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:[EMAIL PROTECTED] tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/