Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: What have we learned?

The pharmacokinetics (PK) of therapeutic antibodies is determined by target and non-target mediated mechanisms. These antibody-specific factors need to be considered during prediction of human PK based upon preclinical information. Principles of allometric scaling established for small molecules using data from multiple animal species cannot be directly applied to antibodies. Here, different methods for projecting human clearance (CL) from animal PK data for 13 therapeutic monoclonal antibodies (mAbs) exhibiting linear PK over the tested dose ranges were examined: simple allometric scaling (CL versus body weight), allometric scaling with correction factors, allometric scaling based on rule of exponent and scaling from only cynomolgus monkey PK data. A better correlation was obtained between the observed human CL and the estimated human CL based on cynomolgus monkey PK data and an allometric scaling exponent of 0.85 for CL than other scaling approaches. Human concentration-time profiles were also reasonably predicted from the cynomolgus monkey data using species-invariant time method with a fixed exponent of 0.85 for CL and 1.0 for volume of distribution. In conclusion, we expanded our previous work and others and further confirmed that PK from cynomolgus monkey alone can be successfully scaled to project human PK profiles within linear range using simplify allometry and Dedrick plots with fixed exponent

Evaluation of Fluorophotometry to Assess the Vitreal Pharmacokinetics of Protein Therapeutics

PURPOSE. In this work, we assessed the ability of fluorophotometry to measure the vitreal pharmacokinetics (PK) of fluorescently-labeled ranibizumab in the rabbit after intravitreal injection. We compared these values to those obtained using enzyme-linked immunosorbent assays (ELISA). Data obtained in this study were also compared to historical ranibizumab ocular PK data, either measured in-house or previously published. METHODS. Three individual in vivo studies were performed in New Zealand White rabbits to assess the feasibility of using fluorophotometry to measure rabbit ocular PK of ranibizumab; explore the dynamic range of dosing fluorescently-labeled ranibizumab; and directly compare ranibizumab concentrations and calculated PK parameters measured by vitreal fluorophotometry to those measured using ELISA. RESULTS. In direct comparisons between fluorophotometry and ELISA, the calculated clearance (CL) values were 0.26 and 0.21 mL/day, the volumes of distribution at steady state (V ss ) were 0.80 and 0.94 mL, the half-lives (t 1/2 ) were 3.1 and 2.9 days and the dose normalized areas under the curve (AUC/D) were 4.7 and 3.9 lgÁday/mL/lg, respectively. These values fell within the ranges of 0.13 to 0.44 mL/day for CL, 0.5 to 1.8 mL for V ss , 2.8 to 3.5 days for t 1/2 , and 2.3 to 7.9 lgÁday/mL/lg for AUC/D that have been either measured previously in-house or published elsewhere. CONCLUSIONS. Although not suitable for measuring retinal concentrations, fluorophotometry is a valuable, noninvasive method to measure vitreous concentrations of protein therapeutics after intravitreal injection. Keywords: fluorophotometry, vitreous pharmacokinetics, protein therapeutics, ranibizumab, 3Rs (replacement, reduction, refinement) O riginally developed as a clinical instrument to determine blood-retinal barrier permeability, early cataract formation, tear flow rates, and aqueous humor turnover, Ocular fluorophotometry allows continuous measurement of fluorescence along the central axis of the eye. The dynamic range and lower limits of quantitation of fluorophotometry are similar to other techniques such as mass spectrometry (MS) and ELISA. However, these methods often require invasive and/or terminal sampling. Those options result in the use of a large number of animals and the inability to measure drug concentrations longitudinally in the same animal. Ocular fluorophotometry may offer a noninvasive alternative to measure ocular concentrations and the PK of protein therapeutics and sustained delivery technologies. Several groups have successfully used fluorophotometry to measure the ocular PK of nonprotein molecules and to investigate different methods of ocular drug delivery

Comparative Physiology of Mice and Rats: Radiometric Measurement of Vascular Parameters in Rodent Tissues

A solid understanding of physiology is beneficial in optimizing drug delivery and in the development of clinically predictive models of drug disposition kinetics. Although an abundance of data exists in the literature, it is often confounded by the use of various experimental methods and a lack of consensus in values from different sources. To help address this deficiency, we sought to directly compare three important vascular parameters at the tissue level using the same experimental approach in both mice and rats. Interstitial volume, vascular volume, and blood flow were radiometrically measured in selected harvested tissues of both species by extracellular marker infusion, red blood cell labeling, and rubidium chloride bolus distribution, respectively. The latter two parameters were further compared by whole-body autoradiographic imaging. An overall good interspecies agreement was observed for interstitial volume and blood flow on a weight-normalized basis in most tissues. In contrast, the measured vascular volumes of most rat tissues were higher than for mouse. Mice and rats, the two most commonly utilized rodent species in translational drug development, should not be considered as interchangeable in terms of vascular volume per gram of tissue. This will be particularly critical in biodistribution studies of drugs, as the amount of drug in the residual blood of tissues is often not negligible, especially for biologic drugs (e.g., antibodies) having long circulation half-lives. Physiologically based models of drug pharmacokinetics and/or pharmacodynamics also rely on accurate knowledge of biological parameters in tissues. For tissue parameters with poor interspecies agreement, the significance and possible drivers are discussed