Abstract
PURPOSE: Physiologically-based pharmacokinetic (PBPK) models provide a rational mechanistic approach for predicting the time course of macromolecules in plasma. Population PBPK models for large molecules necessitate incorporation of lymphatic circulation to mechanistically account for biodistribution. Moreover, characterization of subcutaneous absorption requires consideration of the microvascular transit from the injection site to the systemic circulation. A PBPK model for a pegylated peptide conjugate, previously developed for primates, was modified to describe the lymphatic uptake in a population of humans by incorporation of interindividual variability in the lymphatic circulation and a unique lymphatic drainage compartment (LDC). The model was then used to simulate the time course of the drug in a population of humans and compared to the same drug administered to a group of human subjects participating in a first-in-human study. METHODS: Organ, blood and lymph masses for the population were sampled from either normal or log-normal distributions. Blood flows were calculated for each organ based on mean organ perfusion per gram of organ tissue and lymphatic flow was set as a fixed fraction of blood flow. Interindividual variability in lymphatic volume was assumed to be similar to that of blood volume. The volume of the LDC was parameterzed as a fraction of the injection volume. Sensitivity analysis was performed to study uncertain parameters and distribution assumptions. RESULTS: The population generator was capable of simulating a virtual population incorporating the lymphatic circulation. Incorporation of a LDC resulted in similar line shape relative to the observed data and incorporation of anthropometric variability accounted for individual differences in the absorption and elimination phases across all dose cohorts. Line shape was sensitive to the inclusion of LDC while peak and elimination portions of the time course were influenced by the magnitude of variance assumed for blood volume and renal clearance, respectively. CONCLUSION: Lymphatic circulation can be incorporated into a population PBPK model assuming similar interindividual variability as observed for blood volume. Incorporation of an LDC, where the volume of this transit compartment is proportional to the SC injection volume may be an important mechanistic means of predicting the transit from the SC depot to the systemic circulation.