A Phase I Program to Assess the Pharmacokinetics of a New Salt Form
of CO-1686 and Prototype Formulations in Healthy Volunteers
John McDermott1, Lorna Patrick1, Alyson Connor1, Joanne Collier1, Mei Lai2
1. Quotient Clinical Limited, Nottingham, UK
2. Clovis Oncology, Inc., Boulder, CO, USA
Introduction
RapidFACT
Regulatory
application
Pre-approved
regulatory design
space
Approval was achieved from the Ethics committee and
MHRA in 29 days including the time to respond to
comments. The approval enabled any composition within
the formulation design spaces to be studied, and
decisions regarding which formulation compositions to
assess to be made in direct response to emerging
clinical data
Parameter 2
Real time, adaptive
manufacture
Clinical
“Make-Test”
cycle
Clinical dosing
Figure 1: The RapidFACT process
Existing free
base
formulation
Following initial dosing, the Translational Pharmaceutics
platform also allows GMP drug products to be made in
real-time in response to interim analysis of clinical data,
typically on a 7-14 day cycle
Drug products can be selected from a panel of preapproved fixed formulation compositions. Alternatively,
building upon ICH Q8 Development Pharmaceutics and
Quality-by-Design principles(3), products can be
selected from any point within a continuous formulation
design space (Figure 1). In this scenario, a range of
product performance attributes are obtained by varying
the quantitative composition of one or more formulation
components(4).
+44 115 9749000 (UK)
Free Base
700
HBr salt
600
500
400
300
200
0
*
Period 2
Period 3
Period 4
Period 5
“Xmg” salt
Formulation 1
“Xmg” salt
Formulation 2
“Xmg” salt
Formulation 3
*
*
*
Interim analysis
Real-time manufacturing
0
2
4
6
Time (h)
8
10
12
Figure 4: Geometric mean plasma concentrations following
oral dosing of rociletinib free base and HBr salt
50mg salt
Formulation 1
Methods
RapidFACT uses a Translational Pharmaceutics®
delivery platform which utilises a co-located GMP
production and clinical testing facility (1). Using this
platform drug product can be manufactured within 7 days
of dosing at reduced scale, removing scale-up and
stability data package generation from the critical path to
obtaining clinical data on product performance (2).
800
100
Period 1
Over 100 RapidFACT formulation optimization programs
have now been completed with a wide variety of
parameters assessed/optimized via a design-space
approach. The flexibility to evaluate as many as 5
parameters within a single study has been successfully
implemented.
900
Concentration (pg/mL)
A Rapid Formulation Development and Clinical Testing
(RapidFACT®) study was designed to:
• Transition rociletinib evaluation into healthy
volunteers
• Compare the PK of rociletinib when dosed as FB or
HBr
• Evaluate the impact of the inclusion of functional
excipients on PK
Pharmaceutical
development
program
PK data
Formulations were evaluated in a 5-period, 5-treatment
sequential clinical study in 12 healthy male subjects
(Figure 3).
Dose
Rociletinib (CO-1686) is an oral epidermal growth factor
receptor inhibitor in development for non-small cell lung
cancer. Initial Phase 1 studies had been conducted in
patients using the free base (FB) form, which exhibited
non-linear systemic exposure and variable
pharmacokinetics (PK). Subsequently, a hydrobromide
(HBr) salt form was identified as having the potential to
substantially improve systemic exposure.
Parameter 1
Clinical study
Figure 3: Clinical study design
Three rociletinib HBr formulation prototypes were
identified and a technical transfer was performed to
establish drug product manufacturing at Quotient.
Rociletinib HBr formulations were manufactured using
the same direct compression process; however,
prototype 2 also included a precipitation inhibitor and
formulation 3 also included precipitation inhibitor and an
acidic modifier.
Formulation 1
Formulation 2
Formulation 3
Periods 1 and 2 compared the rociletinib FB form to the
rociletinib HBr form (prototype 1) at a dose selected to
be safe based upon preclinical PK data. Interim PK
analysis was performed to select the rociletinib HBr dose
predicted to exhibit comparable exposure to the
rociletinib FB dose. The three rociletinib HBr prototype
formulations were manufactured and screened in the
remaining study periods at the selected doses to identify
a suitable formulation for downstream development.
80mg
Results
Unit dose
30mg
Precipitation inhibitor
-


Acidic modifier
-
-

The rociletinib HBr salt exhibited a two fold increase in
relative bioavailability (Figure 4) compared to the
rociletinib FB formulation and greater than two fold
reduction in variability.
Figure 2: Formulation design spaces
A formulation design space was used for the rociletinib
HBr prototypes to enable dose strengths between 30mg
and 80mg to be assessed (Figure 2). For doses above
80mg, two tablets were administered.
1-800-769-3518 (USA)
Differences between the prototype rociletinib HBr
formulations were <30%. All formulations were well
tolerated in this study by the 12 healthy male subjects.
There were no serious or severe AEs reported.
AAPS 2015
Conclusion
Rociletinib was effectively transitioned from a FB to a
HBr salt form, delivering improvements in exposure
profile and variability. Three rociletinib HBr formulations
were screened and a formulation suitable for further
development was identified in less than 5 months.
References
1. Scholes PD. RapidFACT – A new paradigm for the
Effective Optimisation of Oral Dosage Forms.
Quotient Clinical White Paper, 2008
2. Scholes PD et al (2009)Translational Pharmaceutics Interactive Drug Development to Enable Rapid
Optimisation of Drug Products in Early Development.
AAPS Poster #T3070
3. ICH Q8 Development Pharmaceutics (EMEA/CHMP/
167068/2004)
4. Patel, A. et al. AAPS Annual Meeting Poster T2130
(2012)
www.quotientclinical.com