2. Single Dose/Multiple Dose Escalation Studies (SAD and MAD)

Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) studies are typically the First-in-Human study (or studies). These are performed as randomised, placebo-controlled trials in healthy volunteers (though, as described above, sometimes in patients). The starting dose is determined by non-clinical toxicology studies and is based on algorithms found in regulatory guidance documents. Common escalation schemes include: 2x, 3.3x (half-long, and modified Fibonacci series). Some stopping rules are: toxicity, absent toxicity (maximised exposure, maximised pharmacodynamics, others).

The information gained from SAD/MAD studies is:

  • Safety/tolerability, identify Maximum Tolerated Dose (MTD)

  • General PK characteristics, variability, linearity, dose proportionality

  • Steady-state parameters (accumulation time-dependency)

  • Preliminary exploration of medicine elimination (metabolite(s) identification)