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Impact of Pharmacometric Analyses on Regulatory Decisions from 2000 to 2008

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Wansu Park

on 16 July 2013

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Transcript of Impact of Pharmacometric Analyses on Regulatory Decisions from 2000 to 2008

Summary of Regulatory Impact
Impact of Pharmacometric Analyses
on Regulatory Decisions
2000-2008년에 198 개의 PM review

Population PK (57%)
Exposure-response analyses (50%)
Pediatric submissions (26%)
Percentage of pharmacometric reviews influencing approval or labeling decisions during 2000~ 2008 as reported by the pharmacometric reviewer
What is Pharmacometrics (PM)?
Division of Pharmacometrics
Case study
Utilization of PM allows for a more efficient drug
development process

Regulatory questions

Role of PM Review

Regulatory action
Everolimus (AFINITOR)
Sponsor NDA for everolimus tablets (a prophylaxis of organ rejection following heart transplantation)
needed to provide safe and effective dosing regimens that would minimize renal toxicity

There was a concern that the
everolimus–‘‘full dose’’ cyclosporine combination regimen
for the prevention of acute rejection following de novo heart transplantation was
associated with a greater nephrotoxicity risk than necessary.
Everolimus is approved for various conditions:

Advanced kidney cancer (approved in March 2009)

Prevention of organ rejection after renal transplant(April 2010)

Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients who are not suitable for surgical intervention (October 2010)

Progressive or metastatic pancreatic neuroendocrine tumors not surgically removable (May 2011)
Regulatory questions
1. Are the effectiveness and renal toxicity clinical outcomes related to drug exposure?

2. What is a
rational dosing regimen
that would maximize effectiveness (benefit) and minimize nephrotoxicity (risk)?
Role of PM Review
1. FDA performed simulations based on the information available from the heart transplantation study to project the range of possible outcomes of altered dosing schemes.

2. Faster cyclosporine dose tapering to achieve lower cyclosporine trough concentrations while maintaining a threshold everolimus trough concentrations had the potential to improve the benet–risk prole of this drug combination in heart transplant recipients.
Regulatory action
The projected benefit and risk at alternative dosing regimens were presented to the Cardio-vascular and Renal Advisory Committee on 16 November 2005. The recommendation of the committee and subsequently the FDA was for
the sponsor to test in future trials an appropriate dosing such as the one derived using simulations.
Varenicline (CHANTIX)
Sponsor conducted five dose-finding and registration clinical trials
to determine the appropriate dosing

The primary effectiveness end point was continuous abstinence from smoking at week 9–12 after the treatment.

The sponsor proposed the use of a 1mg b.i.d. maintenance dose following a starting dose of 0.5mg q.d. on days 1–3 and 0.5mg b.i.d. on days 4–7.
Varenicline (from wikipedia)

Varenicline is indicated for
smoking cessation
. It is more effective than NRTs and nicotine agonists.[1][2] In a 2006 randomized controlled trial sponsored by Pfizer, after one year the rate of continuous abstinence was 10% for placebo, 15% for bupropion and 23% for varenicline.[1] In a 2009 meta-analysis of 101 studies funded by Pfizer, varenicline was found to be more effective than bupropion (odds ratio 1.40) and NRTs (odds ratio 1.56).[2]
Regulatory questions
1. What is the
optimal dose
of varenicline?

2. Is there a
need for dose adjustment in subjects with renal
If so, by how much?
Role of PM Review
The population pharmacokinetics analysis, conducted by the sponsor, showed that the
renal function has the greatest effect on varenicline clearance.
The pharmacokinetics model simulations showed that the average concentrations were similar between healthy subjects who received 1mg varenicline twice daily (b.i.d.) and subjects with severe renal impairment who received 1mg varenicline once daily.

The exposure–response analysis, conducted by the sponsor, showed that the probability of continuous abstinence from smoking at week 9–12 after the treatment is dependent on three main factors: varenicline exposure at steady state (area under curve (AUC)), baseline smoking status, and age. The analysis suggests that increasing the dose from 0.5 to 1mg b.i.d. increases the probability of abstinence by a nominal extent, from 45 to 51%. However, when dose is increased from 0.5 to 1mg b.i.d., the probability of nausea is increased from 25 to 40% in females and from 12 to 20% in males. We essentially accepted the sponsor’s modeling with a minor modication. However, the interpretation of the results, in terms of dose selection, was different.
Regulatory action
A recommendation stating that
patients who cannot tolerate adverse effects of CHANTIX may have the dose lowered temporarily or permanently
is included in the dosing and administration section of the current label
The sponsor proposed a drug to treat patients with mild, moderate, or severe life-threatening disease.

Three registration trials were conducted, which showed inconsistent results based on a well-established clinical end point. In study 1, between 1 and 3mg doses, only 3mg showed significant effect over placebo, but with unacceptable toxicity.

A lower dose, 0.5mg, was studied together with 1mg in the later twostudies. Subsequent studies also did not provide equivocal evidence of effectiveness at lower doses. The submission included both the pre-specified statistical analysis and exposure–response analysis. However, the sponsor’s model was found to be flawed in several aspects, which led the PM reviewer to develop a new exposure–response model
For children age about 2 years, the dosing regimen should be reduced by a factor that depends heavily upon age. For a child aged 1 month, the starting dose should be multiplied by 0.68; the initial starting dose would be (30 X 0.68) = 20 mg/m2 administered 3 times daily.
2012년 임진년 흑룡의 해
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