Blood concentration-time profile, distribution, metabolism and excretion of radioactivity were studied after repeated intravenous administration of ¹⁴C-flecainide acetate at a dose of 5 mg/kg/day for 7 days to rats.
1. Blood concentration-time profile of radioactivity on the 7th day was similar to that on the 1st dose and blood levels of radioactivity were not affected by repeated administration. In the plasma, concentration of the unchanged flecainide was decreased rapidly after the dosing with simultaneous increase of polar metabolites with time. Little change of flecainide/radioactivity concentration ratio in plasma was observed between 1st and 7th dose.
2. Radioactivity was well distributed to many tissues with a relatively high level compared to the plasma. Total radioactivity in tissues and corresponding tissue to plasma concentration ratios after 7th repeated administration were similar to those after the single dose. These tissue levels of radioactivity decreased with time and reached low level at 168 hr and 504 hr after the final dose. In the heart, liver and kidney, the radioactivity constituted mainly of the unchanged flecainide.
3. The excretion ratio for cumulative dose of radioactivity into the urine and feces showed constant throughout the period of repeated administration. At 168 hr after final dosing, 41.5%, 55.6% and 0.2% of a cumulative dose was recovered in urine, feces and carcass, respectively. In these excreta, the unchanged flecainide, meta-O-dealkylated flecainide and meta-O-dealkylated lactam of flecainide, and conjugated metabolites were dominant.

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Blood and plasma concentration-time profile, distribution, metabolism, excretion of radioactivity after a single intravenous administration of ¹⁴C-Flecainide acetate at a dose of 2 mg/kg to dogs, and in vitro and in vivo plasma protein binding were studied.
1. Plasma levels of radioactivity reached a maximal concentration at 0.5 hr after the dose, followed by a decrease with a half-life of 1.9 hr. The AUC_(0-24hr) was 4.82μg eq.·hr/ml and the plasma level decreased to below the detection limit at 48 hr post dose. A maximal concentration of the unchanged flecainide was attained at 5 min, followed by a rapid decrease and by an increase of polar metabolites, including conjugates of meta-O-dealkylated flecainide and meta-O-dealkylated lactam of flecainide, which were found to be dominant in plasma.
2. Plasma protein binding (in vitro) of rat and dog was about 55% and 70%, respectively. The binding (in vivo) of radioactivity to dog plasma ranged from 30.7 to 47.7% during 0.5 to 4 hr after the dosing.
3. Radioactivity was distributed to many tissues and decreased to low level at 168 hr post dose, except for pigment ocular tissues in which radioactivity was distributed at a high level and was retained. In the heart, liver and kidney at 0.5 hr post dose, the unchanged flecainide, polar metabolites and meta-Odealkylated flecainide and meta-O-dealkylated lactam of flecainide were the main constituents of radioactivity and several other minor metabolites were also observed.
4. The excretion ratios of radioactivity into urine and feces were estimated to be 56.2 and 42.1% of the dose after 168 hr post dose, respectively. In urine, radioactivity was constituted mainly of polar metabolites which included conjugate metabolites of meta-O-dealkylated flecainide and meta-O-dealkylated lactam of flecainide.

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Outlines of two guidelines related to pharmacokinetics of guidelines recently adopted in ICH, general guideline (E8) and timing guideline (W), were explained. Both guidelines show that exposure data in animals should be evaluated prior to human clinical trials, and that further information on absorption, distribution, metabolism and excretion in animals should be made available by the time the human pharmacology studies have been completed. This means that pharmacokinetics and ADME data in animals are important at the evaluation of human safety and metabolic pathways.
Two cases in which the Organization for Pharmaceutical Safety and Research (OPSR) advised the sponsor in the clinical trial consultation to take measures to ensure the safety of human subjects because of the discrepancy of pharmacokinetics data between animals and human beings were presented.
It is shown that pharmacokinetics and ADME data are important to evaluate the connections between animals and human beings, healthy adults and patients, adult patients and specified sub-populations such as the elder patients, kidney and liver dysfunction patients. It is expected from now on to develop the pharmacokinetics parameters closely related to the pharmacological effect and their convenient assays.

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Pharmacokinetics (PK) and pharmacodynamics (PD) have become popular approaches for new drug evaluation. Especially, greater deal of attention has been given to the population PK/PD analysis to describe relationships for dose vs. concentration vs. response in a target patient population, and to clarify factors that can affect PK/PD of the drug (genetic, physiological, pathological, or environmental factors). Definition of PK, PD and dose-response in standard patients as well as in special populations such as geriatrics and organ dysfunction, can suggest the clinical need for individualization of dose.
In addition, simultaneous development of new drugs among the U.S., Europe and Japan becomes more and more important to save time, cost and the number of patients. Ethnic difference is one of difficult issues for international harmonization in drug development. A useful concept, “bridging study” is proposed, which is defined as a supplemental study to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extrapolation of the foreign clinical data package to the new region. The docetaxel study is a good example as a methodology to evaluate inter-ethnic differences as well as a bridging study to conduct internationally harmonized drug development. What we learned from this case is that the population PK/PD approach can play an important role as a “bridging study” for global drug development.
In conclusions, useful pharmacokinetic/pharmacodynamic information can be obtained during the premarketing clinical trials. Drug concentration monitoring in patients is essential and the population method is highly useful to analyze the sparsely sampled data. Furthermore, pharmacokinetic and pharmacodynamic approach coupled with population concepts can be an important strategy for the global drug development.

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To discuss ADME studies needed prior to the first clinical trials, it is important to understand the regional differences in the objectives and types of Phase I trials. Screening Phase I trials are clinical trials conducted to select a candidate drug from several similar candidates for further development. Historically, this type of clinical trials has been approved in the US on a case by case basis. In 1996, FDA officially allowed screening Phase I trials based on single dose toxicity studies with expanded toxicological examinations by publishing a paper and by revising the guidance for single dose toxicity studies. In Europe, the screening-purpose Phase I trials can be conducted, but they are called as “investigational clinical trials” and are supported by at least 2-week repeated dose toxicity studies. In Japan the concept of screening drugs in clinical trials has not been socially accepted. The reasons why only the US allowed screening Phase I trials based on the expanded single dose toxicity studies and why this policy has been temporally withheld are discussed. In Japan, the number of ADME studies usually conducted prior to Phase I trials has tended to be more than that in other regions. The recent survey showed that the number has even increased in the past a few years, because studies on such as toxicokinetics, in vitro metabolism, species differences in metabolism and activity of CYP450 are added to the list.

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