Optimized affinity reagent compositions for binding paclitaxel, such as antibodies, antibody fragments, and antibody derivatives, related methods of use, and related kits, are provided herein. Affinity reagents that comprise one or more complementary determining regions (CDRs) optimized from anti-paclitaxel antibodies antibody 8A10 and 3C6 are specifically provided. The disclosed affinity reagents are useful for binding and detecting paclitaxel in a sample, such as for determining or optimizing future doses of paclitaxel in a subject that was previously administered with paclitaxel.