Why Conduct SAD And MAD PK Studies In High ROI Clinical Trials?

SAD or single ascending dose and MAD or multiple ascending dose are typically the first ones being tried and tested in human populations. The main aim of this testing is to gain sufficient information pertaining to the safety and tolerability involving general pharmacokinetic and pharmacodynamic parameters. It also involves further identification and assessment of the maximum tolerated dose (MTD). 

Single Ascending Dose Studies vs Multiple Ascending Dose Studies – 

The key difference between the two is defined in their respective names itself – single ascending dose studies pertains to a single shot of dose while multiple ascending dose studies pertains to multiple doses. Subjects undergoing sad and mad pk studies are subjected to receive multiple doses of the drug candidate under analysis whereas in the SAD or the Single Ascending Dose study, subject receives only a single dose of the drug candidate. SAD and MAD both are accomplished in the early stages of the clinical assessment.

The Single Ascending Dose studies are routinely accomplished first in the preferential order for obtaining a rough understanding of the pharmacokinetic evaluation of the single dose of the potent drug candidate. The pattern of repetitive dosing schedule in the MAD study permits until the steady state is attained which is reached when the drug absorption rate equals to its rate of elimination. As soon as this occurs, drug concentration in the body reaches it stage of equilibrium. 

FDA Guidance – 

Since most of the novel drugs are intended to be administered on a multiple interval, the Multiple Ascending Dose has been necessitated for understanding how the drug can be subjected to use under a clinical setting. Yet, the FDA also puts forth its view of performing the Multiple Ascending Dose study in the following circumstances – 

Whenever there is a difference observed in the absorption rate and the elimination rate of a drug candidate. 

Whenever there is an excessive variability in the drug bioavailability which is most common phenomenon as each individual’s body reacts differently to different molecules 

In the event of low plasma concentration of the drug 

In the event of a drug being administered in its extended-release form 

Designing a MAD study – 

An appropriate Multiple Ascending Dose study is designed in accordance with the needs and resources of every drug discovery and development program. In some cases, the Multiple Ascending Dose study designs are or can be integrated with other drug study designs such as Thorough QT study for providing the necessary information.

In such cases, there is absolutely no need of accomplishing separate studies. The number of subsequent dosing schedules in MAD or Multiple Ascending Dose regimen varies widely; however, is maintained typical between 3 to 6. Approximately, the study starts with the enrolment of 40 subjects. In very rare cases, the study subjects may be diseased; otherwise, only healthy subjects are recruited for conducting trials under MAD study. Nevertheless, such studies require careful planning of the subsequent dosing regimen for attaining steady state levels of the drug candidate under analysis. 

A MAD/SAD trial can further be followed by adopting an adaptive dose-finding trial for identification and subsequently establishing solid evidence of the targeted dose with defined dose response levels. 

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