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The following message was posted to: PharmPK
Hi,
I have been asked by a statistician colleague to provide some clear
cut examples of the benefit of dosing individualization using drug
concentration measurements (i.e. target concentration intervention
(TCI aka TDM (Holford 1999)).
The best example I know is the work of Bill Evans and colleagues at
St Judes who demonstrated a substantial 5 year survival benefit in
children with acute lymphatic leukaemia by using concentration
measurements to individualize the dose (Evans et al. 1998).
Can anyone propose further examples where TCI has been demonstrated
to improve beneficial clinical outcome of the type and magnitude that
would typically be required to support proof of effectiveness for
regulatory purposes?
I am particular interested in examples showing improved clinical
outcome benefit but if you know of examples that demonstrate reduced
toxicity with no loss of clinical benefit then I'd like to hear of
these too. We are not trying to find examples where TCI has been
shown to benefit changes of biomarkers (e.g. serum creatinine). The
endpoint must be a clinical outcome that the patient would be aware of.
Thanks,
Nick
Holford NHG. Target Concentration Intervention: Beyond Y2K. Br J Clin
Pharmacol. 1999;48:9-13.
Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH.
Conventional compared with individualized chemotherapy for childhood
acute lymphoblastic leukemia. N Engl J Med. 1998 Feb 19;338(8):499-505.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Hi Nick:
Some examples related to aminoglycoside therapy include:
1. Zaske et al, Increased burn patient survival with individualized
dosages of
gentamicin. Surgery 91:142-149, 1982
Reports that:
Patients treated with conventional dosing: survival rate - 33%
Patients treated with individualized dosing: survival rate - 64%
2. Destache-CJ; Meyer-SK; Rowley-KMAD: Ther-Drug-Monit. 12(5):
419-426, 1990
Reports that: Patients followed by PK service demonstrated shorter
hospitalizations (320h
v. 440h; p = 0.087) and shorter febrile periods (50h v. 92h;
p<0.05).
3. Burton, et al., A controlled trial of the cost benefit of
computerized bayesian
aminoglycoside administration. Clin Pharmacol Ther 49:685-94, 1991.
Reports that:
Patients dosed by "physician choice" (n=75) resp rate: 48%,
toxicity: 9.7%,
hospital stay: 20.3days
Patients dosed by PK-based individualization (n= 72) response
rate: 60%, toxicity: 5.1%,
hospital stay: 16.0days.
Note: differences in response rate and hospital stay were
statistically
significant.
- Joe
--
Joseph P. Balthasar, Ph.D.
Associate Professor & Director of Graduate Studies
457B Cooke Hall
Department of Pharmaceutical Sciences
School of Pharmacy and Pharmaceutical Sciences
University at Buffalo
The State University of New York
Buffalo, New York 14260
Telephone: 716-645-2842 x270
CoE: 716-881-7542
Fax: 716-645-3693
website: http://www.acsu.buffalo.edu/~jb/
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Several aminoglycoside articles were reported around 1990. My
articles published in Ther Drug Monit were a prospective cost-benefit
study of patients receiving an aminoglycoside for proven or suspected
Gram-negative infection. Patients were randomized to Pharmacokinetic
Service monitoring or physician monitoring (standard of care at the
time at our institution). I used Roger Jelliffe's USCPC Pack
Bayesian pharmacokinetic software to monitor all patients in the
Pharmacokinetic Service group. I was able to demonstrate that the
Pharmacokinetic Service showed an improvement in length of stay, time
to afebrile period, and a reduction in number of patients who
developed aminoglycoside-associated nephrotoxicity (defined as a rise
in serum creatinine of > 0.5 mg/dl).
I also had physicians who did not accept Pharmacokinetic Service
recommendations 100% of the time and I statistically analyzed these
two groups of patients. This also was reported in Ther Drug Monit
issue. Also Dr. Balthasar's comments regarding Mike Burton's article
in CP&T documents improved outcomes when using Bayesian software also.
Let me know if you would like a copy of these manuscripts and I will
send you the PDFs.
Thanks
Chris Destache, Pharm. D., FCCP
Professor of Pharmacy Practice and Internal Medicine
Creighton University
Omaha, NE 68178
402 280 4744
email: destache.-a-.creighton.edu
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The following message was posted to: PharmPK
Atul,
Thanks for reminding me of this study which I have heard Brian Booth
describe at AAPS. It is good to see it in print (Booth et al 2007).
The busulphan study is primarily a pop PK analysis with simulations
based on the parameter estimates which indicate that covariate based
dosing is inadequate to reduce the variability of busulphan
concentrations sufficiently so that that variability is less than or
equal to the safe and effective variability. See Holford 1999 for a
definition of this term and Matthews et al. 2004 for a quantitative
real life example.
The merits of TCI are reviewed as discussion points but there is not
any evidence e.g. by simulation, that TCI would indeed have any
practical benefit. The finding of within subject variability in
clearance of 10% is certainly encouraging but that is just a
necessary condition (Holford 1999) before embarking on further
studies (including simulations) to demonstrate that TCI could be
practical and effective.
I am personally a believer in PK models and the benefits of TCI. The
busulphan case would certainly convince me to use it if I was
responsible for patients who needed treatment with this drug.
However, I am looking for evidence to convince my statistician
colleague who may not be such a believer as we are that PK modelling
is the source of truth :-)
Nick
Booth BP, Rahman A, Dagher R, Griebel D, Lennon S, Fuller D, et al.
Population pharmacokinetic-based dosing of intravenous busulfan in
pediatric patients. J Clin Pharmacol. 2007 Jan;47(1):101-11.
Holford NHG. Target Concentration Intervention: Beyond Y2K. Br J Clin
Pharmacol. 1999;48:9-13.
Matthews I, Kirkpatrick C, Holford NHG. Quantitative justification
for target concentration intervention - Parameter variability and
predictive performance using population pharmacokinetic models for
aminoglycosides. British Journal of Clinical Pharmacology. 2004;58
(1):8-19.
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The following message was posted to: PharmPK
Nick,
Cyclophosphamide dose adjustment work may provide an example of what
you are
looking for. McDonald et al. (2005) compares a non-compartmental
approach to a MAP Bayesian approach backed by a 4 compartment model
(CY, two metabolite
compartments and a compartment to facilitate modeling inducible
clearance).
Salinger et al. (2006) implement the MAP approach in R to provide a
framework
for real-time adjustment of 2nd dose based on metabolite
concentrations over 16 hours the from first dose. In that paper (Fig
3.) you can see a nearly 10-fold variability in peak concentration of
metabolite CEPM from a standard
weight-normalized first dose. High AUC of CEPM is associated with
toxicity
risk. Suggested subsequent doses (to control CEPM AUC) have also
shown a
nearly 10-fold range. Further work is ongoing.
de Jonge et al. 2005 provides another example of PK guided dosing
reducing
toxicity of cyclophosphamide, thiotepa and carboplatin. They report
that 85%
of targeted doses resulted in exposures within 25% of target, as
opposed to 60% without dose adjustment.
McDonald GB, McCune JS, Batchelder AL, et al. Metabolism-based
cyclophosphamide
dosing for hematopoietic cell transplant. Clinical Pharmacology and
Therapeutics. Clinical Pharmacology Therapeutics 2005;78:298-308
Salinger DH, McCune JS, Ren AG, Shen DD, Slattery JT, Phillips B,
McDonald GB
and Vicini P. 2006. Real-time dose adjustment of cyclophosphamide in a
preparative regimen for hematopoietic cell transplant: a Bayesian
pharmacokinetic approach. Clinical Cancer Research 12:4888-4898
de Jonge ME, Huitema AD, Tukker AC, van Dam SM, Rodenhuis S, Beijnen JH.
Accuracy, feasibility, and clinical impact of prospective Bayesian
pharmacokinetically guided dosing of cyclophosphamide, thiotepa, and
carboplatin in high-dose chemotherapy. Clin Cancer Res 2005;11:273-83
David Salinger
RFPK, Dept. of Bioengineering,
Univ. of Washington, Seattle
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The following message was posted to: PharmPK
I strongly recommend the paper of Alexander ATMM Vinks
(van Lent-Evers et al. Impact of goal-oriented and
model-based clinical pharmacokinetic dosing of
aminoglycosides on clinical outcome: A
cost-effectiveness analysis) published in Therapeutic
Drug Monitoring 21:63-73(1999).
You can find out the impact of active therapeutic drug
monitoring on real therapeutic endpoints such as
lengths of febrile period and hospital stay and
mortality as well. The performed pharmacoeconomic
analysis provides data of supportive value.
Regards,
Dimiter T.
--
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
Tel:(+ 359 2)8510639;(+ 359 2)9522293.
Fax:(+ 359 2)8519309. e-mail: dterziivanov.-a-.rilski.com;
terziiv.-a-.yahoo.com
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The following message was posted to: PharmPK
Dimiter,
Thanks. Sander has already told me of this study. Unfortunately while
it may be convincing evidence to you and me the unblinded design
using a historical control means that it is not in the same category
of rigorous clinical outcome based evidence of effectiveness of TCI
that I am seeking.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Dimiter,
Thanks. Sander has already told me of this study. Unfortunately while
it may be convincing evidence to you and me the unblinded design
using a historical control means that it is not in the same category
of rigorous clinical outcome based evidence of effectiveness of TCI
that I am seeking.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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