Re: Time-varing covariate and renal function as a covariate

Dear Matt, I'm not quite sure that I fully understand your question. I would say that a changing renal function and a changing weight over time can be handled as described earlier by Nick Holford, or by the modified approach I suggested. An important point is how to express renal function. Nick's method implies that 'size' should be excluded from 'renal function', so CLCR needs to be normalized / standardized, e.g. using CLCR in ml/min/1.73m2. Now, CLCR is a 'pure' measure of the kidney function (of course, we know that its precision is rather poor, but that is a different topic, interesting as well!). The factor WEIGHT^0.75 deals with the factor 'size'. This approach treats CLCR as a covariate similar to other covariates, making it more suitable for a standardized approach for covariate analysis. In the approach proposed by me, CLCR should be the 'individual's renal clearance of creatinine', so it should expressed in ml/min (or converted to e.g. l/h), and it should not be normalized / standardized. Here, CLCR includes both kidney function and size (in Nick's view a disadvantage, in my view an advantage), and the renal part of the equation does not need further modification to take 'size' into account. This approach treats CLCR as a 'special' covariate, directly related to the renal clearance of the drug. This may be advantageous for clinical purposes, e.g. dose calculation and therapeutic drug monitoring. In my view, both approaches have advantages and disadvantages. best regards, Hans Proost Johannes H. Proost Dept. of Pharmacokinetics, Toxicology and Targeting University Centre for Pharmacy Antonius Deusinglaan 1 9713 AV Groningen, The Netherlands tel. 31-50 363 3292 fax 31-50 363 3247 Email: [email protected] ----- Original Message -----