042: Characterizing the Effect of Recombinant Human Hyaluronidase on Subcutaneous Pharmacokinetics of Drugs

Statement of Purpose: Subcutaneous (SC) delivery provides multiple benefits over intravenous (IV) dosing but also presents challenges in terms of concentrations and volume that can be safely administered. To overcome these challenges, recombinant human hyaluronidase (rHuPH20) has been increasingly used, especially for monoclonal antibodies (mAbs), allowing the administration of larger volume. The effects of rHuPH20 on SC clinical pharmacokinetics (PK) has not been evaluated systematically. In this study, we aim to evaluate the impact of rHuPH20 by reviewing published data. Using three mAbs as examples, we employed model-informed approaches to investigate the effects of rHuPH20 on SC delivery in humans.

Description of Methods & Materials: Publicly available data of different drugs administered with or without rHuPH20 were collected from Drugs@FDA and Clinicaltrials.gov to compare their PK characteristics, including maximum concentration (Cmax), time to reach Cmax (Tmax) and area under the curve (AUC). We modified a published mechanistic animal PK model and implemented it using clinical data in Monolix (2020R1). The developed model included the kinetics of rHuPH20, rHuPH20 effects on the turnover of hyaluronic acid (HA), as well as drug-specific SC absorption and disposition in humans. Clinical mean PK data of three mAbs from literature across different dose levels and rHuPH20 dose levels were used to evaluate the model performance. For each mAb, model parameters for drug disposition using IV PK data were first estimated. Then, we fixed those parameters and estimated the SC absorption parameters using SC PK data without rHuPH20. Finally, we determined the degradation rate of rHuPH20 (kdeg,PH20) and coefficient of HA reduction on SC absorption rate (AI) after fixing the drug-specific SC absorption and disposition parameters. The maximal effects of rHuPH20 on hyaluronic acid degradation of 80.9 day-1 and rHuPH20 dose for 50% of maximum effect of 34.5 U were fixed based on previous research.

Data & Results: Based on the data collected from eight drugs in clinical and pre-clinical studies and across different molecular weight ranges, we found an average increase of about 40% in C_max (range 10%-140%) and about 12% in AUC (range 0%-50%), with a decreased T_max of approximately 50% (30%-75%), when co-dosed with rHuPH20 compared to without rHuPH20 at the same dose levels. The modified PK model was able to describe the observed mean PK profiles of three mAbs following SC administration with or without rHuPH20 (R2 ranging from 0.84 to 0.99). For each mAb, we estimated disposition-specific parameters, first-order SC absorption rate and pre-systemic degradation rate of mAbs with good precision (relative standard error, RSE% < 18%). kdeg,PH20 and AI were estimated and found to be similar among the three mAbs evaluated.

Interpretation, Conclusion or Significance: Employing rHuPH20 for SC delivery of drugs may impact their PK profiles by slightly increasing the average C_max and AUC with a faster T_max. The mechanistic PK model describes the PK of three mAbs when co-administered with rHuPH20. Further work is needed to validate the mechanistic PK model with individual PK data from other mAbs.

Disclosures: Xinxin Yang is a summer intern with Janssen Clinical Pharmacology and Pharmacometrics when working on this project. She is now an ORISE fellow at US FDA.