J. P. Jones, P. J. Fudala, C. Heidbreder, A. F. Nasser; Reckitt Benckiser Pharmaceuticals, Inc., Richmond, VA
BACKGROUND: RBP-7000 is a 28-day SC injection of Ris using the ATRIGEL® Delivery System developed for the treatment of schizophrenia. Dose dumping (DD) is a phenomenon in which environmental factors (e.g., heat, temperature, and exercise) can cause the premature and exaggerated release of drug. The present simulations investigated the possible consequences of dose dumping from RBP-7000 using a model-based approach.
METHODS: A population pharmacokinetic model describing Ris and 9-OH Ris (active metabolite) was developed in 45 schizophrenic patients who received single doses of RBP-7000 (60, 90, or 120 mg). A dual absorption process was used to describe the initial rapid delivery from the SC injection site (Ka1) and a slow, sustained delivery of Ris from the ATRIGEL (Ka2). The model simulated 500 hypothetical subjects following single or multiple dose (60, 90, or 120 mg) administration with the following scenarios at each dose level: Ka2= 0 (worst case), Ka2=25 or 50% of the reference value (Ka2=0.238). The model assumes Ka2 as primary parameter affected by malfunctioning ATRIGEL with no effect on Ka1. The predicted active moiety (Ris+9-OH) concentrations were simulated to evaluate the effect on dopamine D2 receptor occupancy (D2RO) using an established Emax model.
RESULTS: At 120 mg dose with the worst DD scenario, the change from reference in Cmax values after a single dose or multiple doses were between 8.4% and 12%, respectively. Overall, the change in mean Cav and D2RO values were negligible.
CONCLUSION: The differences in active moiety concentrations and D2RO due to possible DD effects were small and not deemed to be clinically relevant. The potential effect of DD on the pharmacokinetic and consequently safety of RBP-7000 will be evaluated in phase III studies.