Clearance of hylan fluid and hylan gel, components of the hyaluronan (HA)-derived viscosupplement hylan G-F 20, following intra-articular injection into normal, healthy rabbits was evaluated. Radiolabeled hylan G-F 20 was injected at a volume of 0.3 mL into both knee joints of 12 rabbits. At sacrifice, synovial fluid, joint tissues, blood, popliteal lymph nodes, liver, spleen, kidney, and lung were analyzed for radioactivity. The half-life of the fluid component, a high-molecular weight hylan, was 1.5 ± 0.2 days while the half-life of the hylan gel component, a crosslinked hylan, was 8.8 ± 0.9 days. There was no radioactivity detected in the blood or the major internal organs following intra-articular injection. A rat model was used to evaluate the clearance of a large intravenous bolus of solubilized hylan gel. No accumulation of hylan gel degradation products was observed in any major organs and the half-life of hylan elimination from the blood was within normal ranges for HA elimination. The dosing used in the nonclinical rabbit intra-articular study was equivalent (v/w) to a single 6 mL dose in humans. These results are consistent with the current clinical data that demonstrates safety and effectiveness of an increased volume of hylan G-F 20 injected into the osteoarthritis knee.

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22 Background: The objective of this study is to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran (a small molecule thrombin inhibitor) and its antidote (a humanized Fab against dabigatran) in the monkey and to develop a combined mechanistic mathematical model to describe the data. Methods: There were three groups: control, antidote alone and dabigatran etexilate (DE) + antidote. Rhesus monkeys (n = 2/group) received either 12 mg/kg/day of DE or vehicle orally on Days 1–4, 15–18 and 29–32 with a single IV dose of the antidote administered 90 minutes after DE on Days 4, 18 and 32. Doses of the antidote were 30, 90 or 175 mg/kg, respectively. PK parameters of the antidote and sum dabigatran (dabigatran plus its glucuronides) were determined after measurements of plasma concentrations. Coagulation activity was measured using a diluted thrombin time assay to determine the activity of the unbound sum dabigatran. Results: The PK of the antidote were not affected by dabigatran. Clearance of the antidote was low (0.87 mL/min/kg) and steady-state volume of distribution was small (0.06 L/kg), indicating that the antidote was mostly restricted to plasma. The plasma profile of the antidote was bi-phasic with a short initial phase t1/2 of 0.4 hour (h) and a terminal phase t1/2 of 4.3 h. Immediately after antidote dosing, plasma concentrations of sum dabigatran increased, a consequence of the rapid redistribution of dabigatran and its glucuronides from tissue to plasma due to binding to the antidote. Complete reversal of dabigatran's anticoagulant activity was observed immediately after antidote dosing at all three dose levels, as measured by the diluted thrombin time assay, which indicates that all dabigatran was bound to the antidote. The degree to which this reversal effect was maintained over an extended period (24 h) was dose-dependent. A mechanistic ordinary differential equation model, based on the mass action kinetics for describing the distribution, binding and elimination of dabigatran and its antidote, was developed by combining the PK models for dabigatran and the antidote and adding the binding interaction (1:1 stoichiometry) between the two compounds. The distribution and elimination parameters of the dabigatran-antidote complex were assumed to be the same as those of the antidote, based on similar measured PK parameters of the antidote with and without dabigatran in the monkey. The combined PK/PD model of dabigatran and antidote was able to describe the in vivo PK/PD data observed in monkeys. Conclusion: The dabigatran-specific antidote successfully reversed the anticoagulant activity of dabigatran in the monkey in a dose-dependent manner, and our combined mathematical model accurately describes monkey PK/PD data of sum dabigatran and its antidote. Insights gained from this model will be used to guide model development for clinical trials. Disclosures: Toth: Boehringer Ingelheim: Employment. Gan:Boehringer Ingelheim: Employment. van Ryn:Boehringer Ingelheim: Employment. Dursema:Boehringer Ingelheim: Employment. Isler:Boehringer Ingelheim: Employment. Coble:Boehringer Ingelheim: Employment. Burke:Boehringer Ingelheim: Employment. Lalovic:Boehringer Ingelheim: Employment. Olson:Boehringer Ingelheim: Employment.

The objective of this study is to determine pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran and its antidote (a humanized Fab against dabigatran) in the monkey and to develop a combined mechanistic mathematical model to describe the data. Rhesus monkeys (n = 2/group) received either 12 mg/kg/day of dabigatran etexilate (DE) or vehicle orally on Days 1-4, 15-18 and 29-32 with a single IV dose of the antidote at 30, 90 and 175 mg/kg administered 90 minutes after DE on Days 4, 18 and 32. PK parameters of the antidote and sum dabigatran (dabigatran plus its glucuronides) were determined after measurements of plasma concentrations. Coagulation activity was measured using a diluted thrombin time assay. The PK of the antidote were not affected by dabigatran. Clearance of the antidote was low (0.87 mL/min/kg) and steady-state volume of distribution was small (0.06 L/kg), indicating that the antidote was mostly restricted to plasma. The plasma profile of the antidote was bi-phasic with a short initial phase t 1/2 of 0.4 hour (h) and a terminal phase t 1/2 of 4.3 h. Complete reversal of dabigatran’s anticoagulant activity was observed immediately after antidote dosing at all 3 dose levels as measured by the diluted thrombin time assay, and the degree to which this reversal effect was maintained over an extended period (24 h) was dose-dependent. A mechanistic ordinary differential equation model, based on the mass action kinetics for describing the distribution, binding and elimination of dabigatran and its antidote, was developed by combining the PK models for dabigatran and the antidote and adding the binding interaction (1:1 stoichiometry) between the two compounds. The combined PK/PD model of dabigatran and antidote was able to describe the in vivo PK/PD data observed in monkeys. In conclusion, the antidote successfully reversed the anticoagulant activity of dabigatran in the monkey in a dose-dependent manner, and our combined mathematical model accurately describes monkey PK/PD data of sum dabigatran and its antidote. Insights gained from this model will be used to guide model development for clinical trials.