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The following message was posted to: PharmPK
Kindly adivice:
1. I am doing a study that requires collecting blood samples from
patients taking nevirapine 200mg bd.
2. I need to determine nevirapine trough concentrations by collecting
the blood sample 12 hours after dose.
3. These patients have been counseled to take their medication at 7pm
in the evening and at 7 Am in the morning.
4. I can only recruit them when they come to the clinic for follow up
and this happens when they have already taken their morning dose.
5. Please advice on which other blood sampling time that can be used
other than trough?
Best regards,
margaret
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Hi Margaret
You can use a sparse sampling approach with Bayesian estimation.
There are several publications on the population pharmacokinetics of
nevirapine (for example see Br J Clin Pharmacol 2002; 54: 378-385).
Regards,
Thomas Kakuda, Pharm.D.
Director, Clinical Pharmacology
Tibotec, Inc.
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Margaret,
You have omitted an important piece of information -- why are you
measuring nevirapine concentrations? What are you hoping to learn from
these measurements? Why do you say you 'need to determine trough
concentrations'?
Some possible reasons:
1. To check on compliance.
It really makes little difference when you take the sample as long as
you know the time in relation to the dose. You can then use this time
with previous PK studies of nevirapine to decide if the patient is
compliant.
2. To estimate individual nevirapine exposure (e.g. average steady
state conc) so that you can do a pharmacodynamic study.
An individual clearance estimate (see below) can then be used with the
patient's dose rate to predict the average steady state conc.
3. To adjust the patient's dose to achieve a target nevirapine conc.
Bayesian methods (see below) can be used to estimate individual PK
parameters (primarily clearance) and this can then be used to predict
the dose rate needed to reach the target conc.
Bayesian methods can be used to predict individual clearance (within
the limits of within subject variability -which is about 20% for
nevirapine (see de Maat et al. 2002)). This can be done with NONMEM or
TCIworks
http://www.tciworks.info/
1. de Maat MMR, Huitema ADR, Mulder JW, Meenhorst PL, van Gorp ECM,
Beijnen JH. Population pharmacokinetics of nevirapine in an unselected
cohort of HIV-1-infected individuals. Br J Clin Pharmacol. 2002;54(4):
378.
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.aaa.auckland.ac.nz
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You can use D-optimality approach to get the most informative time
points for blood sampling.
I recommend to use either of the two available softwares with
validated performance: USCPACK and WinPOPT.
Regards,
Dimiter Terziivanov, MD,PhD,DSc, Professor and
Head, Clinic of Clinical Pharmacology and Pharmacokinetics,
Univ Hosp "St. Ivan Rilski",
15 Acad. Ivan Geshov st, 1431 Sofia, Bulgaria
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The following message was posted to: PharmPK
Dear margaret,
The easy way is to call the patients and ask them to come early (7:00
am) to the clinic and not to take the morning medication, for blood
collection, and then take the morning dose after. You should record
the time of last dose and the time of blood sampling to use it in your
calculations. I hope this will help you.
Regards,
Mahasen A. Radwan, Ph.D.
Professor of Clinical Pharmacy
Dept. of Clinical Pharmacy
College of Pharmacy
King Saud University
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7 pm just before dosing and 7 am just before dosing, Increase the
compensation to improve compliance. And that they come in for
collection.
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Dear All and Dimiter:
Your argument is correct, but there is no D-optimal design package
in the MM-USCPACK software collection. However, Dave D'Argenio made
one for
me, years ago, based on the Adapt software. It is user-hostile and I
have to
walk you through it, because the words that are there mean different
things.
Once this is done, though, it is easy, and I can send it to anyone who
would
like it. Dave also has a module in his Adapt software which is very
probably easier to use.
All the best to all,
Roger
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Dear All,
I agree with Nick, it should be an indication for drug measurement,
most importantly responder versus nonresponder subjects to the drug!
Prof. Ehab ELDesoky.
Professor of pharmacology
Faculty of Medicine
Assiut University,
Assiut. Egypt
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Dear Margaret,
Besides Bayesian methods, another option is determination of
antiretroviral drug concentrations in dried blood spots (e.g. Koal et al
Rapid Commun Mass Spectrom. 2005;19(21):2995-3001, ter Heine et al J
Chromatogr B Analyt Technol Biomed Life Sci. 2008 May 15;867(2):205-12).
It allows non-hospital based sampling, for example for self-sampling.
However, I don't really see the point of measuring "pure" trough levels.
There is not really a strong PK-PD relationship in the therapeutic
concentration range of nevirapine. What is the purpose of your study?
This should guide your sampling strategy.
Sincerly,
Rob ter Heine
---
Rob ter Heine, PhD, PharmD
Meander Medical Center, hospital Pharmacy
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The following message was posted to: PharmPK
Thanks prof Holford.
1-The aim of the study is to perform a population PK study to estimate
the steady state plasma levels of nevirapine in HIV patients in our
population which has not been determined.
2-We shall then relate the drug levels to clinical outcomes of
nevirapine based HAART.
3- Thanks very much for the publication.
Best regards,
margaret
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Margaret,
If you are planning a pop PK study then you should certainly take a
look at using WinPOPT (as suggested previously in this thread).
WinPOPT is free and relatively simple to use. I don't know where you
are based but if by chance you are in South Africa then you might want
to visit the Clinical Pharmacology group at UCT who have experience in
using WinPOPT and pop PK studies of ART drugs.
If you are primarily interested in estimating CL in order to predict
average steady state concs then a conc taken around the middle of the
dosing interval is a much better choice than a trough conc.
Trough samples are usually a bad idea for pop PK studies (See Lee 2001
from the FDA pharmacometrics group). Its much better to have some
variation in timing relative to the dose. WinPOPT can help you with
this if you are trying to estimate a PK model with absorption,
distribution and elimination parameters.
Nick
Lee PID. Design and power of a population pharmacokinetic study. Pharm
Res 2001; 18: 75-82.
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The following message was posted to: PharmPK
Dear Margaret,
If you're going to perform population PK analysis you'll preferably need
observations during the complete dosing interval and not a single
timepoint, and preferably at multiple occasions. A lot of work has been
performed on the population PK of nevirapine, so it's easy to determine
the optimal sampling design.
However, unless you expect lower than normal plasma concentrations which
would make it unethical to perform the study, do you really expect a
PK-PD relationship in the relevant concentration range of nevirapine?
Are you aware of these papers?
Pharmacokinetic parameters of nevirapine and efavirenz in relation to
antiretroviral efficacy. - v Leth et al - AIDS Res Hum Retroviruses.
2006 Mar;22(3):232-9., concluding "...that identifying the Cmin value
for the sole purpose of predicting virologic failure in patients who
report to be adherent to NVP or EFV is questionable because of the
absence of a concentration-response relation (NVP) or the low
sensitivity for such a cutoff value (NVP and EFV)."
Are adverse events of nevirapine and efavirenz related to plasma
concentrations? - Kappelhoff et al - Antivir Ther. 2005;10(4):489-98.
Concluding "Pharmacokinetic parameters of NVP did not have a
relationship to AEs in the 2NN trial when corrected for known
covariates. "
Sincerely,
Rob
--
Rob ter Heine, PhD, PharmD
Meander Medical Center, hospital Pharmacy
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Dear Prof Holford,
1-Thanks very much for the invaluable advice. Iam based in Kenya at
the University of Nairobi.
2- One of my colleagues Dr Faith Okalebo has the UCT connection where
she did her PhD, so will follow up with her to make the contacts for
the WinPOPT program and to finetune the study dasign.
3- Sampling around the middle of the dosing interval would suit my
study since the patients will bw at the clinic during the day atfer
their morning dose and before the evening dose.
4. Faith, This is an ongoing discussion on the design of the NVP study.
5. Its supposed to be a population PK study to estimate the steady
state concentrations of Nevirapine in HIV patient population and to
relate this to clinical outcomes and elucidate risk factors.
6- Faith kindly follow the discussion and make the contacts at UCT for
further support paticularly on the details of the design use of the
winPORT prg.
Best Regards,
margaret
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