PMID- 24464285
OWN - NLM
STAT- MEDLINE
DCOM- 20150119
LR  - 20220408
IS  - 1179-1926 (Electronic)
IS  - 0312-5963 (Linking)
VI  - 53
IP  - 6
DP  - 2014 Jun
TI  - Population pharmacokinetics and prediction of dopamine D2 receptor occupancy 
      after multiple doses of RBP-7000, a new sustained-release formulation of 
      risperidone, in schizophrenia patients on stable oral risperidone treatment.
PG  - 533-43
LID - 10.1007/s40262-014-0132-7 [doi]
AB  - BACKGROUND AND OBJECTIVES: RBP-7000 is a long-acting formulation of risperidone 
      administered once monthly via subcutaneous (SC) injections for the treatment of 
      schizophrenia. The objectives of the present study were to characterize the 
      pharmacokinetics of RBP-7000 after multiple doses in schizophrenic patients on 
      stable oral risperidone therapy and to evaluate the switch between oral 
      risperidone and SC injections of RBP-7000. METHODS: Data were collected in a 
      phase IIa, open-label, multiple-ascending-dose study where 45 patients clinically 
      stabilized on oral risperidone (2, 3 or 4 mg/day) were switched to receive 60, 90 
      or 120 mg/month SC injections of RBP-7000, respectively. Patients were thereafter 
      switched back to oral risperidone. An integrated population pharmacokinetic model 
      describing simultaneously risperidone and 9-hydroxyrisperidone after risperidone 
      oral intake and RBP-7000 administration was developed in NON-MEM using 5,232 
      quantifiable plasma concentrations. Predictions of dopamine D2 receptor occupancy 
      were derived using a previously published model. RESULTS: A two-compartment model 
      with first-order absorption was selected for oral risperidone, while a 
      three-compartment model with first-order absorption and a transit compartment 
      absorption model was selected for RBP-7000. Body mass index was identified as a 
      significant covariate affecting the initial absorption of risperidone following 
      RBP-7000 injection. Steady state was reached after the second or third RBP-7000 
      injection but plasma concentrations close to steady-state values were obtained 
      right after the first injection when switching from oral risperidone therapy. 
      Predicted dopamine D2 receptor occupancy after repeated doses of 90 and 120 mg 
      showed less fluctuation than after oral risperidone with acceptable ranges for 
      clinical efficacy and a potentially safer profile with respect to extrapyramidal 
      side effects. CONCLUSION: This analysis provided additional insight into the 
      pharmacokinetics of RBP-7000 and for the comparison with oral risperidone 
      treatment. The established model was used to support the design of a planned 
      phase III study.
FAU - Laffont, Celine M
AU  - Laffont CM
AD  - Pharmacometrica, La Fouillade, France.
FAU - Gomeni, Roberto
AU  - Gomeni R
FAU - Zheng, Bo
AU  - Zheng B
FAU - Heidbreder, Christian
AU  - Heidbreder C
FAU - Fudala, Paul J
AU  - Fudala PJ
FAU - Nasser, Azmi F
AU  - Nasser AF
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Switzerland
TA  - Clin Pharmacokinet
JT  - Clinical pharmacokinetics
JID - 7606849
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Delayed-Action Preparations)
RN  - 0 (Isoxazoles)
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, Dopamine D2)
RN  - L6UH7ZF8HC (Risperidone)
RN  - R8P8USM8FR (Paliperidone Palmitate)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Antipsychotic Agents/administration & dosage/*pharmacokinetics
MH  - Delayed-Action Preparations
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Injections, Subcutaneous
MH  - Isoxazoles/pharmacokinetics
MH  - Male
MH  - Middle Aged
MH  - Models, Biological
MH  - Paliperidone Palmitate
MH  - Pyrimidines/pharmacokinetics
MH  - Receptors, Dopamine D2/*metabolism
MH  - Risperidone/administration & dosage/*pharmacokinetics
MH  - Schizophrenia/*drug therapy
MH  - Young Adult
EDAT- 2014/01/28 06:00
MHDA- 2015/01/20 06:00
CRDT- 2014/01/28 06:00
PHST- 2014/01/28 06:00 [entrez]
PHST- 2014/01/28 06:00 [pubmed]
PHST- 2015/01/20 06:00 [medline]
AID - 10.1007/s40262-014-0132-7 [doi]
PST - ppublish
SO  - Clin Pharmacokinet. 2014 Jun;53(6):533-43. doi: 10.1007/s40262-014-0132-7.