Steady-state plasma level

AUC is the area under the curve or the integral of the plasma levels from zero to infinite time. Conversely, equation 1 may be used to calculate input rates of dmg that would produce steady-state plasma levels that correspond to the occurrence of minor or major side effects of the dmg. 

A steady plasma level can be achieved by giving the drug in a constant intravenous infusion, the steady-state plasma level being determined by the infusion rate, dose D per unit of time T, and the clearance, according to the equation n... 

A4. Alexanderson, B., Price Evans, D. A., and Sjhqvist, F., Steady-state plasma levels of nortriptlyine in twins influence of genetic factors and drug therapy. Brit. Med. J. iv, 764-768 (1969). 

B19. Braithwaite, R. A., and Widdop, B., A specific gas chromatographic method for measurement of steady state plasma levels of amitriptyline and nortriptyline in patients. Clin. Chim. Acta 35, 461-473 (1971). 

Immediate-release vs controlled-release- Following multiple doses, steady-state plasma levels of between 2 and 4 mcg/mL were attained following either 150 mg every 6 hours (immediate release) or 300 mg every 12 hours (controlled release). 

Absorption/Disthbutton - Oral labetalol is completely absorbed peak plasma levels occur in 1 to 2 hours. Steady-state plasma levels during repetitive dosing are reached by about the third day. Due to an extensive first-pass effect, absolute bioavailability is 25%. Protein binding is approximately 50%. Metabolism/Excretion - Metabolism is mainly through conjugation to glucuronide metabolites, which are excreted in urine and in feces (via bile). Elimination half-life is 5.5 to 8 hours. About 55% to 60% of a dose appears in... 

Mirtazapine- Mirtazapine is rapidly and completely absorbed following oral administration and has a half-life of approximately 20 to 40 hours, with females of all ages exhibiting significantly longer elimination half-lives than males (37 vs 26 hours). Steady-state plasma levels of mirtazapine are attained within 5... 

Unlike isotretinoin, acitretin (Soriatane) is not primarily sebosuppressive. Rather, it promotes normalization of dysregulated keratinocyte proliferative activity in the epidermis and is also antiinflammatory. Oral absorption is optimal when acitretin is taken with a fatty meal peak levels are reached approximately 3 hours after ingestion, while steady-state plasma levels are achieved after approximately 3 weeks of daily dosing. The mean terminal elimination half-life of the parent compound is 49 hours. However, when consumed with ethanol, acitretin may be transesterifled to form etretinate, a retinoid that is stored in adipose tissue, resulting in a much longer half-life (3-4 months or longer). 

Geller, B. Cooper, T.B., Chestnut, E.C., Anker, J.A., Price D.T., and Yates, E. (1985b) Child and adolescent nortriptyline single dose kinetics predict steady state plasma levels and suggested dose preliminary data. / Clin Psychopharmacol 5 154—158. 

Geller, B. and Fetner, H.H. (1989a) Children s 24-hour serum lithium level after a single dose predicts initial dose and steady-state plasma level [letter]. / Clin Psychopharmacol 9 155. 

Clonidine is also available as a transdermal patch (Catapres-TTS [transdermal therapeutic system]) that has the advantages of avoiding the need for repeated doses during the day and of reportedly lower rates of dry mouth and drowsiness (Burris, 1993). Steady-state plasma levels are reached within 2-3 days after applying the patch and clonidine concentrations reportedly diminish gradually over 2-3 days following patch removal, without rebound hypertension in adult hyper-... 

Clinical pharmacology. Following absorption, peak plasma concentrations occur 1-3 hours after oral administration (Franc et al. 1991). Following extensive hepatic metabolism, the bioavailability of nefazodone is between 15% and 23%, after which it is 99% protein bound. Nefazodone reaches steady-state plasma levels in 3 days and is eliminated from the body within 24 hours, reflecting its half-life of 2-4 hours (Franc et al. 1991). Therapeutic doses in young adults have been found to range from 100 to 300 mg twice daily (E. Fontaine 1994). Lower doses are recommended in patients with concomitant liver disease and the elderly, as plasma concentrations can be double those seen in younger patients. 

Madakasira S, Preskorn SH, Weller R, et al. Single dose prediction of steady state plasma levels of amitriptyline. J Clin Psychopharmacol 1982 2 136-139. 

Case Example Because of a patient s partial response to 5 months of clozapine therapy at 600 mg/day, risperidone was added for augmentation (started with 0.5 mg b.i.d. and increased to 1 mg b.i.d. after 1 week). Before this addition, the clozapine plasma level was 344 ng/mL, but after 2 weeks of risperidone augmentation, the level was elevated to 598 ng/mL with no adverse effects and substantial clinical benefit. In another report, there was an increase in the steady-state plasma levels of clozapine (675 mg/day) and its active metabolite norclozapine after the addition of risperidone 2 mg/day in a patient treated for 2 years. Before the addition of risperidone, her clozapine and norclozapine levels were 829 and 1,384 ng/mL, respectively. Two days after risperidone was added, these levels rose to 980 and 1,800 ng/mL. Clozapine dosage was reduced to 500 mg/day, and after 5 days of combined treatment with 4 mg/day of risperidone, the clozapine and norclozapine levels were 110 and 760 ng/mL, respectively. Aside from some mild oculogyric crises, she had no symptoms of clozapine toxicity or clinical changes during the period of cross-tapering. In another case, risperidone was added to clozapine because the patient had relapsed after discontinuation of fluphenazine and had not responded to clozapine. The addition of risperidone resulted in an acute remission of psychosis ( 100). 

Javaid Jl, Janicak PG, Hedeker D, et al. Steady-state plasma level prediction for haloperidol from a single test dose. Psychopharmacol Bull 1991 27 83-88. 

Silkey B, Preskorn SH, Golbech A. Interindividual variability in steady-state plasma levels of bupropion and its major metabolites. 40th Annual Meeting NCDEU, Boca Raton, Florida, 2000. 

Lane HY, Jann MW, Chang YC, et al. Repeated ingestion of grapefruit juice does not alter clozapine s steady-state plasma levels, effectiveness, and tolerability. J Clin Psychiatry 2001 62(10) 812-817. 

A transdermal patch preparation is available containing 0.5 mg hyoscine. This is effective for up to 72 h, but absorption is slow, reaching a steady state plasma level only after 5 h, so that the patch needs to be applied early, i.e. 5-6 h before travel and similarly before surgery. 

Individual differences in metabolic rate depend on the nature of the drug itself. Thus, within the same population, steady-state plasma levels may reflect a 30-fold variation in the metabolism of one drug and only a two-fold variation in the metabolism of another. 

In order to rapidly achieve a steady-state level of the compound in the plasma so that the organism is exposed to a fairly constant level, the dosage interval and half-life should be similar (Fig. 3.30). For steady-state conditions, the half-life determines the plasma level. That is, substrates with a long half-life attain a higher steady-state plasma level than compounds with shorter half-lives. It is obviously important to measure this plasma concentration for an assessment of chronic toxicity (Fig. 3.30). 

Hundley et al. (1993a) exposed rats and mice to atmospheres of 10,250 and 500 ppm [30, 750 and 1500 mg/m ] dimethylformamide for single 1-, 3- and 6-h periods or for 6 h per day on 10 days over two weeks. Dimethylformamide was not detected in the plasma after the 10 ppm dose, while at the 250 ppm dose, steady-state plasma levels were approached after 6 h of exposure this was not the case at 500 ppm, where plasma levels increased two-fold in rats and three-fold in mice between 3 and 6 h of exposure. The area under the plasma concentration curve (AUC) values for dimethylformamide after a single 6-h exposure increased disproportionately (8-fold and 29-fold increases in rats and mice, respectively) compared with the increase in dimethylformamide exposure concentration (from 250 ppm to 500 ppm). Multiple 500 ppm dimethylformamide exposures resulted in... 

The serum concentrations of "classical neuroleptics and their metabolites vary considerably in patients, even when the dose of drug administered has been standardized. Such interindividual variation may account for the differences in the therapeutic and side effects. High interindividual variations in the steady-state plasma levels have been reported for pimozide, fluphenazine, flupenthixol and haloperidol, some of these differences being attributed to differences in absorption and metabolism between patients. 

The in vitro approaches feature human liver microsome incubations that contain drug candidates at a range of concentrations that span the anticipated maximum steady state plasma levels. The microsomal incubations also contain a specific probe substrate where the concentration closely approximates that Km value for the reaction under investigation. Quantitative analysis of the specific marker metabolites and internal standards using MRM provides a simple assessment of the potential inhibitory effects drug candidates have on the metabolism of specific CYP probe substrates. 

Using the same protocol as in the study of Dalen et al. in Caucasians (48), we investigated the influence of the Asian specific CYP2D6 10 allele on the disposition of nortriptyline in Chinese subjects living in Sweden (50). Morita et al. (51) related the CYP2D6 10 allele to steady-state plasma levels of nortriptyline and its metabolites in Japanese depressed patients. From these two studies it may be concluded that the Asian CYP2D6 10 allele... 

Scordo MG, Spina E, Facciola G, Avenoso A, Johansson I, Dahl M-L. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxy risperidone. Psychopharmacology 1999 147 300-305. 

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