Population Pharmacokinetic Models and

1
Poster 71
Population Pharmacokinetic Models and
Individualized Bayesian Dose Optimization in
HIV-Infected Patients Michael Neely MD and
Roger Jelliffe MD
Los Angeles, California, USA
Laboratory of Applied Pharmacokinetics www.lapk.or
g
Introduction Standard antiretroviral dosing is
size-based for children and fixed for adults.
This may be problematic for an individual
patient. If the patient is not average then the
average dose may not achieve the efficacy goal,
or may be toxic. Dose-dependent and
dose-independent toxicity are difficult to
distinguish. Sub-optimal adherence may be
undetected prior to development of virologic
failure and resistance alternatively,
sub-optimal dosing may be mistaken for poor
adherence. There is little or no information on
when to change from pediatric to adult
dosing. There is no ability to adjust the
recommended dose in an individual patient with
any assurance of success. All of these problems
can cause poor outcomes viral resistance,
toxicity, unnecessary regimen changes or
combinations of these. There are now several
clinical investigations 1-7 and numerous
reviews or position papers, e.g. 8-13, that
affirm the usefulness of incorporating
measurement of antiretroviral drug concentrations
into the clinical management of selected
HIV-infected patients. Here, we report four case
vignettes of HIV-infected patients whose therapy
was optimized using an approach and software
developed in our lab. These vignettes illustrate
the benefit of dose individualization and
optimization in common clinical scenarios.
Results/Case Histories Patient 1 was a 13-year
old antiretroviral-naïve African boy (Tanner
stage 2), started on an efavirenz-based regimen
at the recommended dose for his age. After 2
weeks, his mother reported that he was too drowsy
to attend school, more severe than the typical
transient drowsiness after starting efavirenz.
Suspecting that he was a genetic slow
metabolizer, we empirically reduced his dose by
half, and a week later measured a serum
concentration of 1.37 mg/L 22 hours after his
previous dose. His 24-h trough concentration was
predicted to remain above a target of 1 mg/L
22 therefore, he continued on this dose. A
follow-up sample confirmed his therapeutic
concentrations on 50 dose, and he has maintained
an undetectable HIV viral load with no further
somnolence for the past 2 years. (Figure
1A) Patient 2 was a 10 year-old girl (Tanner
stage 2) who weighed 30.7 kg. Based on the
standard pediatric dose of 55 mg/kg, given
formulation limitations, she was prescribed 1875
mg. Since the recommended maximum is the adult
dose of 1250 mg, we measured a random serum
concentration of 4.9 mg/L 4 hours after her
previous dose to ensure that she was not in a
toxic range. Her predicted peak concentration was
5.5 mg/L and her 12-h trough was 2.1 mg/L, both
within a suggested therapeutic range of 1 - 6
mg/L 22, and she never demonstrated toxicity
despite the continued supra-maximal dose.
(Figure 1B) Patient 3 was a 45 year-old woman
(Tanner stage 5) with a long history of
medication intolerance. She was started on a
fos-amprenavir containing regimen (without
ritonavir), 2 x 700 mg tablets twice daily. After
starting the new regimen, she complained of
daytime fatigue, which she attributed to the
morning dose. She enquired about taking the
entire dose at night. Prior to making changes, we
measured a serum amprenavir concentration of 1.4
mg/L 4.5 hours after her previous dose. Modeling
suggested that although 2800 mg once daily would
not maintain her trough concentration above the
minimum target of 0.23 mg/L 22, a regimen of 1
tablet at 8am followed by 3 tablets at 6pm (a
10-14 hour schedule) would achieve this goal. She
was changed to the latter regimen, and has
achieved an undetectable viral load without any
further complaints of fatigue. A follow-up level
of 0.9 mg/L 4 hours after the morning dose on the
new regimen confirmed that her predicted troughs
were likely to be therapeutic. (Figure
1C) Patient 4 was a 14-year old male (Tanner
stage 4) with poor adherence and limited
treatment options. To encourage better adherence,
he was changed to a once-daily regimen that
included atazanavir given in combination with
low-dose ritonavir. There were no published
pediatric PK data at the time. The usual adult
dose of atazanavir is 300 mg when given with
ritonavir, so he was started on 200 mg based on
his small size. We obtained a random atazanavir
concentration of 0.782 mg/L 18 hours after his
previous dose. His predicted trough concentration
was 0.380 mg/L, above the minimum target of 0.150
mg/L 23, so the dose was continued. He
initially achieved an undetectable viral load but
persistently poor adherence (self-reported)
allowed his viral load to rebound partially to
about 2000 copies/mL, despite a second confirmed
therapeutic concentration of atazanavir. (Figure
1D)
Methods Antiretroviral population pharmacokinetic
models, each with oral absorption into a single
compartment, were constructed using the
MM-USCPACK software collection 14 (available
at www.lapk.org). PK parameter estimates
obtained or derived from over 30 published
studies were used to generate, by Monte Carlo
simulation with noise, populations of n50 for
each drug. Final parameter values for the models
in this report are shown in Table 1. Simulated
populations were then analyzed using the
Non-Parametric Adaptive Grid (NPAG) program in
MM-USCPACK 15 to generate a population PK
model for each antiretroviral drug. The models
were applied as part of comprehensive clinical
care to outpatients in our HIV clinic using
MM-USCPACKs multiple-model, Bayesian adaptive
control to individualize therapy.
B
A
C
D
Figure 1 MM-USCPACK output for each patient.
Black lines are weighted average
Bayesian-posterior predicted concentrations, red
dots are measured serum concentrations, and blue
lines are dose events. Intervals between measured
serum concentrations have been compressed for
clarity. Target concentrations have been added
as a reference. A) Patient 1, efavirenz B)
Patient 2, nelfinavir C) Patient 3 amprenavir
given as fos-amprenavir D) Patient 4, atazanavir.
Conclusions Our methods and software for
converting reported PK data into population PK
models can be used locally to optimize safety and
efficacy in individual patients. Successful
therapeutic drug management tailored to patients
representing four scenarios was presented 1)
altered metabolism 2) supra- maximal doses
related to pediatric vs. adult dosing 3) altered
dosing schedules 4) dosing with limited relevant
published PK data Individualized Bayesian
adaptive control can move population PK/PD models
beyond their current primary domain of drug
development to the optimized care of patients.
Table 1 Mean model parameter values. Models
based on pediatric studies were used for patients
with a Tanner Sexual Maturity Rating stage 3.
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Acknowledgements This work was supported by
Department of Health and Human Services,
NIH-NIAID, 1 K23 AI076106-01 and NIH-NBIB, R01
EB005803-01A1