Pharmacokinetic phase, defined

Define the terms pharmacokinetic phase and pharmacodynamic phase in the context of drug action. List the main general factors that affect these phases. 

Human pharmacology (Phase I) Assess tolerance Define/describe pharmacokinetics and pharmacodynamics Explore drug metabolism and drug interactions Estimate activity Dose-tolerance studies Single and multiple dose PK and/or PD studies Drug interaction studies... 

Animal data serve as the springboard to estimating a safe and effective range of doses for human therapeutic purposes. Initial doses in phase 1 studies are based on preclinical pharmacokinetic and safety data. First estimates of safe and effective drug concentrations in plasma in human studies are also based on animal data. The Clinical Studies section in the product label includes information derived from tolerance studies of the drug (phase I), pivotal human data demonstrating efficacy at a defined dose or dose range, and a description of untoward effects observed in... 

The clinical development stage comprises three distinct components or phases (I, II, and III), and culminates in the filing of the NDA/MAA. Each phase involves process scale-up, pharmacokinetics, drug delivery, and drug safety activities. During phase I clinical development, the compound s safety and pharmacokinetic profile is defined. The determination of maximum concentration at steady state (Cmax), area under the plasma concentration time curve (AUC), elimination half-life, volume of distribution, clearance and excretion, and potential for drug accumulation is made in addition to studies that provide estimates of efficacious doses. Dose levels typically... 

After acceptable safety and pharmacokinetic data are observed in phase I trials, phase II studies are initiated with the goal of establishing efficacy, determining the effective dose range, and obtaining safety and tolerability data. In phase II, the dose and dosing interval to be employed in the patient population and the estimated noeffect dose are defined. Phase II studies may require 1-1.5 years to complete and may involve several hundred patients. 

The Phase I study was designed as a randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the pharmacokinetics and pharmacodynamics of the new ERA. Cohorts of nine subjects with baseline hemoglobin levels less than 14.5 g/dl were randomized to receive ERA treatment (N= 6) or matched placebo (N= 3) at each dose level. The various dose levels considered in this study were lx, 3x, lOx, 30x, lOOx, and 300x. The objective of the study was to identify the pharmacological effective dose (PED), defined as the dose level where four or more treated subjects achieved more than 1 g/dl increase from baseline in hemoglobin within 28 days. 

Figure 10.1 Schematic of the basic processes involved in pharmacokinetic (PK) - dynamic (PD) models. The phases I, II, and III refer to processes that take place in the prereceptor, receptor, and postreceptor proximity, respectively. The symbols are defined in the text.

Pharmacokinetics When EE was administered in combination with Drag XYZ, arithmetic mean 11/2 and Tmax values were comparable for both treatments. Geometric mean Cmax and AUCo-24values were approximately 20 % to 30 % lower, respectively, than when EE was administered with placebo. For AUCq-24, the lower and upper limit of the 90 % Cl were below the pre-defined 90% Cl of 0.8-1.25. Therefore, a pharmacokinetic interaction between Drug XYZ and EE can be concluded. The mechanism for this statistically significant reduction in systemic exposure to EE is unknown, however, since Drag XYZ is known to induce CYP 1A2 in man, and CYP 1A and phase II enzymes in animals, the observed effect could reflect a metabolic interaction between Drag XYZ and EE. 

Pharmacokinetic/pharmacodynamic modeling plays an important role during the NDA submission and review phase by integrating information from the pre-clinical and development phases. Existence of a well-defined PK/PD model furthermore enables the reviewer to perform PK/PD simulations for various scenarios. This ability helps the reviewer gain a deeper understanding of the compound and provides a quantitative basis for dose selection. Thus, PK/PD modeling can facilitate the NDA review process and help resolve regulatory issues. ... 

FARAD estimates of withholding intervals may rely on pharmacokinetic data to help define the final terminal elimination phase of a drug. In these cases, it is assumed that the final edible tissue elimination phase will be at least as long as that observed in blood. Although specific safety factors are not built into these estimates, the estimated withholding times are expanded to help ensure that residues drop well below the established tolerance by the end of the recommended period. ... 

Even though the absorption rate constant (kf) defines the rate of absorption, its accurate determination is largely dependent on the adequacy of the plasma concentration-time data associated with the absorption phase of the drug. When a drug is administered orally, as a conventional (immediate-release) dosage form, or injected intramuscularly as an aqueous parenteral solution, the absorption and disposition kinetics can often be analysed in terms of a one-compartment pharmacokinetic model with apparent first-order absorption. The plasma concentration-time curve is described by the equation... 

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