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Dear All
I've been developing PK-PD models (using NONMEM/WinNonlin) for about 10 years. Our group also now has interests in quantifying toxicokinetics. I have never before worked with TK data so I would be very grateful for some guidance on possible approaches to data analysis and what limitations should be expected. We are still refining our protocols but we plan to collect blood and urine samples from hospital paediatric patients to measure parent and metabolite concentrations. We are interested in biological concentrations of phthalate plasticisers leached from PVC medical devices. We will collect samples from patients on admission (for baseline concentrations) and at various times points after exposure to plastic-containing products. I anticipate that we will have limited numbers of samples (particularly of blood) but will be able to sample from reasonable numbers of patients. For some patients (non-elective) we may only have post-exposure samples.
I'd be very grateful for your thoughts, suggestions and advice on any of the following matters:
1) What kind of analytical approach might be suitable for these types of data? 2) Are there any software packages that you'd recommend (instead of NONMEM?) for working with TK data of this type?
3) Can anyone recommend specific reading material or papers on this topic?
Thoughts, comments or suggestions on any other aspect also gratefully received J
With thanks and all best wishes
Ann
--
Ann Rigby-Jones PhD MRSC
Research Fellow in Pharmacokinetics & Pharmacodynamics
Aneasthesia Research Group
Peninsula College of Medicine & Dentistry, Plymouth, UK
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The following message was posted to: PharmPK
Dear Ann,
GastroPlus handles this type of analysis, allowing you to fit models using
all of your data, including multiple metabolites, and metabolites of
metabolites, etc. to any level.
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-at-.simulations-plus.com
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The following message was posted to: PharmPK
Hi Ann
TK = PK
Hope this helps. We have analysed a few "TK" datasets and essentially they are just PK with some subtle differences relating to guessing dose and time of dose.
Steve
--
Stephen Duffull.
[I've always thought of TK as PK at higher doses, thus non-linar kinetics may be more prevalent. However, if you are looking for trace materials, as Steve says TK = PK (but with more sensitive assays). - db]
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Dear Ann,
Out of interest:
1. How do you intend to determine or estimate the input parameters for phthalate intake (dose, frequency, duration, etc.)?
2. How will you be sure measured phthalate is coming from the medical devices and not from other sources?
3. What biological parameter(s) or endpoint(s), if any, will you use to relate to the TK (i.e. TK-TD)?
Best wishes,
Frederik Pruijn
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Hi Ann
I agree with Steve that TK=PK.
Attached are couple of articles which may help
Kumar VV etal, The effect of decontamination on the pharmacokinetics of venlafaxine in overdose, CPT, 2009,86(4), 403-410.
Isbister GK etal, Pharmacokinetics of quetiapine in overdose and effect of activated charcoal, CPT, 2007,81(6),821-827.
Best
Pavan
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The following message was posted to: PharmPK
Dear Ann !
Toxicokinetics (TK) can be regarded as an expansion of PK as it is rather unrealistic assuming similar PK processes with toxicological doses than with therapeutic doses as the ability of the body to cope with a compound is extended to the limit (Welling, 1995).
Welling PG (1995). Difference between Pharmacokinetics and Toxicokinetics. Toxicol Pathol 23(2):143-147.
These types of studies are frequently performed using incomplete sampling designs due to restrictions in blood volume (i.e. serial sampling or batch designs). In the case that you are interested in estimating and comparing systemic exposure you may find the following papers of interest.
Jaki T and Wolfsegger MJ. Estimation of pharmacokinetic parameters with the R package PK. Pharmaceutical Statistics, published online ahead of print. DOI:10.1002/pst.449.
Jaki T, Wolfsegger MJ, Lawo J-P (2010). Establishing bioequivalence in complete and incomplete data designs using AUCs. Journal of Biopharmaceutical Statistics, 20(4):803-820. DOI:10.1080/10543401003618835.
Wolfsegger MJ and Jaki T (2009). Assessing systemic drug exposure in repeated dose toxicity studies in the case of complete and incomplete sampling. Biometrical Journal, 51(6):1017-1029. DOI:10.1002/bimj.200900151.
Wolfsegger MJ and Jaki T (2009). Non-compartmental estimation of pharmacokinetic parameters in serial sampling designs. Journal of Pharmacokinetics and Pharmacodynamics, 36(5):479-494. DOI:10.1007/s10928-009-9133-9.
Jaki T and Wolfsegger MJ (2009). A theoretical framework for estimation of AUCs in complete and incomplete sampling designs. Statistics in Biopharmaceutical Research, 1(2):176-184. DOI:10.1198/sbr.2009.0025.
Jaki T, Wolfsegger MJ, Ploner M (2009). Confidence intervals for ratios of AUCs in the case of serial sampling: A comparison of seven methods. Pharmaceutical Statistics, 8(1):12-24. DOI:10.1002/pst.321.
best regards
martin
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The following message was posted to: PharmPK
Dear Frederik
Many thanks for your interest in our work and for your questions, which I will attempt to answer below :-)
1. How do you intend to determine or estimate the input parameters for phthalate intake (dose, frequency, duration, etc.)?
There are published works describing estimation of phthalate doses from the measurement of urinary metabolites (e.g Koo et al, 2002:110(4). Environmental Health Perspectives). Additionally, we will be noting times and duration of exposure to PVC-containing medical devices. We have conducted laboratory studies quantifying the kinetics of phthalate leaching from typical PVC infusion lines which again will help to inform our estimates of dose.
2. How will you be sure measured phthalate is coming from the medical devices and not from other sources?
This is difficult with a ubiquitous substance as you point out. Where possible, we will be collecting samples before patients have undergone medical procedures to establish baselines concentrations resulting from general environmental exposure. By measuring secondary metabolites, we can be sure that these have come from the patient. There is always the possibility that the parent compound and the primary metabolite (which can also occur via degradation) may result from contamination.
3. What biological parameter(s) or endpoint(s), if any, will you use to relate to the TK (i.e. TK-TD)?
Again, another very good question! We are interested primarily in the endocrine disrupting nature of the compounds. We are fortunate to have colleagues at our University with great expertise in this area. Currently we are focussing on the TK with the view that when we are informed of the biological concentrations that our patients may be exposed to, we can then try to determine the biological significance of this exposure.
All best wishes
Ann
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