Dose proportionality

Bolla KI, McCann UD, Ricaurte GA Memory impairment in abstinent MDMA ( ecstasy ) users. Neurology 51 1532—1537, 1998 Borgen L, Lane E, Lai A Xyrem (sodium oxybate) a study of dose proportionality in healthy human subjects. J Clin Pharmacol 40 1053, 2000 Borgen LA, Okerholm R, Morrison D, et al The influence of gender and food on the pharmacokinetics of sodium oxybate oral solution in healthy subjects. J Clin Pharmacol 43 59-65, 2003... 

V. P., Thiazides X lack of dose proportionality in plasma chlorothiazide levels following oral solution doses, Curr. Ther. Res. 1982, 32, 379-385. 

At each of these stages, not only do the questions of interest change, but so also does the quality of the information available to answer these questions (Fig. 1 panel b). During target specification, all available pharmacokinetic characteristics are used to build a suitable model (e.g., disposition of the drug after administration of an immediate-release (IR) tablet, oral solution, or intravenous dose dose-proportionality time-dependence metabolism and pharmacological activity of metabolites efficiency of absorption from various sites etc.). However, since no formulations have yet been developed, the in vitro release behavior is unknown, as is the... 

It should be noted that pharmacokinetic data are included, which places a strain on the bioanalysts and laboratory facilities. However, with proper planning and adequate development time, preliminary but reasonably reliable data can usually be obtained within 2 or 3 days of receiving samples. Knowledge of maximum concentrations, dose proportionality of AUC and half-lives of the parent molecule and major metabolites greatly adds to making rational decisions about adverse events, times for sampling and measurements, the appropriate next dosage increment and the interval that should be allowed between study occasions. 

Elderly Dose proportionality was observed in nalmefene AUC following 0.5 to 2 mg IV administration to elderly male subjects. There was an apparent age-related decrease in the central volume of distribution that resulted in a greater initial nalmefene concentration in the elderly group. While initial plasma concentrations were transiently higher in the elderly, it would not be anticipated that this population would reguire dosing adjustment. 

Pharmacokinetics A mean elimination half-life of approximately 5 hours has been reported after intravenous doses of Roferon-A. Pharmacokinetic parameters are similar in healthy subjects and cancer patients after intramuscular doses. Dose-proportionate increases in serum levels occur with doses up to 198 MIU. The bioavailability of interferon alfa-2a after intramuscular administration is 80% to 83%, and its volume of distribution is 0.223 to 0.748 liter/kg. The total body clearance of interferon alfa-2a has been reported to range from 2.14 to 3.62ml/min per kg. 

Dose proportionality has been established for the reference hsted product, and aU reference product strengths are compositionally proportional or qualitatively the same, have the same release mechanism, and the in vitro dissolution profiles of aU strengths are similar. 

Yao, M., Swaminathan, A., and Srinivas, N. (2007). Assessment of dose proportionality of muraglitazar after repeated oral dosing in rats via a sparse sampling methodology. Biopharm. Drug Dispos. 28 35-42. 

The pharmacokinetic dose proportionality and relative bioavailability of cyclosporine from the microemulsion formulation were compared to those of the regular formulation over the dosage range of 200 to 800 mg. The AUC for Sandimmun increased in a less than proportional manner with respect to dose, whereas that for Neoral was consistent with linear pharmacokinetics. In addition, the relative bioavailability of cyclosporine from the microemulsion formulation ranged from 174% at the 200 mg dose to 239% at the 800 mg dose compared to the regular formulation [41]. 

Cundy, K. C., Annamalai, T., Bu, L., et al. XP13512 [( )-l-([(a-isobutanoyloxyethoxy) carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J. Pharmacol. Exp. Ther. 311 324-333, 2004. 

Dose proportionality was assessed using the power model. AUC0 24 and Cmax did not change over day of administration, but did increase with increasing dose (p <0.0001 see Fig. 13.3). For AUC0 24, the 90% Cl for the slope related to dose was 0.96, 1.18 with a point estimate of 1.07. The 90% Cl for the slope related to Cmax was 1-02, with a 90% Cl of 0.92, 1.13. Hence, the 90% Cl for both AUC0 24 and Cmax contained the value 1.0 and both parameters were dose-proportional. The between-subject variability for AUC0 24 and Cmax was 32% and 40%, respectively. 

J. McKellar. 1995. Assessment of dose proportionality Report from the Statisticians in the Pharmaceutical Industry/Pharma-cokinetics UK Joint Working Party. Drug Information J. 29 1039-1048. 

From a pharmacokinetic perspective, BA data for a given formulation provide an estimate of the relative fraction of the orally administered dose that is absorbed into the systemic circulation when compared with the BA data for a solution, suspension, or intravenous dosage form [21 CFR 320.25(d)(2) and (3)]. In addition, BA studies provide other useful pharmacokinetic information related to distribution, elimination, the effects of nutrients on absorption of the drug, dose proportionality, linearity in pharmacokinetics of the active moieties, and, where appropriate, inactive moieties. BA data may also provide information indirectly about the properties of a drug substance before entry into the systemic circulation, such as permeability and the influence of presystemic enzymes and/or transporters (e.g., p-glycoprotein). 

In a double-blind, placebo-controlled, dose-ranging study in 35 antiretroviral-naive HIV-infected patients (Protocol 004), subjects were randomized to receive placebo or one of four raltegravir doses (100, 200, 400, or 600 mg) twice daily over 10 days. Although dose proportionality was not observed (possibly due to intersubject variability and the small number of patients), the pharmacokinetic data gathered in this study supported the selection of a 400-mg dose for raltegravir.27... 

Explorative dose-proportionality was to be investigated in parallel to the progress of the dose escalation, using dose normalized values (on a dose per body weight basis) for AUC, Cmax, and Ae (characterized by an additional suffix norm ) and/or by adequate regression analyses of all parameters. Predictions for the next dose steps were to be derived, based on these findings. 

Typically, a dose-proportional increase of exposure (AUC) cannot be expected, if a concentration-dependent mechanism of distribution and elimination exists. Especially the renal clearance of a drug is quite often concentration dependent, if strong binding to blood constituents (proteins, cells) plays a major role. In those cases it is recommendable to use free fractions of the drug instead, in order to find a parameter independent of the total concentrations, which then might be predictive for dose-proportionality. 

All bioanalytical data, derived PK data, and safety data were listed and descriptive statistics calculated. Individual and median data were plotted. The log-transformed PK parameters AUC and Cmax were analyzed for dose proportionality. The PK parameters AUC(0-24) and Cmax were also descriptively analyzed for accumulation ratio. 

Mean Cmax and AUC(o 24) (= AUCX) both on day 1 (Cmax 0.46, 1.16 and 3.29 pg/mL AUCX 7.12, 16.37 and 39.85 pg h/mL) and on day 7 (Cmax,ss 0.91, 2.31 and 5.95 pg/rnL AUCX,SS 14.17, 33.55 and 74.48 pg h/mL) increased with increasing dose although the increases were marginally higher than strict dose proportionality would predict the deviation from linearity was however minor. The median time to reach maximum plasma concentration was 6 h on both profile days and at all doses. The terminal phase half-fife of XYZ1234 on day 7 was quite constant with mean values between 19 to 23 h a slight reduction in half-life (accompanied by a reduced terminal phase volume of distribution) was observed at the higher doses. 

Median Cmax,ss values of 0.79,2.3 and 5.0 (ig/mL at 6 h post dose were observed slightly higher increases were apparent than strict dose proportionality would predict. 

The mean data for Cmax,mit (and to a lesser extent AUCx init) on day 1 confirm the descriptive observation already made that the increases with increasing dose were slightly higher than strict dose proportionality would predict. Median Tmax,init was very constant (6 h) throughout the dose range studied. 

Dose proportionality could be shown for the dose dependent parameters AUC(o-inD> AUQo-t) and all the three possibilities of treatment comparisons(B vs A, C vs A, C vs B). The 95 % confidence interval contains all of the expected ratios. 

For the parameter AUC, 0-24.1 only the expected ratio of the comparison of C and A is not contained in the confidence interval. So dose proportionality could be shown for the two other comparisons. 

For the parameter Cmax dose proportionality could not be shown for all of the three comparisons. The three expected comparisons are not contained in the confidence intervals. 

Evaluate absolute bioavailability, distribution and disposition, and linearity of kinetics over toxicology dose range, i.e., dose proportionality, in pharmacology and toxicology animal species. 

Pharmacokinetic and bioavailability (absolute and relative) experiments are usually designed and conducted to evaluate dose proportionality over the dose range used, or expected to be used, in toxicology studies and possible species-to-species differences in pharmacokinetic profiles. With the incorporation of one or two I.V. dose levels into the study protocol, the drug candidate s absolute... 

For saturation of absorption to be used for dose selection, information that the absorption process has been saturated using the intended route of administration is necessary. These data can usually be obtained during well-designed pharmacokinetic studies that evaluate linearity of absorption and dose proportionality using the route and frequency of dosing projected for human clinical studies. 

Absolute Bioavailability, Pharmacokinetics, and Dose Proportionality in Nonhuman Primates... 

Purpose To evaluate the absolute bioavailability and pharmacokinetics, including dose proportionality, of a small organic molecule drug candidate in a nonhuman primate. 

Is there dose proportionality such that if the dose of the drug is doubled, the blood levels also will double ... 

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