Re: Renal function as a covariate

Dear Nick, Thank you for your extensive reply. I agree with your view, but I still have two comments. > There is a problem with the method you propose of using non-size standardized > CLCR to account for a component of clearance. Even if there is no renal > elimination of a drug, then if there is a reasonable distribution of size in > the sample being studied, then THETA(3) may appear to be different from zero > because it reflects differences in size not just renal function. I don't understand this. In this case there is no information about THETA(3) in the data, so any value should be considered suspicious, and I don't think that your approach will avoid this. If CLCR is reported in mL/min, why do any conversion to this value to get CL? Consider a drug A that has the same PK properties as creatinine. Assuming that CLCR (in mL/min, or L/h) has been estimated accurately (which cannot be true, but that is another discussion). Then the renal clearance of drug C is equal to CLCR. For modeling and dosing purposes, no further conversion is required. For any other drug B, assuming that its renal clearance is proportional to CLCR, the renal clearance is THETA(3) * CLCR, where THETA(3) is a proportionality factor, which, in my view, is expected to be independent of size, weight etc. This is more straightforward than your approach, avoiding unnecessary conversions. best regards, Hans 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]