Download Impaired Renal Function Clinical Trial

Impaired Renal Function Clinical Trial:
[email protected]
Early Phase Planning to Minimize Risks and Accelerate Drug Development
altasciences/ImpairedRenalFunction
40
30
Assessment
The assessment of an investigational drug’s behavior on patients with impaired renal function
is determined when the drug is renally excreted or used in this population (see Table I). The
different renal impairment stages are illustrated in Table II.
Study design
No study required
Renal
Reduced PK study
(in ESRD patients)2
Full PK study
Negative
Positive3
1. Applied to metabolites (active/toxic)
2. ESDR patients not yet on dialysis
3. Determinants of “positive”:
• magnitude of PK change
• exposure-response relationships
• the target patient populations
Dose adjustment
No dose adjustment
Label
Label
Label
Table II Phase I - Special Population
Stage
Description
eGFR
1
Control (normal glomerular filtration rate; GFR)
≥ 90 mL/min/1.73m2
2
Mild decrease in GFR
60-89 mL/min/1.73m2
3
Moderate decrease in GFR
30-59 mL/min/1.73m2
4
Severe decrease in GFR
15-29 mL/min/1.73m2
5
End Stage Renal Disease (ESRD)
< 15 mL/min/1.73m2
Algorithme Pharma Phase I Model: Case Study
This new model was built to efficiently conduct new drug development with the CRO as
central management.
Goal
Population
Sites
Dosage
• Determine the impact of the
drug PK behavior on renal
function (Stages 1 - 4)
• Healthy volunteers with normal
renal function (stage 1; control
group)
• A single-dose study
• Determine the safety of the
drug in patients with renal
impairment
• Patients with mild, moderate
or severe renal impairment
(Stages 2-4), 32 patients
(8 per cohort)
• Algorithme Pharma
Study Management,
Clinical conduct
(Stages 1 and 2)
• Careful demophysical matching
of the healthy with the renally
impaired subjects
• Hospital MaisonneuveRosemont (HMR)
Patients (Stages 3 and 4)
• Samples were collected over
24 hours post-dose
Parent Drug
10
Metabolite
150
Concentration (ug/mL)
30
Chronically administered oral, iv, sc
and likely to be administered to
target population
Non-renal
(Metabolism/transport)
20
40
Investigational Drug1
Single-dose use
Volatile Inhalation
Unlikely to be used in renal
impaired patients
Mild Impairment
Mod erate Impairment
Normal Function
Severe Impairment
0
0
5
10
Mild Impairment
Moderate Impairment
Normal Function
Severe Impairment
20
100
Concentration (ug/mL)
Table I
Legend
Conclusion - Study Results
Concentration (ug/mL)
Impaired Renal Function
15
20
25
Mild Impairment
Moderate Impairment
Normal Function
Severe Impairment
Time (h)
50
10
0
0
0
5
10
15
20
0
25
5
15
10
25
20
Time (h)
Time (h)
Plasma concentration-time profiles
◆◆ The study results demonstrate that systemic exposure, as indicated by Cmax and AUCs, to the orally
administered parent drug is not significantly altered by the presence or severity of renal impairment.
Conversely, systemic exposure to its main metabolite was significantly impacted by degrees of impaired
renal function.
◆◆ Irrespective of the severity of renal impairment, the majority of the orally administered dose of the parent
drug was excreted in urine over the first 24 hours as the main metabolite.
◆◆ As the main metabolite was less active, adjustment of the parent drug dosage regimen in patients with
impaired renal function was concluded to be unnecessary.
Timeline Impact
This new Algorithme Pharma model significantly improves timelines due to parallel enrollment of
patients and central management.
IRB / CTA
approval
Models
Patients
Patients
(Stage 2) (Stages 3 and 4)
Healthy normal
volunteers (Stage 1)
CSR sent
to client
Typical hospital
model
(estimated timeline)
Algorithme
Pharma
0
1
2
3
4
5
6
7
Time (months)
8
9
10
11
12
13