Butorphanol Pharmacokinetics Across Species: Meta-Analysis Integrating Allometric Scaling and Minimal Physiologically Based Pharmacokinetic Modeling

Butorphanol, an opioid agonist–antagonist used in human and veterinary medicine, lacks systematic interspecies comparisons. Butorphanol pharmacokinetics (PK) was assessed across species using a minimal physiologically based PK (mPBPK) model and allometric scaling, termed mPBPK allometric meta-analysis (MAMA). PK data from 13 species following intravenous (IV) and extravascular (EV) (intramuscular [IM], intranasal [IN], subcutaneous [SC]) doses were digitized and analyzed via MAMA. Clearance (CL) and steady-state volume of distribution (V_SS) were assessed for allometric relationships with body weight (BW). An mPBPK model including blood, three lumped tissues, and extravascular depot compartments was developed using species-specific physiological parameters. Nonlinear mixed effects modeling (NONMEM) was used for joint fittings of IV and IV + EV data. PK parameters were generally comparable across species, except for the Asian elephant. Allometric scaling revealed that CL and V_SS correlated with BW (CL: R² = 0.911, b = 0.700; V_SS: R² = 0.891, b = 0.824). The allometrically scaled mPBPK model captured the PK profiles across all 13 species. Joint fitting yielded a generalized tissue-to-plasma partition coefficient (K_p) of 4.07 (CV% 4.7), except the horse required a specific K_p of 1.14 (14.3) and a distinct fraction of cardiac output. Butorphanol exhibits consistent disposition across most species with generally BW proportional CL values, conserved K_p values, rapid absorption rates, and moderate to high bioavailability across three EV routes. The application of mPBPK modeling with allometric scaling offers a robust framework for characterizing the interspecies PK of butorphanol to assess both conservation and differences in determinants of PK.