Trough-to-peak ratios

Trough-to-peak ratios, therapeutic regimes and the smoothness index... 

Elliott and Meredith (1994) point to a number of methodological difficulties in implementing the trough-to-peak ratio requirements. The first is the presence of placebo effects. Elliot and Meredith point out that defining the effects in terms of difference from baseline will overestimate the effect of the active treatment. Table 21.2 is adapted from table 2 of Elliott and Meredith (1994), which in turn was based on an example of Rose and McMahon (1990) and show the example of felodipine extended release. The placebo effect is considerable, and depending whether the treatment effect is corrected for the placebo effect or not, the troughipeak ratio for 10 mg, for example, is either 33% or 60%. 

Table 21.2 Trough-to-peak (T P) ratios for felodipine for systolic blood pressure.

Tissue-to-plasma ratio is commonly determined from the ratio of average concentrations at specified time points. It is not uncommon, in practice, for the ratios to be calculated at selected time points corresponding to peak and trough concentrations, and the variations in the ratios are usually very large. This finding could be attributed in part to the variations in the concentrations and a lack of accounting for the correlation in observations from the biological matrices sampled from each subject. 

Plasma dmg concentrations rise at a gradual, controlled rate after dosing, and reach a plateau at approximately 6 h after the first dose with minimal fluctuations over the 24 h dosing interval. Subsequent doses maintain the plasma concentration at this plateau. The extended release tablets taken once daily have reduced by fourfold the fluctuations (ratio of peak to trough plasma concentration) observed with the conventional immediate release Procardia tablets taken three times daily (81). 

Absorption/Disthbution - Maximal serum concentrations (Cmax) occur between 72 to 96 hours postdose. Steady-state serum levels are reached within 5 to 8 weeks of once-weekly dosing. The peak-to-trough ratio at week 48 is approximately 2. 

The ratios of the anisotropy powers below the peak at l 50, at the big peak at ss 220, in the trough at / 412, and at the second peak at / 546 were precisely determined using the WMAP data which has a single consistent calibration for all Us. Previously, these I ranges had been measured by different experiments having different calibrations so the ratios were poorly determined. Knowing these ratios determined the photon baryon CDM density ratios, and since the photon density was precisely determined by FIRAS on COBE, accurate values for the baryon density and the dark matter density were obtained. These values are Ct h2 = 0.0224 4%, and Vtmh2 = 0.135 7%. The ratio of CDM to baryon densities from the WMAP data is 5.0 1. 

The peak to trough ratio (data not shown) increased with dose, reflecting the higher than dose proportional increase in Cmax,ss-... 

A modified-release formulation (Carbolithium Once-A-Day) produced a reduction in peak/trough lithium ratio compared with a standard formulation (519), and an interim analysis of an open switch to the modified-release formulation suggested better tolerability and efficacy at 4 weeks (n = 27) and 6 weeks (n = 15) (520). A paucity of detail, however, prevents firm conclusions. 

Select maintenance dose (as percentage of loading dose) to continue peak serum concentrations indicated above according to desired dosage interval and the patient s creatinine clearance. To maintain usual peak/trough ratio, use dosage intervals in clear areas. 

Major descriptive PK parameters of exposure are peak concentration (Cmax), trough concentration (Cmin), area under the plasma concentration versus time curve (AUC), and bioavailability (F) as illustrated in the time-plasma concentration profile in Figure 3.1. Primary mechanistic PK parameters contributing to the extent of drug exposure are clearance (CL) and volume of distribution (Vdss). The ratio of Vdss-to-CL is the mean residence time (MRT), an intrinsic parameter that characterizes the residence time of drug molecules in the body. CL, Vdss, and MRT can be called dispositional PK parameters as well. Fraction absorbed (/(,), gut bioavailability (Fgut), and hepatic bioavailability (Fh) are the three major mechanistic parameters that control the total bioavailability (F). 

In order to maximize the exposure and thus the viral spectrum of 12 in the clinic, the highly water soluble Tris salt (aqueous solubility >10 mg/mL) of prodrug 13 was selected for advancement. To reduce the relatively high peak to trough ratio observed after oral dosing with this class of molecules, a slow release formulation was developed and was shown to facilitate absorption from the entire GI tract [69],... 

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