Table 2.

Methods for estimating a starting dose in FIH clinical trials

Method	Advantages	Disadvantages
MRSD approach (dose‐by‐factor)	Good safety record, easy to calculate	Empirical approach based only on dose, arbitrary safety factor applied, neglects pharmacological activity, and dose escalation
Similar MOA	Easy to use; minimal data required	Only applicable to a limited number of drugs, does not account for differences in PK or PD between the two drugs
MABEL	Based on pharmacology rather than an empirical scaling factor; safest approach for high‐risk drug candidates with a high degree of species‐specificity or targeting the immune system	Requires more extensive nonclinical data; unclear which nonclinical model/data is most predictive
PK model	Accounts for species differences in PK parameters rather than empirical scaling of dose; ability to calculate safety margins; demonstrated to work well for compounds that are eliminated renally and monoclonal antibodies with linear elimination	Neglects species differences in pharmacology (assume concentration‐effect relationship is the same for animals and humans); dependent on accuracy of nonclinical PK and scaling approach
PKPD model	One step further than the PK‐guided approach in that it accounts for species differences in both PK and PD; accounts for pharmacologic activity and can support dose escalation	Requires an experienced modeler and extensive nonclinical data

FIH, first‐in‐human; MABEL, minimum anticipated biologic effect level; MOA, mechanism of action; MRSD, maximum recommended safe starting dose; PD, pharmacodynamic; PK, pharmacokinetic.