Prospective dose selection and acceleration of paliperidone palmitate 3-month formulation development using a pharmacometric bridging strategy

Abstract

Aims: To prospectively select the dose of the paliperidone palmitate 3-month (PP3M) formulation, using a pharmacometric bridging strategy based on the paliperidone palmitate 1-month (PP1M) formulation previously approved for schizophrenia treatment.

Methods: Pharmacokinetic (PK) data from a 6-month interim analysis of a single dose PP3M Phase I clinical trial was integrated with a previously developed PP1M population-PK model. The model was updated to incorporate formulation as a covariate on absorption parameters and to explore the most critical design element of the Phase III study: the PP1M-to-PP3M dose multiplier for patients switching formulations. Plasma paliperidone concentrations were measured at predetermined intervals during Phase III, enabling comparison of the multiple-dose PK between PP1M and PP3M. Exposure matching was assessed graphically to determine whether paliperidone plasma concentrations from the two formulations overlapped.

Results: Prospective steady-state PK simulations revealed that a 3.5 multiple of the PP1M dose would yield a corresponding PP3M dose with comparable exposure. The prospective pharmacometric simulation and observed Phase III PK data agreed closely. Phase III results confirmed the hypothesis that efficacy of PP3M was noninferior to that of PP1M. The similarity in exposures between the two formulations was likely a key determinant of the equivalent efficacy between the two products observed in the Phase III study.

Conclusions: Successful prospective PP3M Phase III clinical trial dose selection was achieved through the use of pharmacometric bridging, without conducting a Phase II study and using only limited Phase I data for PP3M. We estimate that this strategy reduced development time by 3-5 years and may be applicable to other drug development projects.

Trial registration: ClinicalTrials.gov NCT01559272 NCT01515423.

Keywords: paliperidone palmitate; pharmacometric bridging; prospective validation.

© 2016 The British Pharmacological Society.

Figures

Figure 1

Flowchart summarizing the pharmacometric bridging exercise. Abbreviations: PP1M, paliperidone‐1 month; PP3M, paliperidone‐3 month; PK, pharmacokinetics

Figure 2

Simulated exposure using a 3.5‐fold dose multiplier between PP1M and PP3M based on a fit‐for‐purpose model built on single dose interim PK data from Phase I. This scenario simulates switching 100 mg‐eq. PP1M to 350 mg‐eq. PP3M vs. 100 mg‐eq. PP1M maintenance therapy. The lines/shaded‐hatched areas represent the model‐based median/90% prediction interval. 150/100 mg‐eq. injections on days 1/8 in the deltoid muscle is the recommended initiation regimen for PP1M. This was followed by 100 mg‐eq. PP1M on weeks 5, 9 and 13. Starting at week 17, a fixed dose of PP3M (350 mg‐eq.) or PP1M (100 mg‐eq.) were simulated

Figure 3

Dose normalized (100 mg‐eq. for PP1M and 350 mg‐eq. for PP3M) mean ± standard deviation (SD) semi‐logarithmic observed plasma concentration–time profiles of paliperidone comparing PP1M vs. PP3M in Phase III. Data are normalized to 100 mg‐eq. for PP1M and 350 mg‐eq. for PP3M as these two strengths represent the median doses for the two formulations in Phase III. The study design was as follows: open label phase with 150 mg‐eq. PP1M on day 1, 100 mg‐eq. PP1M on day 8, flexible dose of 50, 75, 100 or 150 mg‐eq. PP1M on week 5, week 9 and week 13 based on patient/physician preference, followed by a DB phase starting at week 17 with a fixed dose of PP3M (175, 263, 350 or 525 mg‐eq.) or PP1M (50, 75, 100 or 150 mg‐eq.). Data are presented only for the DB phase since dosing was fixed during this period, which allows dose normalization. The time period indicated by the dark grey shaded area between weeks 53 and 57 represents a phase of semi‐intensive PK sampling around steady‐state. Other than this semi‐intensive period, the PP1M samples were all collected at trough, but PP3M samples were not all trough