Maximal drug concentration

Total systemic exposure to an administered drug is usually measured by the area under the drug concentration curve. For each participant the drug concentration (in nanograms/milliliter) can be plotted as a function of time, as displayed in Figure 7.1. The maximal drug concentration (Cni ) and the time at which it is observed... 

The bootstrap cannot just be applied to any problem. There do exist situations where the bootstrap will fail, particularly those situations where the statistic depends on a very narrow feature of the original sampling process (Stine, 1990), such as the sample maximum. For instance, the bootstrap may have poor coverage in estimating the Cl associated with maximal drug concentrations (Cmar). The bootstrap will also have trouble when the sample size is small although what constitutes small is debatable. The number of possible combinations drawn from an n-size sample with replacement is... 

Estimating the Bmax value is technically difficult since it basically is an exercise in estimating an effect at infinite drug concentration. Therefore, the accuracy of the estimate of Bmax is proportional to the maximal levels of radioligand that can be used in the experiment. The attainment of saturation binding can be deceiving when the ordinates are plotted on a linear scale, as they are in Figure 4.2. 

Figure 9.23)). The use of the pro-drug optimally produces a maximally effective concentration of the active drug in the eye, the target organ. 

EC50 represents the drug concentration required to cause 50% of the respective maximal relaxation of rabbit aorta, independently from its extent From reference [70] From reference [148] See Fig. 8 From reference [149]... 

Fig. 4.2. Effects of triphenylethylene SERMs on spontaneous and depolarization-induced contractions in visceral smooth muscle. Tamoxifen (a) and ethylbromide tamoxifen (EBTx, b) rapidly and reversibly inhibit spontaneous peristaltic activity in duodenal muscle. Both compounds also inhibit depolarization-induced tonic contraction of uterine muscle (c). The inhibition of L-type voltage-dependent calcium channels underlies the relaxing effects illustrated here. Drugs concentrations were 10 xM in all cases. %RA percent of activity related to maximal activity...

The usual definitions of maximal effect (E ) and potency EC or IC50) require another look at this stage before proceeding to developing mathemahcal relationship between drug concentration, dose, and body fxmchons using a PK/PD approach. ... 

The plasma half-life of cathinone is 1.5 hours. The primary metabolites are norpseudoephedrine, norephedrine, 3,6-dimethyl-2,5-diphenyl-pyrazine, and l-phenyl-l,2-propanedione (Szendrei 1980 Brenneisen etal. 1986 Guantai and Maitai 1983). However, norpseudoephedrine and norephedrine also originate directly from the leaves, as well as being metabolic products (Widler et al. 1994). Maximal plasma concentrations of norephedrine and norpseudoephedrine are reached at about 3.3 and 3.1 hours, respectively. These two drugs have a much longer duration of action than cathinone, where terminal half-lives could not be calculated after 10 hours. 

This figure demonstrates that there is a maximally efficient drug concentration at which the highest effect per unit stimulus is obtained (Ceffmax)- The value of Ceffmax IS Only a function of C5o% and 5 as Ceffmax = C5o%(l — This is true for 5 > 1, while efficiency is ever increasing with decreasing concentrations for < 1. 

Answer Famciclovir is a prodrug that is rapidly converted to penciclovir, with a bioavaUabiUty of 77%. Maximal plasma concentrations of penciclovir are reached within 45 to 60 minutes of famciclovir administration. Mr. Smith developed an allergy to topical penciclovir when he was treated with this drug during college. This prior contact sensitization to penciclovir allowed him to develop an anaphylactoid reaction following the conversion of oral famciclovir to penciclovir by hepatic first-pass metabolism. 

Figure 5.2 Plasma concentration curve of drug after single and repeated administration Csj. nax, maximal steady-state plasma concentration after repeated administration Css av, average steady-state concentration after repeated administration Css mm- minimal steady-state concentration after repeated administration n. maximal plasma concentration after single oral dose t Inax. time to maximal concentration after single oral dose t plasma half-life after single oral dose AUC, area under the concentration vs. time curve...

Maximal plasma concentrations occur 2 to 3 hours after oral administration of reboxetine (178). Reboxetine has linear pharmacokinetics over its clinically relevant dosing range and a half-life of approximately 12 hours. For this latter reason, a twice a day, equally divided dosing schedule was used during clinical trial development. Its clearance is reduced and half-life becomes longer as a function of advanced age (mean = 81 years of age) and renal and hepatic impairment ( 178, 322, 323). Reboxetine is principally metabolized by CYP 3A3/4 such that its dose should be reduced when used in combination with drugs that are substantial inhibitors of CYP (e.g., certain azole antifungals, certain macrolide antibiotics). Reboxetine itself, however, does not cause detectable inhibition of CYP 3A3/4 based on formal in vivo pharmacokinetic interaction studies as well as its own linear pharmacokinetics. 

The effects of GFJ were studied for clarithromycin (115) and erythromycin (116). A decrease in the time to reach the maximal plasma concentration (Tmax) was found for clarithromycin. The exposure of erythromycin was mildly increased when administered concomitantly with GFJ. It seems unlikely that the reported interactions with the above drugs would be relevant in a clinical setting. 

Relations between drug concentration and drug effect (A) or receptor-bound drug (B). The drug concentrations at which effect or receptor occupancy is half-maximal are denoted by EC50 and Kd, respectively. 

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