Dose-dependent pharmacokinetics

Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Cotreau MM, Harmatz JS, Shader RI. (1997). Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans. J Clin Pharmacol. 37(8) 693-703. 

King SYP Joslin MA, Raudibaugh K, et al. Dose-dependent pharmacokinetics of warfarin in healthy volunteers. Pharm Res 1995 12 1874-1877. 

In these phase I studies, trastuzumab displayed dose-dependent pharmacokinetics, with a serum half-life ranging from 1 day at the 10-mg dose level to 14 days at the 500-mg dose level. Importantly, when administered at the higher dose levels, consistent serum trough concentrations of trastuzumab above 10 pg/ml were achieved, which was the target concentration based on the in vitro antiproliferative activity. Soluble HER ECD was detected in 24 of 28 patients and was correlated with altered trastuzumab pharmacokinetics. Also, in contrast to 4D5 therapy, no human antihuman antibodies (HAHA) were observed following trastuzumab administration. 

Tanaka C, Kawai R, Rowland M. Dose-dependent pharmacokinetics of cyclosporine A in rat events in tissues. Drug Metab Dispos 2000 28 582-589. 

Fong KL, Crysler CS, Mico BA, Boyle KE, Kopia GA, Kopaciewicz L, Lynn RE. Dose-dependent pharmacokinetics of recombinant tissue-type plasminogen activator in anesthetized dogs following intravenous infusion. Drug Metab Dis 1988 16 201-6. 

Borgstrom L, Kagedal B. 1990. Dose dependent pharmacokinetics of N-acetylcysteine after oral dosing to man. Bio-pharm Drug Dispos 11 131-136. 

Voriconazole exhibits dose-dependent pharmacokinetics. Voriconazole has 96% oral bioavailability and reaches peak plasma concentrations in 2 to 3 hours after oral administration. Please refer to the general pharmacology section for antifungal drugs. 

Cheng, W.S.C., Murphy, T.L., Smith, M.T., Cooksiey, W.G.E., Haiiiday, J.W., Powell, L.W. Dose-dependent pharmacokinetics of caffeine in humans relevance as a test of quantitative liver functions. Clin. Pharmacol. Ther. 1990 47 516-524... 

Lin, J.H. Dose-dependent pharmacokinetics experimental observations and theoretical considerations. Biopharm Drug Dispos. 1994, 75(1), 1-31. 

Brown, S.A., Coppoc, G.L., Riviere, J.E. Anderson, V.L. (1986) Dose-dependent pharmacokinetics of gentamicin in sheep. American Journal of Veterinary Research, 47, 789-794. 

Pharmacodynamics and causes of dose-dependent pharmacokinetics of flavone-8-acetic acid (LM-975 NSC-347512) in mice. Cancer Chemother. Pharmacol. 24, 15-22. 

Rituximab demonstrates dose-dependent pharmacokinetics. At a dose of 375 mg/m, the mean sernm half-life was 76.3 hours (range, 32 to 153 honrs) after one dose and... 

Monshouwer, M. Witkamp, R.F. Pijpers, A. Verheijden, J.H.M. Van Miert, A.S.J.PA.M. Dose-dependent pharmacokinetic interaction between antip3nine and paracetamol in vivo and in vitro when administered as cocktail in pig. Xenobiotica, 1994, 24, 347—355... 

Gehring, P. J., The relevance of dose-dependent pharmacokinetics in the assessment of carcinogenic hazards of chemicals. In Origins of Human Cancer (H. H. Hiatt, J. D. Watson, and J. A. Winsten, eds.), pp. 187-203, New York Cold Spring Harbor Laboratory (1977). 

Rituximab demonstrates dose-dependent pharmacokinetics. At a dose of375 mg/nf, the mean serum tj was 76 hours after one dose and 206 hours r er the last dose, with considerable interindividual variation. The wide range oftj likely reflects differences in patient tumor burden and normal B-cell populations. Rituximab toxicities are mostly related to infusion reactions, although there are increasing reports of late-onset neutropenia and rare reports of severe skin toxicity (Table 51-4). 

Trastuzumab has dose-dependent pharmacokinetics with a mean t of 5.8 days at the 2-mg/kg maintenance dose. Steady-state levels were achieved between the 16th and the 32nd weeks. The infusion effects of trastuzumab are typical of other monoclonal antibodies and include fever, chills, nausea, dyspnea, and rashes. Allergic reactions also may be observed. Cardiac dysfunction is an unexpected and potentially serious side effect that was observed in the pivotal trial of trastuzumab chemotherapy. Left ventricular dysfunction was seen most commonly in those patients who received doxorubicin and cyclophosphamide. 

Watanabe, P. J., Young, J. D. and Gehring, P. J. "The Importance of Non-Linear (Dose-Dependent) Pharmacokinetics in Hazard Assessment" J. Environ. Path. Toxicol. (1977),... 

In another study the area under the plasma concentration-time curve for prednisolone for the 20 mg dose was 77.89 % of that calculated for the 10 mg dose. This change in area represented an increase in prednisolone clearance from 1,7 ml/min kg to 2.2 ml/min kg when the dose was increased (141). Rose et al. (142) found dose-dependent pharmacokinetics of prednisolone where the plasma half-life increased from 3 to 5 h as the oral dose of prednisone was increased from 5 to 50 mg. Tanner et al (143) reported the pharmacokinetics of prednisolone at different dose levels in 43 subjects. Each subject received only a single dose, 5 - 200 mg of oral prednisolone. Kinetic parameters of oral prednisolone are presented in table 5 and fig. 13 illustrates concentration-time profile of prednisolone. The mean half-life of prednisolone remained fairly constant between 3.4 to 3.8 h. Bioavailability of prednisolone was 98.5 i 4 %. Furthermore as the prednisolone dose increased, the area under the curve increased but not proportionally to the dose, such that a fivefold increase in dose from 20 to 100 mg resulted in only a two-to threefold increase in area under the curve. 

It appears that prednisolone may exhibit dose-dependent pharmacokinetics, so that with increasing dose values volume of distribution, plasma clearance and half-life may increase. It is believed to be related to changes in the plasma protein binding of prednisolone. Prednisolone appears to bind to plasma proteins in a non linear manner over the range of doses used (131). 

Figure 15.2 Relationship between the plasma concentration (Cp) at a time at steady state (a) and the area under the plasma concentration versus time (AUC) curve (b) against the administered dose for a drug that exhibits dose-dependent pharmacokinetics.

Figure 15.5 Relationship between elimination rate and the plasma concentration of a drug that exhibits dose-dependent pharmacokinetics. At high drug concentrations, where saturation occurs, the elimination rate approaches its maximum, Umax.

Figure 15.6 Plasma concentration (Cp) versus time profile following the administration of an intravenous bolus dose of a drug that exhibits the characteristics of dose-dependent pharmacokinetics, (a) Rectilinear plot (b) semilogarithmic plot.

Joos AAB, Konig F, Frank UG, Kaschka WP, Morike KE, Ewald R. Dose-dependent pharmacokinetic interaction of clozapine and paroxetine in an extensive metabolizer. Pharmacopsychiatry (1997) 30, 266-70. 

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