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Clinical Trial
. 2018 Oct;43(5):573-585.
doi: 10.1007/s13318-018-0472-z.

A Population Pharmacokinetic and Pharmacodynamic Analysis of RP5063 Phase 2 Study Data in Patients with Schizophrenia or Schizoaffective Disorder

Marc Cantillon  1 , Robert Ings  1 , Arul Prakash  1 , Laxminarayan Bhat  2
Affiliations
Clinical Trial

A Population Pharmacokinetic and Pharmacodynamic Analysis of RP5063 Phase 2 Study Data in Patients with Schizophrenia or Schizoaffective Disorder

Marc Cantillon et al. Eur J Drug Metab Pharmacokinet. 2018 Oct.

Abstract

Background and objective: RP5063 is a novel multimodal dopamine (D)-serotonin (5-HT) stabilizer possessing partial agonist activity for D2/3/4 and 5-HT1A/2A, antagonist activity for 5-HT2B/2C/7, and moderate affinity for the serotonin transporter. Phase 2 trial data analysis of RP5063 involving patients with schizophrenia and schizoaffective disorder defined: (1) the pharmacokinetic profile; and (2) the pharmacokinetic/pharmacodynamic relationships.

Methods: Pharmacokinetic sample data (175 patients on RP5063; 28 doses/patient) were analyzed, utilized one- and two-compartment models, and evaluated the impact of covariates. Pharmacodynamic analysis involved development of an Emax model.

Results: The pharmacokinetic analysis identified a one-compartment model incorporating body mass index influence on volume as the optimum construct, with fixed-effect parameters: (1) oral clearance (Cl/F), 5.11 ± 0.11 L/h; (2) volume of distribution (Vc/F), 328.00 ± 31.40 L; (3) absorption constant (ka) 0.42 ± 0.17 h-1; (4) lag time (t lag) of 0.41 ± 0.02 h; and (5) a calculated half-life of 44.5 h. Pharmacokinetics were linear related to dose. An Emax model for total Positive and Negative Syndrome Scale (PANSS) scores as the response factor against cumulative area under the curve (AUC) provided fixed-effect estimates: (1) Eo = 87.3 ± 0.71 (PANSS Units; pu); (2) Emax = - 31.60 ± 4.05 (pu); and (3) AUC50 = 89.60 ± 30.10 (µg·h/mL). The predicted PANSS improvement reflected a clinical dose range of 5-30 mg.

Conclusions: Pharmacokinetics of RP5063 behaved predictably and consistently. Pharmacodynamics were characterized using an Emax model, reflecting total PANSS score as a function of cumulative AUC, that showed high predictability and low variability when correlated with actual observations.

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Conflict of interest statement

Conflict of Interest

Arul Prakash, M. Pharm., Laxminarayan Bhat, PhD, and Marc Cantillon, MD are employees of Reviva Pharmaceuticals, Inc., and Robert Ings, PhD is a consultant to Reviva Pharmaceuticals, Inc.

Ethical Approval

All procedures performed in the phase 2 REFRESH trial were in accordance with the 1964 Helsinki declaration (and its amendments). This study was approved by institutional review boards for each of the investigative sites located in India, Philippines, Malaysia, Moldova, and USA. Written informed consent was obtained from participants directly, or from parents or care givers of all participants.

Figures

Fig. 1
Fig. 1
Chemical structure of RP5063
Fig. 2
Fig. 2
Diagnostic plots reflected a fit of the final model to the data: observations vs population predictions, with superimposed identity line (a) and observations vs individual (empirical Bayes) predictions (b)
Fig. 3
Fig. 3
Population bootstrap predictions for the final model showed the data for all doses with superimposed median (solid lines) and 95% bootstrap point-wise confidence bands (dashed lines) for 15 mg (a), 30 mg (b), and 50 mg (c) RP5063
Fig. 4
Fig. 4
Treatment PANSS versus AUCt, using Emax model (Solid line represents the smoothing function and the thick dotted line represents the model fit using cumulative RP5063 AUC)
Fig. 5
Fig. 5
Treatment PANSS versus predicted PANSS Model (Thin line is the line of the identity. Solid line represents the smoothing function and the thick dotted line represents the model fit using cumulative RP5063 Predicted PANSS)
Fig. 6
Fig. 6
Predicted dose–response relationship of RP5063 in schizophrenic patients as measured by total PANSS (solid line: base model; dashed line: model incorporating the geographic site effect on Emax)
See this image and copyright information in PMC

References

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