population pharmacokinetics raymond miller, d.sc. pfizer global research and development raymond...
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POPULATION PHARMACOKINETICS
POPULATION PHARMACOKINETICS
RAYMOND MILLER, D.Sc.Pfizer Global Research and Development
RAYMOND MILLER, D.Sc.Pfizer Global Research and Development
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Population Pharmacokinetics
Definition
Advantages/Disadvantages
Objectives of Population Analyses
Impact in Drug Development
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Population pharmacokinetics describe
The typical relationships between physiology (both normal and disease altered) and pharmacokinetics,
The interindividual variability in these relationships, and
Their residual intraindividual variability.
Sheiner-LBDrug-Metab-Rev. 1984; 15(1-2): 153-71
Definition
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E.g.: A simple Pk model Ri = Cl·Cpss
Cpss = Rate in / Rate out
Rate in = infusion rate
Rate out = drug clearance
= measurement error, intra-individual errorD
rug
Con
c
Time
Definition
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E.g.: A simple Pk model
Cpss = Rate in / Rate out
Rate in = infusion rate
Rate out = drug clearance
= measurement error, intra-individual error
Dru
g C
onc
Time
N(0,)
Definition
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Cpss = Infusion rate / Cl
CL = Infusion rate / Cpss
Dru
g C
onc
Time
Definition
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Cl = metabolic clearance + renal clearance
Cl = 1 + 2• CCr
Dru
g C
lea
ran
ce
Creatinine Clearance
Dru
g C
onc
Time
Definition
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Cl = metabolic clearance + renal clearance
Cl = 1 + 2• CCr
Dru
g C
lea
ran
ce
Creatinine Clearance
N(0,)
Definition
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Graphical illustration of the statistical model used in NONMEM for the special case of a one compartment model with first order absorption. (Vozeh et al. Eur J Clin Pharmacol 1982;23:445-451)
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4321
333213
322223
312111
332313
322212
312111
Mean, expected value, or some other point estimate:
Variability among subjects around that mean:
Residual (unexplained) variability and/or model misspecification:
Definition
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Responses on data input requirements from a questionnaire survey of producers of software for population pharmacokinetic-pharmacodynamic analysis
Program Nature of input, Constraints Dosing histories specified in a flexible manner How is covariate information specified?
BUGS ASCII, S-Plus data set User has to supply code Variable in data set
MIXNLIN SAS data set User has to supply code Classified as inter- and intra-individualNone, but must conform to covariates SAS conventions
NLINMIX SAS data set User has to supply code Variables in the SAS data set
NLME ASCII, spreadsheets and data bases User has to supply code Variables in the data set
NLMIX ASCII, user responsible for writing input routine User has to supply code As for input
NONMEM ASCII Yes (specified by the routine PREDPP) Variables in the data set None (some dimensions areinitially set but these may bechanged by the user)
NPEM ASCII via USC*PACK program Yes Either linked to a pharmacokinetic99 days of time, 99 doses, or numerical value. Interpolation99 values of dependent between covariate values is possiblevariables (maximum of 6)
NPML ASCII User has to supply code Variables in the data set
PPHARM Dedicated data base ASCII Yes Variables in data base or in ASCII file
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Objectives
1. Provide Estimates of Population PK Parameters (CL, V) - Fixed Effects
2. Provide Estimates of Variability - Random Effects
• Intersubject Variability• Interoccasion Variability (Day to Day Variability)• Residual Variability (Intrasubject Variability,
Measurement Error, Model Misspecification)
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Objectives
3. Identify Factors that are Important Determinants of Intersubject Variability
• Demographic: Age, Body Weight or Surface Area, gender, race
• Genetic: CYP2D6, CYP2C19• Environmental: Smoking, Diet• Physiological/Pathophysiological: Renal (Creatinine
Clearance) or Hepatic impairment, Disease State • Concomitant Drugs• Other Factors: Meals, Circadian Variation,
Formulations
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Advantages
•Sparse Sampling Strategy (2-3 concentrations/subject)–Routine Sampling in Phase II/III Studies–Special Populations (Pediatrics, Elderly)
•Large Number of Patients –Fewer restrictions on inclusion/exclusion criteria
•Unbalanced Design–Different number of samples/subject
•Target Patient Population–Representative of the Population to be Treated
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Disadvantages
•Quality Control of Data–Dose and Sample Times/Sample Handling/
Inexperienced Clinical Staff
•Timing of Analytical Results/Data Analyses
•Complex Methodology –Optimal Study Design (Simulations) –Data Analysis
•Resource Allocation•Unclear Cost/Benefit Ratio
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Dru
g C
onc
Time
Models are critical in sparse sampling situations:
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Dru
g C
onc
Time
Models are critical in sparse sampling situations:
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Dru
g C
onc
Time
Models are critical in sparse sampling situations:
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Dru
g C
onc
Time
Models are critical in sparse sampling situations:
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Dru
g C
onc
Time
Models are critical in sparse sampling situations:
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Dru
g C
onc
Time
Models are critical in sparse sampling situations:
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Study Objectives
To evaluate the efficacy of drug treatment or placebo as add on treatment in patients with partial seizures.
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Data Structure
Study N Doses Explored
1 308 0, 600 mg/day (bid & tid)
2 287 0, 150, 600 mg/day (tid)
3 447 0,50,150,300,600 mg/day (bid)
Total 1092
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Baseline Placebo
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Count Model
!)(
xexYP
x
i
represents the expected number of events per unit time
E(Yij)=itij
The natural estimator of is the overall observed rate for the group.
timeTotal
countsTotal
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!)(
xexYP
x
i
Suppose there are typically 5 occurrences per month in a group of patients:- =5
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!)(
xexYP
x
i
The mean number of seizure episodes per month (λ) was modeled using NONMEM as a function of drug dose, placebo, baseline and subject specific random effects.
drugplaceboBaseline
Baseline = estimated number of seizures reported during baseline period
Placebo = function describing placebo response
Drug = function describing the drug effect
= random effect
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Sub-population analysis
Some patients are refractory to any particular drug at any dose.
Interest is in dose-response in patients that respond
Useful in adjusting dose in patients who would benefit from treatment
Investigate the possibility of at least two sub-populations.
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11111 drugplaceboBaseline
22222 drugplaceboBaseline
Population A (p)
Population B (1-p)
Mixture Model
A model that implicitly assumes that some fraction p of the population has one set of typical values of response, and that the remaining fraction 1-p has another set of typical values
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101 11.0
186
111.11
%75
eDDDose
Dose
APopulation
Final Model
201 44.126.011.15
%25 eDD
BPopulation
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Expected percent reduction inseizure frequency
Monte Carlo simulation using parameters and variance for Subgroup A
8852 individuals (51% female)
% reduction from baseline seizure frequency calculated
Percentiles calculated for % reduction in seizure frequency at each dose
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Results
Estimated population parameters for the exposure-response relationship of seizure frequency to pregabalin or gabapentin dose. Parameter Parameter Estimates (95% CI) Gabapentin Pregabalin BaseA (seizures/month) 14.0 (12.4,15.6) 11.1 (10.2,12.0) BaseB (seizures/month) 16.8 (8.8,24.8) 15.1 (12.3,17.9) EmaxA (maximal fractional change) -0.25 (-0.31,-0.18) -1.0 EmaxB (maximal fractional change) 2.34 (0.20,4.48) 0.26(-0.15,0.66) PlaceboA (maximal fractional change) -0.15 (-0.29,-0.009) -0.11 (-0.18,-0.03) PlaceboB (maximal fractional change) 4.34 (-0.80,9.47) 1.44 (0.66,2.22) ED50 (mg) 463.0 (161.3,764.7) 186.0 (91.4,280.6) ProportionA 0.95 (0.93,0.98) 0.75(0.61,0.88)
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Conclusions
A comparison of the dose-response relationship for gabapentin and pregabalin reveals that pregabalin was 2.5 times more potent, as measured by the dose that reduced seizure frequency by 50% (ED50).
Pregabalin was more effective than gabapentin based on the magnitude of the reduction in seizure frequency (Emax)
Three hundred clinical trials for each drug were simulated conditioned on the original study designs. Each simulated trial was analyzed to estimate % median change in seizure frequency. The observed and model-predicted treatment effects of median reduction in seizure frequency for gabapentin and pregabalin are illustrated for all subjects and for responders. Data points represent median percentage change from baseline in seizure frequency for each treatment group (including placebo). The shaded area corresponds to predicted 10th and 90th percentiles for median change from baseline in seizure frequency.
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Relationship Between %Change in Seizure Frequency (Relative to Baseline) and Daily Dosage of Gabapentin and Pregabalin
• Dose-response model in epilepsy using pooled analysis of 4 gabapentin studies + 3 pregabalin studies
Dose (mg/Day)
Me
dia
n %
Ch
an
ge
in
Se
izu
re F
req
ue
ncy
fro
m B
ase
line
0 300 600 900 1200 1500 1800
-60
-40
-20
02
0
GabapentinPregabalin
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Relationship Between %Change in Seizure Frequency (Relative to Baseline) and Daily Dosage of Gabapentin and Pregabalin in Responders to Treatment
Dose (mg/Day)
Med
ian
% C
hang
e in
Sei
zure
Fre
quen
cy f
rom
Bas
elin
e
0 300 600 900 1200 1500 1800
-80
-60
-40
-20
02
04
0
GabapentinPregabalin
• Dose-response model in epilepsy using pooled analysis of 4 gabapentin studies + 3 pregabalin studies
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Impact in Drug Development
Gabapentin was subsequently approved by FDA for post-herpetic neuralgia
Approved label states under clinical studies: “Pharmacokinetic-pharmacodynamic modeling provided confirmatory evidence of efficacy across all doses”
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PHN Study Designs
Used all daily pain scores
Exposure-Response analysis utilized titration data for within-subject dose response
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Fits to Data
Time Dependent Placebo Response, Emax Drug Response and Saturable Absorption,
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Outcomes
Model and Data Provided with Submission• FDA reviewers used model to test various scenarios• Supported doses and conclusions of Pfizer• Provided confidence to eliminate need for replicate
doses• FDA proposed language in the label on PK-PD
modeling and clinical trials
FDA/Pfizer publication to discuss modeling and impact on regulatory decision-making• clinical endpoints• similar study design• familiarity with drug class