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Re: Outcome based evidence for merits of TCI/TDM (fwd)

From: Nick Holford <n.holford>
Date: Wed, 28 Mar 2007 10:53:54 +1200

Jeannine,

Thanks for your suggestions. Busulphan was already proposed based on a recent paper by Booth et al. which showed by simulation that covariates alone were insufficient to achieve target concs in children and proposed that TCI should be helpful. [There is a parallel thread on pharmpk]

But I am looking specifically for TCI trials that would fulfill the criteria that would be used for approving a new drug in terms of showing clinical outcome effectiveness (not biomarker changes). Most of the examples that have been proposed to me so far have failed on one of the criteria of being double blind randomized and prospective. I realise that there is a weight of other evidence (there are journals like Therap Drug Monit that are devoted to this) but I am specifically trying to find rigorous examples.

The review of randomized concentration controlled trials by Holger Kraiczi et al. has some examples.

I will take a look at the papers you cite but from your knowledge of the area do you know of any double blind randomized and prospective trials of TCI vs traditional or RCCT trials of busulphan?

Nick

1. 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.
2. Kraiczi H, Jang T, Ludden T, Peck CC. Randomized concentration-controlled trials: motivations, use, and limitations. Clin Pharmacol Ther. 2003 Sep;74(3):203-14.


"Jeannine S. McCune" wrote:
>
> Hi Nick -
>
> I'd suggest you provide the example of busulfan TCI/TDM for your statistician colleague. There are numerous manuscripts demonstrating the pharmacodynamic relationships of busulfan AUC with either toxicity (sinusoidal obstruction syndrome) or efficacy (rejection or relapse) in patients receiving busulfan/cyclophosphamide conditioning prior to hematopoietic cell transplant. Notably, there are differences in the PD relationships based on the conditioning regimen and underlying malignancy which have taken 20+ years to demonstrate because of the relative paucity of homogenous populations in which intensive sampling can be performed. I listed a couple reviews below that you can provide.
>
> In terms of the practical benefit, I agree that busulfan TCI was slowly accepted into practice (the first PD studies were in the early 1990s) but it has been rapidly gaining in use over the past 5 years. I have 3 full time technical staff plus myself part-time as the clinical director dedicated solely to busulfan TCI. We have 50+ transplant centers for which we provide this service. The recent increase in its use has been due to TCI of IV busulfan, of which there is a debate about whether or not it truly does have less interpatient variability than the oral formulation. Presently, we're doing either noncompartmental or compartmental pharmacokinetic modeling in WinNONLIN. However, based on our success with cyclophosphamide (which Dave Salinger described yesterday), we're keenly interested in determining if popPK model with limited kinetic samples can be of benefit for busulfan TCI.
>
> I am new to the list so I didn't want to give too many details. Please tell me if you need any additional references or insight into the use of busulfan TCI.
>
> All the best,
>
> Jeannine McCune, PharmD
> Associate Professor, University of Washington
> Affiliate Investigator, Fred Hutchinson Cancer Research Center
> Clinical Director, SCCA Pharmacokinetics Laboratory
>
> Grochow LB. Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. Semin Oncol. 1993 Aug;20(4 Suppl 4):18-25; quiz 26.
> (Note - clearly shows that TCI reduces VOD)
>
> McCune JS, Gibbs JP, Slattery JT. Plasma concentration monitoring of busulfan: does it improve clinical outcome? Clin Pharmacokinet. 2000 Aug;39(2):155-65.
> (Note - review of oral bu/cy regimen PD relationships)
>
> Radich JP, Gooley T, Bensinger W, Chauncey T, Clift R, Flowers M, Martin P, Slattery J, Sultan D, Appelbaum FR. HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood. 2003 Jul 1;102(1):31-5. Epub 2003 Feb 20. (Note - shows that TCI decreases relapse rates)
>
> Aggarwal C, Gupta S, Vaughan WP, Saylors GB, Salzman DE, Katz RO, Nance AG, Tilden AB, Carabasi MH. Improved outcomes in intermediate- and high-risk aggressive non-Hodgkin lymphoma after autologous hematopoietic stem cell transplantation substituting intravenous for oral busulfan in a busulfan, cyclophosphamide, and etoposide preparative regimen. Biol Blood Marrow Transplant. 2006 Jul;12(7):770-7.
>
> ---------- Forwarded message ----------
> Date: Mon, 26 Mar 2007 11:25:50 -0700 (PDT)
> From: David H Salinger <salinger
> To: Jeannine S McCune <jmccune
> Subject: Re: [NMusers] Outcome based evidence for merits of TCI/TDM (fwd)
>
> Hi Jeannine,
>
> Nick Holford posted to the NONMEM listserve asking for examples showing the
> benefit of dose individualizations using concentration measurements. He was
> particularly interested in examples showing improved clinical outcomes, but
> also interested e.g. in examples showing reduction in toxicity. Below is my
> reply... I thought you might be interested.
>
> Dave
>
> ---------- Forwarded message ----------
> Date: Mon, 26 Mar 2007 10:08:54 -0700 (PDT)
> From: David H Salinger <salinger
> To: Nick Holford <n.holford
> Cc: nmusers <nmusers
> Subject: Re: [NMusers] Outcome based evidence for merits of TCI/TDM
>
> 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
>
> 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
> >> 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/
> >

--
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 Tue Mar 27 2007 - 18:53:54 EDT

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