Download Population PK/PD analysis of the bactericidal activity of sutezolid

Population PK/PD analysis of the bactericidal
activity of sutezolid and its major metabolite
against intracellular Mtb in whole blood cultures
of TB patients
Tong Zhu1, Sven Friedrich2, Andreas Diacon2, and Robert Wallis1
1Pfizer,
Groton CT; 2Stellenbosch University, Cape Town, South Africa
Sutezolid
• First oxazolidinone developed for TB
• Parent: PNU-100480 or U-480
• Metabolite: PNU-101603 or U-603
• MICs are similar when tested on agar
• After oral dosing, plasma concentrations of metabolite
are several fold higher than parent
• Louie & Drusano found killing of extracellular Mtb in
hollow fibers mainly due to the metabolite
• Converse & Nuermberger found killing of intracellular
Mtb in cell culture models mainly due to the parent
Objective
• To develop a PK/PD model describing the relative
contributions of sutezolid and its metabolite
against intracellular Mtb in vivo in patients with
pulmonary tuberculosis.
Methods
• Data (plasma concentrations of U-480 and U-603, and
corresponding whole blood bactericidal activity [WBA]) came
from patients treated with sutezolid 600 mg BID (N=25) or 1200
mg QD (N=25) enrolled the sutezolid EBA trial (B1171003).
• A 4 parameter sigmoid curve was used to describe the
concentration-activity relationship, based on prior observations
that killing was concentration-dependent at low concentrations,
but did not increase further once a maximal response (Imax)
was reached.
• The activities of U-480 and U-603 were assumed competitive,
based on prior observations that U-603 did not further increase
the activity of optimal concentrations of U-480.
Equations
𝑃+𝑀
𝑊𝐵𝐴 = 𝑊𝐵𝐴0 − 𝐼𝑚𝑎𝑥 ∗
𝑃+𝑀+1
𝐶480
𝑃 = 0.5 ∗
𝐼𝐶50 480
𝐶603
𝑀 = 0.5 ∗
𝐼𝐶50 603
𝛾480
𝛾603
Value
the
absence
of drug
Predicted
result
Fraction
of
ICfactor
Maximal
effect
Dilution
Shapein(Hill)
factor
50
Data set
• 690 PK and 345 WBA determinations at 0, 1, 2, 3, 6,
8, and 12 hrs post dose measured on days 13-14
• The median ratio of U-603/U-480 plasma
concentrations was 7.1 (range, 1 to 28).
• High ratios mainly occurred at late time points in
the dosing interval.
• The wide range of values facilitated modeling of the
relative contributions of parent and metabolite.
Diagnostic plots
Parameters
Parameter
Fixed effects
WBA0
Imax
IC50480 ng/mL
IC50603 ng/mL
g480
g603
Random effects
WBA0 (%)
Sigma (%)
Estimate
0.182
0.597
70.4
1200
2.25
(0.94)
27.4
31.0
90% CI
0.154 to 0.209
0.559 to 0.636
56.0 to 84.9
17x 839 to 2960
1.7 to 3.2
2x
19.4 to 35.2
27.4 to 33.8
Predicted drug activity (in vitro)
0.2
U-603
U-480
log/d
0.0
11x
-0.2
-0.4
0.01
0.1
1
Concentration (g/ml)
10
Predicted drug activity (in vivo)
Discrete
timepoints
Cumulative
activity
BID superior
80%
of activity
dueQD
to
to parent
Conclusions
• Killing of intracellular Mtb by oral sutezolid is mainly
due to the parent, despite the higher plasma
concentrations reached by the metabolite.
• Intracellular drug accumulation may account for this
• Mtb subpopulations have distinct roles in TB:
• Extracellular: resistance and treatment failure
• Intracellular: persistence and relapse
• Factors that differentially affect exposure to parent and
metabolite (e.g., dosing schedules, induction of
metabolism) may have different effects on these 2
outcomes.