Dose optimization and body size

Therapeutic biologics and anticancer small molecules are often administered based on body size. A previous study has found that fixed dosing performs similarly to body size-based dosing in reducing intersubject variability in drug exposure across the monoclonal antibodies (mAbs) studied. A few studies have questioned body surface area (BSA) based dosing for anticancer drugs. This dissertation extends the evaluation from mAbs to other therapeutic proteins and peptides. This dissertation also for the first time evaluates fixed dosing and BSA-based dosing using population pharmacokinetic simulation. Eighteen therapeutic proteins and peptides as well as 28 anticancer drugs with published population pharmacokinetic (PK) models were selected for dosing approach evaluation. The relationships between body size and drug exposure were evaluated, and simulation studies were conducted to compare the performance of the 2 dosing approaches. The results showed that fixed dosing performed better for more selected biologics and anticancer drugs than body size-based dosing in terms of reducing intersubject variability in exposure at both population and individual levels. This result is consistent with the findings for mAbs, and previously published review for anticancer drugs. Therefore, fixed dosing is recommended for first-in-human studies of proteins and peptides and small oncology drugs. The final dosing approach for Phase III studies should be determined based on a full assessment of body size effect on PK/PD when data are available and the therapeutic window of the drug. The pediatric dosing for protein and peptides was also discussed in this dissertation and selected proteins and peptides were reviewed for their body size-based dosing. Pediatric dosing is more complicated than adult dosing. For most of the evaluated proteins and peptides, body size-based dosing was appropriate. However, for certain biologics, a simplification can be made, such as one fixed dose for a range of body weight/age and another fixed dose for a different range of body weight/age.