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Re: Outcome based evidence for merits of TCI/TDM

From: Nick Holford <n.holford>
Date: Mon, 26 Mar 2007 01:16:27 +1200

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
> http://www.health.auckland.ac.nz/pharmacology/staff/nholford/

--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
Received on Sun Mar 25 2007 - 09:16:27 EDT

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