Personalized Management of Palbociclib and Ribociclib Using TDM, Pharmacogenetics, and Drug–Drug Interaction Assessment: A Clinical Case Series

A substantial person-to-person variability in clinical outcomes with cyclin-dependent kinase 4 and 6 inhibitors (CDKis) has been documented. Here, we describe a series of five individuals receiving palbociclib or ribociclib who were evaluated through our clinical pharmacology consultation service, which included therapeutic drug monitoring (TDM), pharmacogenetic assessment, and drug–drug interaction review to assist physicians in optimizing CDKi therapy for metastatic breast cancer. Plasma samples used for TDM were obtained at steady state and quantified via an LC-MS/MS procedure to determine minimum plasma concentrations (Cmin). Drug underexposure or overexposure was assessed in relation to mean Cmin values reported in population pharmacokinetic investigations. Genetic variants in selected ADME-related genes (CYP3A4, CYP3A5, ABCB1, SLCO1B1, and ABCG2) were examined. Three of the five patients showed CDKi levels exceeding population means and were evaluated for toxicity. One carried a reduced-function ABCB1 haplotype (ABCB1-rs1128503, rs1045642, and rs2032582), which may explain enhanced oral absorption and elevated drug concentrations. Two subjects demonstrated subtherapeutic exposure, and one of these experienced early disease progression. In another case, a CYP3A5*1/*3 genotype was identified as a possible driver of increased metabolic activity and reduced plasma drug levels. This more detailed pharmacologic strategy in a real-world setting appears to help treating oncologists refine drug and dose selection and may ultimately improve both the safety and therapeutic performance of CDKi regimens.