Butorphanol Pharmacokinetics Across Species: Meta-Analysis Integrating Allometric Scaling and Minimal Physiologically...

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.