Pharmacokinetics dose-proportionality

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]. 

Ezzet F, Spiegelhalter D (1993) Pharmacokinetic dose proportionality practical issues on design, sample size and analysis. In 2nd International Meeting on Statistical Methods in Biopharmacy. Societe Francaise de Statistique, Paris. 

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... 

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. 

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. 

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... 

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. 

Khoo KC, Szuna AJ, Colburn WA, Aogaichi K, Morganroth J, Brazzell RK. Single-dose pharmacokinetics and dose proportionality of oral cibenzoline. J Clin Pharmacol 1984 24(7) 283-8. 

Gupta S, Banfield C, Affrime M, Marco A, Cayen M, Herron J, Padhi D. Desloratadine demonstrates dose proportionality in healthy adults after single doses. Clin Pharmacokinet 2002 41(Suppl l) l-6. 

D. J. Nichols, G. J. Muirhead, and J. A. Harness, Pharmacokinetics of sildenafil after single oral doses in healthy male subjects absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol 53(Suppl 1) 5S-12S (2002). 

The designs performed similarly in characterizing dose proportionality (Figure 29.6). This was not unexpected since dose proportionality was assumed in the simulation. The model parameters were estimated to a similar degree of precision by each of the designs. This further supported the confirmation of dose proportionality (Table 29.1). The linearity of the pharmacokinetics can be observed from the nature of the disposition phase of the concentration-time profiles shown in Figure 29.7. The code for simulating the PK profile is in Appendix 29.2 and 29.3. 

Phase 1 FTIH studies provide an excellent opportunity for learning about an NME s safety, tolerability, and pharmacokinetics (including dose proportionality) in humans. It is important to choose a study design that will enable the primary and secondary objectives of the FTIH study to be met. This would make it possible for the knowledge needed for mission-critical decision making to be extracted from the data collected from such a study. 

K. Gough, M. Hutchinson, O. Keene, B. Byrom, S. Ellis, L. Lacey, and J. McKellar, Assessment of dose proportionality Report from Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Joint Working Party. Drug Inf J 29 1039-1048 (1995). 

Table 5.1 Pharmacokinetic parameters and their relationship to dose assuming dose proportionality.

Once the study is completed and the plasma or serum samples are analyzed for drug concentrations and AUC and Cmax are determined for each subject. AUC and Cmax are treated as the dependent variables (Y) in the analysis. At this point, there are a number of ways to assess for dose proportionality. The Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Joint Working Party (SPI/PUK JWP) have reviewed the statistical methods used to assess dose proportionality and have published a summary of their findings (Gough et ah, 1995). These methods will now be summarized. In the untransformed regression approach, the simple linear model is fit to the data... 

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