Population pharmacokinetic - pharmacodynamic analysis of dopamine D2 receptor occupancy following doses of TV 46000, an extended release suspension of risperidone for treatment of schizophrenia
Itay Perlstein (1), Avia Merenlender Wagner (2), Anthe Zandvliet (3), Farina Hellmann (3), Eline van Maanen (3), Nele Plock (3), Floris Fauchet (3), Yu-Wei Lin (3), Anna Elgart (2) and Rajendra Singh (4)
(1) Magic Wand Research LLC, Philadelphia, PA USA; (2) Teva Pharmaceutical Industries Ltd Netanya, Israel; (3) Certara, Princeton, NJ, USA; (4) Teva Branded Pharmaceuticals West Chester, PA, USA
Background: TV‑46000 is a long-acting subcutaneous risperidone injection with flexible dosing either once monthly (q1m) or once every two months (q2m) in development for the treatment of schizophrenia. Population pharmacokinetic (PopPK) modeling was used to characterize the pharmacokinetics (PK) of the parent drug, risperidone and the active metabolite, 9-OH risperidone, and to describe the time course of total active moiety (risperidone + 9-OH risperidone, TAM) exposure in comparison to oral risperidone dose regimens. Dopamine D2‐receptor occupancy (D2RO) level is recognized as one of the drivers of clinical efficacy and safety response to antipsychotic drugs. Optimal D2RO will range between high enough levels to maintain efficacy and below levels that lead to an increased risk of side effects. The relationship between TAM concentrations and striatal D2RO was previously described by an Emax model [1], where Emax represents the maximal receptor occupancy that can be achieved. Pharmacokinetic/pharmacodynamic modeling (PK/PD) was applied to predict D2RO levels from observed (oral risperidone) and predicted (TV‑46000) TAM concentrations.
Methods:
The PopPK model included data from both the phase 1 and phase 3 studies. The PK of risperidone was described by a 1-compartment model, with a complex, double first-order absorption route (1 fast and 1 slow, the later having transit compartments) and first-order elimination. The PK of 9-OH risperidone was described by a 1-compartment model with first-order input from the risperidone compartment and first-order elimination. The PopPK model predicted TAM concentrations in the PK/PD simulations to determine TV-46000 dose levels and intervals that will maintain estimated median D2RO levels within clinically acceptable range over the dosing interval. [2,3]
Results: Simulations of TAM concentrations following TV-46000 administration identified that dose strengths for either q1m (50, 75, 100, or 125 mg) or q2m (100, 150, 200, or 250 mg) provide adequate exposure over 28 and 56 days (respectively) with comparable exposure to daily doses of oral risperidone exposure 2-5mg. The previously described relationship between TAM concentrations and D2RO was used to estimate the D2RO profile (a simple Emax model with Emax 100% and kd of 10.1 ng/mL).1 The majority of the simulated D2RO profiles for the q1m and q2m dose regimens were within the preferable range of 40% to 80%. For the highest doses (125 mg q1m and 250 mg q2m), the estimated median D2RO exceeded 80% for part of the dosing interval.
Conclusions: The sequential parent metabolite model adequately described the PK of risperidone and 9-OH risperidone. Estimated TAM exposure following TV-46000 q1m and q2m dosing regimens was sustained over time and comparable to established oral risperidone regimens. For both the q1m and q2m dose regimens, the majority of the estimated median profile throughout the dosing interval was within the recommended range of D2RO. However, it is generally understood that high doses of oral risperidone (or equivalent doses of TV‑46000) would be therapeutic in some patients, but not well tolerated in others. TV-46000 treatment at doses ranging from 50 to 125 mg q1m or 100 to 250 mg q2m was found to be generally safe and to have a comparable safety profile to oral risperidone and other risperidone formulations. These results supported the selection of TV-46000 dosing regimens that would provide therapeutic plasma and D2RO levels to treat patients with schizophrenia.
References:
[1] R. Gomeni, C. Heidbreder, P.J. Fudala, A.F. Nasser. A Model‐Based Approach to Characterize the Population Pharmacokinetics and the Relationship Between the Pharmacokinetic and Safety Profiles of RBP‐7000, A New, Long‐Acting, Sustained‐Released Formulation of Risperidone. The Journal of Clinical Pharmacology. 2013; 53:1010–1019.
[2] Nordstrom AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C, Uppfeldt G. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effect: a double-blind PET study of schizophrenic patients. Biol Psychiatry. 1993;33: 227–235.
[3] Vanover KE, Davis RE, Zhou Y, Ye W, Brašić JR, Gapasin L, Saillard J, Weingart M, Litman RE, Mates S and Wong DF. Dopamine D2 receptor occupancy of lumateperone (ITI-007): a Positron Emission Tomography Study in patients with schizophrenia. Neuropsychpharmacology. 2019; 44:598–605; https://doi.org/10.1038/s41386-018-0251-1.