Transcript Slide 1

Model Based Dose Selection of a Quinolone to Minimize Drug Induced Serum Creatinine Elevation
S. Song1, S. Rohatagi1, P.K. Wickremasingha1, T. Khariton2, S. Kshirsagar2, T.J. Carrothers2, J. Kuwabara-Wagg2
1 – Daiichi Sankyo Pharma Development, Edison, NJ; 2 – Pharsight Corporation, Mountain View, CA
Objective: To utilize preclinical and phase I PK/PD data from a new quinolone (Q) and relevant
public domain data to develop an exposure-response model for serum creatinine level increase by
Q to support dose selection for subsequent clinical studies. Background: Reversible serum
creatinine elevations were observed during development of a novel Q that may confound clinical
safety monitoring. Glomerular filtration rate (GFR) remained constant while creatinine urinary
clearance decreased suggesting the Q selectively inhibits creatinine renal tubular secretion.
Methods: A population PK model was linked to a PD model of creatinine dynamics assuming
competitive inhibition, consistent with preclinical data suggesting competitive inhibition of
creatinine transport by Q. The PD model consisted of the following equation:
d[Crn]/dt = ([Crn].GFR + RateCrnIn - RateCrnSec*[Crn])/VolCrn; where [Crn], GFR, RateCrnIn,
RateCrnSec and VolCrn denote serum creatinine concentration (mg/dL), glomerular filtration rate
(dL/Hour), zero order creatinine production rate (mg/Hour), creatinine tubular secretion rate
(dL/Hour) and creatinine volume of distribution (dL). RateCrnSec was described as RateCrnSec =
Vmax*[Crn]/(Km*(1 + [Q]/Ki) + [Crn])) where [Q] denotes the Q serum concentration. The
resulting model was used to simulate Q dose dependent increase in serum creatinine. Creatinine
dynamics parameters were derived from the literature. Results: Model supported competitive
inhibition of serum creatinine secretion (Ki 156 ng/mL, ED50, 40 mg) by Q. Simulations showed
that maximum serum creatinine increase occurred at Q doses of 200mg IV QD. Conclusion: Q may
competitively inhibit serum creatinine secretion with near maximum increase at 200mg IV QD.
Hence IV Q doses above 200mg will not produce major additional increases in serum creatinine
level.
BACKGROUND
Q is a novel quinolone antibiotic in phase I development
Serum creatinine elevations in response to Q administration were observed
preclinically in rats, rabbits and monkeys
Preclinical in-vitro studies demonstrate that:
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14C-creatinine
is transported predominantly via hOCT2 (a human organic
cation transporter), moderately, by hOCT2-A, and to a negligible extent by
other organic cation transporters (hOCT1 & hOCT3) and organic anion
transporters (hOAT1, hOAT2, hOAT3 & hOAT4)
Q inhibits creatinine transport by hOCT2 and hOCT2-A transporters
The kinetics of this inhibition are competitive
Ki values for Q mediated inhibition of creatinine transport are estimated to
be 1.8 and 0.7 μM for hOCT2 and hOCT2-A mediated transport, respectively
Genetic variants of the hOCT2 and hOCT2-A genes associated with decreased
transporter substrate affinity and/or increased turnover rates have been
identified
An early multiple dose phase I investigation of Q was stopped due to observed
moderate elevations of serum creatinine (400 and 800 mg dose groups)
• Most subjects experienced such elevation with a mean elevation from
baseline of 35%
Comparable elevations were observed in an earlier single dose study (100 and
200 mg dose groups)
SCHEMATIC OF GENERAL APPROACH
Q effects on renal creatinine clearance were characterized in a phase I renal function
study
Public Domain Creatinine
Dynamics Model
Q Dosing
Regimen
[Q] Plasma (time)
PK Model
Physiological
Creatinine
Turnover Model
[Creatinine]Serum(time)
Are predicted &
observed
creatinine profiles
consistent?
Phase I PK Data
Preclinical In-Vitro Data
Phase I Renal Function Study
Phase I Studies:
Serum Creatinine
Elevations
METHODS
Exploratory analysis of phase I renal function study data completed
● Mean and median serum creatinine percentage changes from baseline plotted
as a function of time for both placebo and Q treatment arms
● Difference between the median % change in serum creatinine from baseline for
the Q treatment group and the comparable change from baseline for the
placebo group calculated and plotted as a function of time
● Concurrent changes in estimated Glomerular Filtration Rate (GFR) and
Creatinine Urinary Clearance before, during and after Q dosing, plotted as a
function of time.
OBJECTIVES
To utilize preclinical and phase I PK/PD data for a new quinolone, Q, and relevant
public domain data to develop a exposure-response model for serum creatinine
elevation
The objective was to assess whether Q-mediated serum creatinine elevation reflect Qmediated decreases of glomerular filtration rate (GFR) and/or renal tubular creatinine
secretion
800 mg Q was administered daily for 4-days as an I.V. infusion
Creatinine clearance was calculated using a 24-hour urine specimen and estimated two
days prior to dosing, on the last day of dosing, and, 1-week after the final dose
Phase I PK data used to developed a PK Model for Q
RESULTS: Q RENAL EFFECT
Q renal effect is predominantly at the level of
creatinine tubular secretion
The creatinine dynamics model consists of a single compartment into which
creatinine is released at constant rate (RateCrnIn), and, from which
creatinine is cleared via the renal mechanisms of glomerular filtration
(GFR) and tubular secretion (RateCrnSec). Renal reabsorption of
creatinine is assumed to be negligible as is extrarenal clearance of
creatinine. The volume of creatinine distribution (VolCrn) is assumed to be
equal to the volume of total body water. Under these assumptions, the rate
of change of serum creatinine concentration is given by the equation below.
Plasma (central) Q levels were
described using a 2-compartment
PK model
Simulated serum creatinine as
a function of time for
administration
of 50, 100, 400 and 800 mg
QD IV for 14-days.
Simulations were based on
a physiological model of
serum creatinine dynamics in
which Q mediates a
competitive inhibition of
creatinine renal tubular
secretion.
Glomerular
Filtration
Dose
I.V. infusion
Based on preclinical data, Q is assumed
to act as a competitive inhibitor of renal
tubular secretion such that RateCrnSec is
a function of plasma Q levels, [Q].
K12
K21
Central
V1
Creatinine Renal
Tubular Secretion
Median % change in creatinine clearance (normalized for body surface
area) for placebo and active treatment arms. Active treatment reduced
creatinine clearance by about 25%. The effect was reversible upon
cessation of dosing. Placebo effects were negligible.
% change in median GFR (normalized for body surface) from baseline
for placebo and treatment arms. Error bars denote standard deviations.
The effects of placebo and active treatment on GFR were negligible.
Simulated % Change from Baseline of Serum Creatinine vs Time
for DX619 QD IV dosing regimens of 14 days duration
30.0%
20.0%
DX619 dose = 400 mg
DX619 dose = 800 mg
400 mg Phase I Data
Simulated percentage change
from baseline of serum
creatinine as a function of
time for adminstration of 400
and 800 mg IV Q for 14 days.
Filled triangle and squares
denote the observed
median % changes of serum
creatinine from placebo for
the 400 and 800 mg
treatment arms of a phase I
study.
800 mg Phase I Data
10.0%
0.0%
Since creatinine clearance is
given by the sum of GFR and
renal tubular secretion, and, Q
has minimal effects on GFR, the
effects of Q on creatinine
clearance are inferred to be
mediated by reduced renal
tubular secretion of creatinine.
Simulated and observed serum creatinine profiles qualitatively compared
RateCrnSec was described as a saturating function of plasma Q levels [Q] as outlined
below.
The difference between estimated median creatinine clearance and
GFR is the estimated change in renal tubular secretion. Note that
active treatment reduced renal tubular secretion of creatinine but
that placebo treatment effects were negligible.
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9 10 11 12 13 14 15 16 17 18 19 20
Time (Days)
Linked PK/PD model equations were solved for dosing regimens of
interest to simulate:
• Plasma Q levels as a function of time
• Serum creatinine levels as a function of time
The serum creatinine elevation effect is near
maximum at 200 mg QD
SUMMARY OF MAJOR FINDINGS
Serum creatinine elevations occur in association with Q exposure
• Mean maximal elevation above baseline was approximately 35%
• Majority of elevation occurs within the first 24 hours of exposure
• In most cases, creatinine levels remain within the normal range
This effect is not expected to be dose-limiting since
● Elevation appears to saturate at doses greater than 200 mg IV QD
● Elevations are completely reversible upon cessation of Q dosing
and return to normal within 6 days of Q last dose
The general approach consisted of the following steps:
Exploratory data analysis of phase I data
Utilize phase I PK data to develop a PK model for Q
Implement an established, public-domain, creatinine turnover model
Based on preclinical in-vitro and phase I data link the PK model to the
creatinine turnover model
• Simulate the relationship between Q dosing regimen and serum creatinine
elevation
• Compare the observed to the predicted serum creatinine elevations
Tubular
Secretion
PK MODEL SUMMARY AND PK/PD LINK
Exploit the model to establish whether the clinically observed time course and
extent of serum creatinine elevation in response to Q administration is consistent
with Q mediated competitive inhibition of creatinine renal tubular secretion
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VolCrn
CL
Linked PK/PD model then used to simulate the time course of serum creatinine
elevation as a function of Q dosing regimen
Serum Creatinine Elevations at 800 mg QD
average about 30% above baseline
Simulated serum creatinine profiles as a function
of regimen are comparable to those observed in
phase I studies
RateCrnIn
Peripheral
V2
The PK and PD models were linked under the assumption of Q mediated
competitive inhibition of creatinine renal tubular secretion
EXPLORATORY ANALYSIS
CREATININE SIMULATION RESULTS
Physiologically, urinary creatinine clearance consists of two components, one reflecting
glomerular filtration (GFR) and another reflecting renal tubular secretion. This is because
renal tubular creatinine reabsorption is negligible.
An established model of creatinine dynamics implemented (PD model)
● Parameter values obtained from the literature
CREATININE DYNAMICS MODEL
Glomerular Filtration Rate (GFR) was measured using the cold iohexol “gold standard” two
days prior to dosing, on the last day of dosing, and, 1-week after the final dose
Pooled phase I study data then used to calculate and plot the median % change
from baseline of serum creatinine as a function of dose and an Emax function of
dose fitted to the data
• Smaller elevations were also observed in lower dose groups (single dose
study), e.g., 25 and 50 mg
Serum creatinine elevations were also noted in at least two other phase I
studies
RENAL FUNCTION STUDY
% Chg Serum Creatinine from BL
ABSTRACT
Preclinical data suggest that serum creatinine elevation results from Q
mediated, competitive inhibition of creatinine renal tubular secretion
Left Panel: Median % change of serum creatinine from baseline as a function of
day for Q treatment (upper curve) and placebo (lower curve) arms of a phase I
renal function study. Note that 800 mg Q was administered via a 1-hour
infusion on days 1, 2, 3 and 4. These days are denoted by the space between the
solid vertical lines. Right Panel: Corresponding median % change of serum
creatinine from placebo as a function of day for the phase I renal function study.
Median % changes of serum creatinine from placebo for the 400
and 800 mg treatment arms of a phase I study as a function of time.
The majority of maximal effect is achieved within the first 24-hours
of dosing. The effect is maintained over the duration of dosing.
Following the final Q dose, creatinine levels return to baseline
levels over a period of several days.
24-hour post-first dose median change of serum creatinine from
baseline as a function of dose for data pooled across three phase
I studies (SAD and MAD studies combined).
Simulations based on a physiological based model of human creatinine
dynamics demonstrate that the proposed mechanism of elevation is
consistent with the general time course of clinically observed
creatinine elevations
*During PK model development, a saturable component of Q renal
clearance was identified. The D50 of this effect was 31 mg
comparable to that observed for the serum creatinine elevation
effect (39 mg).
Note:
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Minimal steady-state Q accumulation
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Dotted horizontal line denotes Q KI value of 156 ng/mL