Time of maximum drug concentration

Pharmacokinetic studies in drug discovery research deal with the measurement of the drug eoneentration in plasma with respeet to time and the key parameters involved are volume of distribution (Fd), bioavailability (F), exposure (measured as the area under the curve or AUC), maximum plasma concentration attained (Cmax), time of maximum drug concentration (T ax). clearance (Cl) and half-life ( 1/2). These parameters and their role in drug discovery have been diseussed in detail in most text books related to drug metabolism and pharmaeokineties (DMPK), and have been discussed only briefly here. Eaeh of the above are defined as follows ... 

Time of maximum drug concentration (r , ) is defined as the time taken to achieve the maximum concentration of the drug in systemic circulation, that is, the time taken to achieve C ax and is expressed in hours (Figure 7.3). ... 

Prolongation of the QT interval is a recognized effect of 4-aminoquinolines. In 20 adult Cameroonian patients with non-severe falciparum malaria treated with amodiaquine (total dose 30 mg/kg or 35 mg/kg over 3 days) there was asymptomatic sinus bradycardia (n = 16) and prolongation of the PQ, QRS, and QT intervals at the time of maximum cumulative concentration of drug (day 2 of treatment) (1). 

Two primary mechanisms of vitreal drug distribution and elimination are (i) diffusion from the lens region toward the retina with elimination via the retina-choroid-sclera and (ii) anterior diffusion with elimination via the hyaloid membrane and posterior chamber (18). Distribution to the retina from an intravitreal injection site is relatively slow, considering juxtaposition of the vitreous and retina, with the time for maximum drug concentration (tmax) in retina typically achieved at 4 to 12 hours, and reflects the inefficiency of diffusion over the distances encountered within the vitreous body. For example, ranibizumab, an ocular specific monoclonal VEGF antibody, distributes to the retina with of 6 to 24 hours. While relatively rapid therapeutically, this is slow compared with the rate of redistribution in stirred compartments. (249). 

In this special case when the time between dosings is equal to the half-life time of the drug, we can deduce that the minimum (steady-state) plasma concentration with repeated dosing is equal to the peak concentration, obtained from a single dose. Under this condition, the corresponding maximum (steady-state) concentration is twice as much as the minimum one. 

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. 

In the case of metoprolol succinate and metoprolol fumarate, the maximum drug concentration in the plasma( max) and the area under the plasma drug concentration-time curve were statistically equivalent, based on a 90% conLdence interval (Sandberg et al., 1993). With fenoprdffcQmthe following administration of its calcium salt was reached somewhat later thaCmjpassociated with the sodium form (Rubin et al., 1971). This was attributed to the slower dissolution rate for the calcium salt in acidic pH. Bioavailability and the measured distribution and elimination parameters, however, were reported to be similar. 

Should an early decision be made to develop the eutomer, then the drug development program would be the same as for conventional NCEs, with the possible exception that assessment of in vitro and/or in vivo chiral inversion may be desirable. However, if development continues with the racemate, time, cost, and staff resource commitments become magnified. For example, a very important variable to consider is spedes differences in enantiomer exposure. Appropriate toxicokinetic studies are advisable in order to assure that, at toxicological doses, the animal species tested have attained suffident plasma concentrations of each enantiomer to support clinical evaluation at therapeutic doses in humans. The enantiomeric ratio (based on maximum drug concentrations fCmax] and/or area under the plasma drug concentration-time curve [ALJC]) should be evaluated, and... 

The three major parameters examined in urinary excretion bioavailability studies are the cumulative amount of drug excreted unmetabolized in the urine ( Xu)-, the maximum urinary excretion rate (ERmax) and the time of maximum excretion rate (Tmax)- In simple pharmacokinetic models, the rate of appearance of drug in the urine is proportional to the concentration of drug in the systemic circulation. Thus, the values for Tmax and ERmax for urine studies are analogous to the Tmax and Cmax values derived from blood level studies. The value of r ax decreases as the absorption rate of the drug increases, and increases as the... 

The time to peak plasma drug concentration (units = hours, minutes, etc.) The tniax is measure of the rate of drug absorption and is the time required to reach the maximum drug concentration after drug administration. The is obtained directly from the plasma concentration time profile. 

In the traditional systems, the release time increases with drug concentration in frict after the maximum, the curves, for the differ t peaks, are parallel. Increasing the initial concentration is not the only way to prolong the effecrt of traditional systems. Another possibility is the use of subsequently administraticms obtaining a step-trend. 

Fig. 1. Blood—drug concentration curve used to determine bioavailabiLitv and bioequivalence. C is the maximum dmg concentration in the blood and corresponds to some The AUC (shaded) represents the total amount of orally adininistered dmg the time from points A to B represents dmg onset, from points B to D, the duration MEC = minimum effective concentration MTC = minimum toxic concentration and TI = therapeutic index.

Shintani et al. (1967) developed and proposed the methodology that currently seems to be more utilized. It uses the lateral vastus muscle and includes a methodology for evaluation, scoring, and grading of irritation. Additionally, Shintani et al. investigated the effects of several factors such as pH of the solution, drug concentration, volume of injection, the effect of repeated injections, and the time to maximum tissue response. This method also constitutes the USP method (USP, 1985). 

The Time for Maximum Concentration, 7max, is the third important component of bioavailability studies. It is a measure of the rate of drug absorption. A lower 7max represents a faster absorption and a higher Tmax represents a slower absorption. Similar to Cmax, the 7max is read directly from the plasma concentration versus time profile. The 7max in Figure 12.2 is 6 hours. 

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