The path to drug approval involves drug discovery and drug development. In drug discovery, compounds are screened for favorable biological activity against a target(s) and lead compounds are chosen to be moved forward through drug development. Drug development evaluates these candidates for toxicity and ADME properties. An important part of preclinical drug development is to define the dose and schedule for Phase I clinical trials (First In Man).
Before conducting in vivo PK and ADME studies to determine the dosing schedule, the dose has to be defined. There are typically five options for defining a dose: Maximum Tolerated Dose (MTD), Maximum Feasible Dose (MFD), limit dose (1000mg/kg), exposure saturation, and dose providing a 50-fold margin of exposure. The most common of these, the maximum tolerated dose, is defined as the highest dose of a drug that does not cause unacceptable side effects or overt toxicity in a specific period of time. These side effects can range from mild effects such as reduced weight gain, moderate effects such as weight loss up to 20% or substantial effects such as unresponsiveness. The MTD can be determined by acute toxicity studies, short duration dose escalation studies and dose ranging studies. These studies are designed with a minimum number of animals and include toxicological endpoints such as clinical observations and clinical pathology, for example blood tests for liver function. This maximum tolerated dose is then used for longer-term safety assessments. The rationale for using the MTD in long term studies is to maximize the likelihood of detecting any chronic disease effects or other hazards of a drug candidate. It is also more humane to determine the MTD before conducting any PK or ADME studies to minimize animal morbidity. Maximum tolerated dose studies are not designed to cause mortality, therefore death is not an appropriate end point.
It is not essential to demonstrate the MTD in every study, in some cases one of the other methods such as MFD, limit dose, exposure saturation or 50X margin of exposure would be more appropriate. All of these options for determining the high dose for toxicology studies are described in ICH M3(R2), Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals.
Pacific BioLabs performs preliminary toxicity studies in vivo to determine appropriate dosage, frequency and route of administration. Our toxicology team has extensive knowledge and experience to help our clients determine maximum tolerable dose (MTD) for their novel compounds for single and multiple dosing. Visit PBL’s in vivo toxicology webpage to learn more.