Out Of The Pipeline

Risperidone extended-release injectable suspension

Author and Disclosure Information



How the Atrigel system works. The Atrigel system was developed in the late 1980s and consists of a solution of a resorbable polymer in a biocompatible carrier.11 After in vivo administration (typically via subcutaneous injection), the polymer undergoes a phase change from a liquid to a formed implant (Figure 1). Being in liquid form, this system provides the advantage of placement by simple means, such as injection by syringes. The absorption rates of various polymers and the release rates for various drugs are tailored to the desired indication. Approved uses for Atrigel include the subgingival delivery of the antibiotic doxycycline for chronic adult periodontitis (approved September 1998), and the monthly subcutaneous injectable form of the anti-androgen leuprolide, which was approved in January 2002.8,12 Release periods up to 4 months have been achieved with Atrigel; 1 month is the most often desired release period. The biodegradable polymer used for RBP-7000 is designed to provide effective plasma drug levels during the first week of treatment, and sustained levels with a 1-month dosing interval. The small subcutaneous implant that is formed is gradually resorbed over the course of 1 month.

Pharmacokinetics. As with all LAI medications, the half-life with repeated dosing vastly exceeds that achieved with oral administration. Following oral administration, mean peak plasma levels of risperidone occur at 1 hour, and those for the active metabolite 9-OH risperidone occur at 3 hours.13 Oral risperidone has a mean half-life of 3 hours, while the active metabolite 9-OH risperidone has a mean half-life of 21 hours.14 Due to its longer half-life, the metabolite comprises 83% of the active drug levels at steady state.14 Although risperidone is susceptible to interactions via cytochrome P450 (CYP) inhibitors and inducers, particularly CYP2D6 (Table 210), the pharmacokinetics of the combined total of risperidone and 9-OH risperidone levels (deemed the active moiety) are similar in CYP2D6 extensive and poor metabolizers, with an overall mean elimination half-life of approximately 20 hours.13

The kinetics for RBP-7000 are markedly different than those for oral risperidone (Figure 215). After a single subcutaneous injection, RBP-7000 shows 2 absorption peaks for risperidone. The first lower peak occurs with a Tmax of 4 to 6 hours due to initial release of risperidone during the implant formation process; a second risperidone peak occurs after 10 to 14 days and is associated with slow release from the subcutaneous depot.9,16,17 For both 9-OH risperidone levels and the total active moiety (risperidone plus 9-OH risperidone levels), the median Tmax of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days. Following a single subcutaneous injection of RBP-7000, the apparent terminal half-life of risperidone ranges from 9 to 11 days, on average. The mean apparent terminal half-life of the active moiety ranges from 8 to 9 days.9,16,17 Based on population pharmacokinetic modeling, the 90 mg and 120 mg doses of RBP-7000 are estimated to provide drug exposure equivalent to 3 mg/d and 4 mg/d of oral risperidone, respectively.9,16,17

Continue to: Efficacy of RBP-7000

Next Article: