Re: signficant covariate question

From:Nick Holford Subject:Re: [NMusers] signficant covariate question Date:Wed, 09 Oct 2002 08:24:43 +1300 Peter, In collaboration with Ivan Mathews and Carl Kirkpatrick I have recently examined this issue with a large aminoglycoside PK dataset. 56% of overall variability in clearance was predictable from serum creatinine, age, sex and weight (Cockcroft & Gault model), 36% was unexplained between subject variability and 8% was within subject (between occasion) variability. A study of topotecan in cancer patients was able to assign 47% of overall variability in clearance using the same covariates to predict renal clearance (plus a clinical performance index (ECOG) on non-renal clearance) (Mould DR, Holford NHG, Schellens JHM, et al. Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. Clinical Pharmacology & Therapeutics 2002;71:(5)334-348 ). So I think this about as good as you can get. Aminoglycosides are excreted ~90% in the urine. Prediction of renal clearance from creatinine clearance is an unusually strong mechanistic covariate model. But its still not one "silver bullet" covariate because you need serum creatinine, age, weight and sex in most cases to predict creatinine clearance. Nick Nick Holford, Divn Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/ ___________________________________