emergency. 

Terminal elimination half-life tmax Time to maximum plasma concentration... 

The pharmacokinetic properties of fluoroquinolone antibacterial agents have been well described [23]. Gemifloxacin is rapidly absorbed with a time to maximum plasma concentration (T ax) of 0.5-2 h in healthy subjects and displays linear pharmacokinetics over the dose range studied (20-800 mg), with an apparent plasma terminal half-life (fi/2) after single or repeated administration of about 8 h. A minimum of 20-30% of the oral dose is excreted imchanged in the urine. Following repeat oral... 

The time to maximum plasma-concentration (Tmax) of coadministered soluble paracetamol and nifedipine is significantly decreased when subjects are standing or lying on their right side compared with when they lie on their leftside. These postures also resulted in a significantly higher peak plasma-concentration and area imder the plasma-concentration-time curve of nifedipine. 

Fexofenadine hydrochloride was rapidly absorbed following oral administration of a single dose of two 60 mg capsules to healthy male volunteers with a mean time to maximum plasma concentration... 

Oral oseltamivir phosphate is absorbed rapidly and cleaved by esterases in the GI tract and liver to the active carboxylate. Low levels of the phosphate are detectable, but exposure is only 3 to 5% of that of the metabolite. The bioavailability of the carboxylate is estimated to be approximately 80%. The time to maximum plasma concentrations of the carboxylate is about 2.5 to 5 hours. Food does not decrease bioavailability but produces the risk of GI intolerance. After 75-mg doses, peak plasma concentrations average 0.07 pg/mL for oseltamivir phosphate and 0.35 pg/mL for the carboxylate. The carboxylate has a volume of disttibution similar to extracellular water. Broncho-alveolar lavage levels in animals and middle-ear fluid and sinus concentrations in humans are comparable with plasma levels. Following oral administtation, the plasma half-life of oseltamivir phosphate is 1 to 3 hours and that of the carboxylate ranges from 6 to 10 hours. Both the prodrug and active metabolite are eliminated primarily unchanged through the kidney. Probenecid doubles the plasma half-life of the carboxylate, which indicates tubular secretion by the anionic pathway. 

One study found that ranitidine 150 mg twice daily for one day reduced the absorption of procainamide from the gut by 10% and reduced its renal excretion by 19%, increasing the procainamide and A-acetylprocainamide AUC by about 14%. However, no change in the steady-state pharmacokinetics of procainamide was found with ranitidine 150 mg twice daily in another study, except that ranitidine delayed the time to maximum plasma concentration (from 1.4 to 2.7 hours). In a further study, ranitidine 150 mg twice daily for 4 days caused no significant changes in the mean pharmacokinetics of oral procainamide 1 g in 13 healthy subjects. However, it appeared that subjects had either a modest 20% increase or decrease in procainamide clearance, with the direction of change related to their baseline procainamide clearance the higher the baseline clearance the greater the decrease caused by ranitidine. ... 

In a placebo-controlled, crossover study, 18 women taking an oral contraceptive (ethinylestradiol/levonorgestrei 30/150 micrograms) for at least 3 months were also given ziprasidone 20 mg twice daily for 8 days. The only change in the pharmacokinetics of the two steroids was an approximately 30-minute increase in the time to maximum plasma concentration of the levonorgestrel, but this was not considered to be clinically significant. No adverse effects occurred. It was concluded that combined use is safe and that ziprasidone does not affect the efficacy of this oral contraceptive and is also unlikely to affect the metabolism and therefore effieaey of other similar contraceptives. 

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed [33] and validated for the determination of donepezil in human plasma samples. Diphenhydramine was used as the IS. The collision-induced transition m/z 380 > 91 was used to analyze donepezil in selected reaction monitoring mode. The signal intensity of the m/z 380 —> 91 transition was found to relate linearly with donepezil concentrations in plasma from 0.1 to 20.0 ng/ml. The lower limit of quantification of the LC/MS/MS method was 0.1 ng/ml. The intra- and inter-day precisions were below 10.2% and the accuracy was between 2.3% and +2.8%. The validated LC/MS/MS method was applied to a pharmacokinetic study in which healthy Chinese volunteers each received a single oral dose of 5 mg donepezil hydrochloride. The non-compartmental pharmacokinetic model was used to fit the donepezil plasma concentration-time curve. Maximum plasma concentration was... 

A general study in psychiatric patients found that when data on benzodiazepines was pooled, they caused a modest 23% increase in serum citalopram levels, which is almost certainly too small to be clinically relevant. Alprazolam was the only benzodiazepine to cause an elevation of citalopram levels (by 13%) when analysed alone. In another study, citalopram was found to have no effect on alprazolam plasma levels, although the time to maximum alprazolam concentration was increased by 30 minutes. Similarly, a study in 17 healthy subjects found no pharmacokinetic interaction between triazolam and citalopram, and it was suggested that triazolam and other substrates of the cytochrome P450 isoenzyme CYP3A4 are unlikely to have pharmacokinetic interactions with citalopram. ... 

Figure 11.8 plots the change from baseline at T (time to maximum drug concentration in the plasma). The x-axis is the baseline value, and the y-axis represents the QTc change from baseline. Horizontal reference lines at 30 and 60 ms allow the reader to quickly identify any changes from baseline above... 

These effects could result from the progression of the disease but as they are a feature of levodopa therapy a change in the central response to levodopa or changes in its peripheral kinetics are more likely. The latter does not occur since the maximum plasma concentration, the time to reach it and the plasma half-life are still similar after 10 years of treatment to those achieved initially, although continuous infusion of dopa can smooth out the swings. 

Fig. 14 (A, B) Maximum acetaminophen plasma concentration (Cmax) and time to achieve that concentration (TmllK) as a function of gastric emptying half-time. (From Ref. 82.) (C) Percent of an acetaminophen dose emptied from the stomach (O) and acetaminophen plasma concentrations ( ) as a function of time in one subject. (D) The same plot and for the same subject as in (C) after a 10 mg intramuscular dose of heroin. (C and D from Ref. 83.)...

Commercial samples containing approximately 400 mg of ephedra per capsule yield roughly 5 mg of ephedrine, 1 mg of pseudoephedrine, and less than 1 mg of methylephedrine (White et al. 1997). For a dose of four capsules, yielding approximately 20 mg of ephedrine, the elimination half-life is 5.2 hours. The time to reach maxium concentration is 3.9 hours. Compared to pure ephedrine tablets, the elimination kinetics of ephedra are comparable. However, ephedra showed somewhat different absorption kinetics (e.g., lag time, area under the concentration-time curve, and maximum plasma concentration). So, ephedra tablets may vary from pure ephedrine in the onset of action, but the durations of action are grossly equivalent. 

Time to maximum observed plasma concentration Unbound volume of distribution of the free drug... 

Somewhat surprisingly, microdialysis has also revealed that the time to maximum concentration (T ax) within the CNS is close to the Tj ax value in blood or plasma, irrespective of lipophilicity. For example, the CNS Tj ax for atenolol (log D7 4 = - 1.8) occurs at 2 min in the rat after intravenous administration [8]. In addition the rate of elimination (half-life) of atenolol and other polar agents from the CNS is similar to that in plasma or blood. The implication of these data is that poorly permeable drugs do not take longer to reach equilibrium with CNS tissue than more lipophilic agents... 

Onset/Duration The extent and time course of BP reduction by minoxidil do not correspond closely to its plasma concentration. When minoxidil is administered chronically, once or twice a day, the time required to achieve maximum effect on BP is inversely related to the size of the dose. Thus, maximum effect is achieved on 10 mg/day within 7 days, on 20 mg/day within 5 days and on 40 mg/day within 3 days. 

Pharmacokinetics Disulfiram is slowly absorbed from the Gl tract and eliminated slowly from the body. The average time to reach maximum plasma concentrations... 

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... 

Effect of food Maximum plasma concentrations and area under the plasma concentration-time curve (AUC) were 2- to 3-fold higher underfed conditions compared with fasting. 

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). 

After administration of milligram Ginkgoselect Phytosome formulation (24% ginkgo-flavone glycosides and 6% terpenoids in phospholipid complex, 1 2). Abbreviations. N, number of subjects i.v., intravenous C ax, maximum plasma concentration tmux, time at ti/2(p), elimination half-life CL/F, clearance with regard to bioavailability F/F, volume of distribution with regard to bioavailability. 

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],... 

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