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We have carried out "chronopharmacokinetic study of metoprolol used for the treatment of
hypertension". We have peak and trough concentrations of metoprolol for the morning and evening
doses ( 8 AM and 8 PM). We have the B.P measurements too. We are able to establish PK-PD correlation
which seems quite positive. If someone can kindly through some light on how to go about the analysis
of the data it will be helpful. Also kindly share some publication in this regard.
Thanks in advance.
Best regards,
Shobha Rani
Dr.Shobha Rani.R.Hiremath
Principal
Professor and Head
Dept.of Pharmacy Practice
Al-Ameen College of Pharmacy
Hosur Road
Near Lalbagh Main Gate
Bangalore-560027
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Dear Dr. Rani:
You could start by making 2 separate population PK models - one based on the data from the 8
AM dose, and one based on the data of the 8 PM dose. I would strongly suggest that you use Pmetrics,
which is free at www.lapk.org, and is the most capable pop modeling software I know, better than any
parametric software such as NONMEM or S-Adapt. Then later, you might pool the data and develop a
covariate relationship between day and night on the elimination rate constant for example. You can
develop maximally precise dosage regimens with this software, and you also get the most likely
results given the data, compared to parametric methods. You might check this by looking at
Bustad A, Terziivanov D, Leary R, Port R, Schumitzky A, and Jelliffe R: Parametric and Nonparametric
Population Methods: Their Comparative Performance in Analysing a Clinical Data Set and Two Monte
Carlo Simulation Studies. Clin. Pharmacokinet., 45: 365-383, 2006.
And
Neely M, van Guilder M, Yamada W, Schumitzky A, and Jelliffe R: Accurate Detection of Outliers and
Subpopulations with Pmetrics, a Nonparametric and Parametric Pharmacometric Modeling and Simulation
Package for R. Therap. Drug Monit. 34: 467-476, 2012.
Then maybe you can correlate this with your BP data. You might also look at
Bleyzac N, Allard-Latour B, Laffont A, Mouret J, Jelliffe R, and Maire P: Diurnal Changes in the
Pharmacokinetic Behavior of Amikacin. Therap. Drug Monit. 22: 307-312, 2000.
As there may be diurnal changes in creatinine clearance, less when recumbent during the night,
greater when up and around during the day. Maybe this might also be the case with hepatic metabolism
as well.
Hope this is useful to you,
Roger Jelliffe
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