A guide to rational dosing of monoclonal antibodies.

摘要: Dosing of therapeutic monoclonal antibodies (mAbs) is often based on body size, with the perception that size-based dosing would reduce inter-subject variability in drug exposure. However, most mAbs are target specific a relatively large window and generally small contribution size to pharmacokinetic variability. Therefore, paradigm for should be assessed context these unique characteristics. The objective this study was review current strategy provide scientific rationale using modelling simulation approach. In analysis, weight-based or weight-independent (fixed) regimens were systematically evaluated. A generic two-compartment first-order elimination model developed. Individual population profiles simulated as function weight effects clearance (θbw_cl) central volume distribution (θbw_vl). exposure (the area under serum concentration-time curve [AUC], trough concentration [Cmin] peak [Cmax]) compared between fixed entire population. deviation light heavy subjects from median also measured. results then evaluated clinical characteristics various given either by case study. Results analysis demonstrated dependent magnitude effect pharmacokinetics. contrast conventional assumption, does not always offer advantages over reducing general, when exponential functions θbw_cl θbw_vl 0.5, less than dosing. scenarios >0.5, impact different each measure. had little moderate (θbw_cl <0.5 ∼0.5). difference 20% percentages subpopulations 40%. provided insights into conditions which superior differences across introduced regimen relative observed pharmacodynamics, efficacy safety. mAb can flexible. Given many practical advantages, recommended first option first-in-human studies mAbs. later stages development could determined combined knowledge pharmacokinetics, safety early trials.