Multiple dosing accumulation

When drugs are administered on a multiple dosing regimen, each dose (after the first) is administered before the preceding doses are completely eliminated. This results in a phenomenon known as accumulation, during which the amount of drug in the body (represented by plasma concentration) builds up as successive doses are administered. The phenomenon of accumulation for a drug administered IV is shown in Fig. 14. 

The progressive increase of chemical and/or metabolites in the body. Accumulation is influenced by the dosing interval and half-life of the chemical. The process can be characterized by an accumulation factor, which is the ratio of the plasma concentration at steady state to that following the first dose in a multiple dosing regimen. 

Excretion - Following oral administration of an 80 mg dose of C-isotretinoin as a liquid suspension, C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects underfed conditions, the mean elimination half-lives of isotretinoin and 4-oxo-isotretinoin were approximately 21 and 24 hours, respectively. After single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne. 

Concentration-time profile for a hypothetical drug administered orally in multiple doses. The drug is administered once every half-life (i.e., every 8 hours). Drug continues to accumulate (i.e., concentrations rise) until steady state (rate in = rate out) is reached at approximately 5 half-lives (about 40 hours). 

Less than 20% of indinavir is excreted unchanged in the urine. The mean urinary excretion of unchanged drug was 10.4 4.9% (mean S.D.) (n=10) and 12,0 4.9% (n=10) following a single 700-mg and 1000-mg dose, respectively. Indinavir was rapidly eliminated with a half-life of 1.8 0.4 hours (n=10). Significant accumulation was not observed after multiple dosing at 800 mg every 8 hours [28]. 

Onset and duration of BZD clinical activity are not necessarily related to elimination half-life. When given in single doses, BZDs with long half-lives may have a shorter duration of action than BZDs with shorter half-lives because of extensive distribution. During multiple dosing, however, BZDs with longer half-lives accumulate slowly, and after termination of treatment disappear slowly, whereas BZDs with short half-lives have minimal accumulation and disappear rapidly when treatment stops (185). 

Figure 3.30 Average plasma concentrations of two foreign compounds after multiple dosing. Compound A, half-life 24 hours compound B, half-life 12 hours and dosage interval in each case is 8 hours. The accumulation plateau is directly proportional to the half-life, while the rate of accumulation is inversely proportional to the half-life. Source. From Ref. 9.

In renal impairment the half-life of repaglinide is prolonged. Patients with severe renal impairment (creatinine clearance 20-40 ml/minute) had excess accumulation of the drug after taking multiple doses for 5 days (55). 

Pharmacokinetic data were available for 97 patients. The tasidotin plasma concentrations declined rapidly, and were less than 1% of maximal concentrations within about 8 h after dosing (Fig. 13.2). With such a short effective half-life, accumulation with daily tasidotin administration was not likely - once-daily multiple doses resemble a series of single doses. Concentrations appeared to decline in a biphasic manner (Fig. 13.2). The presence of a third, gamma phase was observed in some patients, but was not consistently detected, and for this reason the effective half-life was calculated instead of the terminal elimination phase half-life. 

If the substrate dmg has a long half-life and accumulates, the probability of seeing an effect may be enhanced by giving the substrate dmg as a single dose and the interacting dmg as multiple doses. One example of this design... 

Careful dose-response studies on the effect of nitrophenols on the development of methemoglobinemia, in multiple species, both sexes, and at multiple doses, would provide information on an effect that is relevant to humans. Studies in rabbits could provide data on what appears to be the most sensitive species, as judged by data on acute lethality by the oral route (Williams 1938). The limited pharmacokinetic data do not suggest route-specific target organs. Because 2-nitrophenol and 4-nitrophenol are rapidly removed from the circulation and excreted (see Chapter 2.3), they will not accumulate. This is particularly important in intermittent-exposure studies and in occupational settings and applies to intermediate- and chronic-duration studies, as well. However, additional studies that use continuous exposure would provide information relevant to potential exposure by populations surrounding hazardous waste sites. 

Benazeprilat, the active metabolite of benazepril, is excreted mainly in the urine, with only about 11-12% being excreted in the bile. The effective half-life for accumulation of benazeprilat is 10-11 h following administration of multiple doses of benazepril. The elimination of benazeprilat is... 

Schentag JJ, Jusko WJ, Vance JW, Cumbo TJ, Abrutyn E, DeLattre M, Gerbracht LM. Gentamicin disposition and tissue accumulation on multiple dosing. J Pharmacokinet Biopharm 1977 5 559-77. 

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