PK/PD model-informed dose selection for oncology phase I expansion: Case study based on PF-06939999, a PRMT5...

Area of Science:

• Oncology
• Pharmacology
• Clinical Trial Design

Background:

• Optimal dosing for targeted oncology therapeutics often differs from maximum tolerated doses.
• Pharmacokinetic/pharmacodynamic (PK/PD) modeling integrates clinical data to identify optimal therapeutic doses.
• PF-06939999 is a novel small-molecule inhibitor targeting protein arginine methyltransferase 5.

Purpose of the Study:

• To demonstrate the utility of population PK/PD modeling in selecting the recommended dose for expansion (RDE).
• To determine the optimal dose for the first-in-patient (FIP) study of PF-06939999.

Main Methods:

• Conducted a dose escalation FIP trial (NCT03854227) with 28 solid tumor patients.
• Administered PF-06939999 at various once-daily (q.d.) and twice-daily (b.i.d.) doses.
• Utilized semimechanistic population PK/PD modeling to analyze plasma drug concentrations, symmetrical dimethyl-arginine (SDMA) levels, and platelet counts.

Main Results:

• Population PK/PD models accurately described the PK, SDMA, and platelet count profiles.
• Simulations indicated that 6 mg q.d. achieved the target PD of 78% SDMA reduction while maintaining an acceptable probability of avoiding grade ≥3 thrombocytopenia.
• The RDE for PF-06939999 was determined to be 6 mg q.d.

Conclusions:

• Model-informed drug development facilitated a rational dose selection for PF-06939999.
• Population PK/PD modeling is a valuable tool for optimizing early-phase clinical trial dosing strategies in oncology.
• The selected dose balances therapeutic effect with patient safety, specifically concerning thrombocytopenia.