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Re: Outcome based evidence for merits of TCI/TDM

From: David H Salinger <salinger>
Date: Mon, 26 Mar 2007 10:08:54 -0700 (PDT)


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

On Mon, 26 Mar 2007, Nick Holford wrote:

> 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.
> "Bhattaram, Atul" wrote:
>> Hello Nick
>> Busulfan might be one example, although it was not done prospectively,
>> but it used the principles you were interested in during approval. I am
>> sure you would have heard about it before from Joga, Brian Booth et al.
>> Venkatesh Atul Bhattaram
>> Pharmacometrics
>> US Food and Drug Administration
>> "The contents of this message are mine personally and do not necessarily
>> reflect any position of the Government or the Food and Drug
>> Administration."
>> -----Original Message-----
>> From: owner-nmusers
>> On Behalf Of Nick Holford
>> Sent: Saturday, March 24, 2007 12:31 AM
>> To: pharmpk; nmusers
>> Subject: [NMusers] Outcome based evidence for merits of TCI/TDM
>> 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
> --
> Nick Holford, Dept Pharmacology & Clinical Pharmacology
> University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
> email:n.holford

Received on Mon Mar 26 2007 - 13:08:54 EDT

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