Re: Renal function as a covariate

On 27/08/2013 9:56 a.m., J.H.Proost wrote: > 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. Think about the simpler case when a drug is eliminated totally by metabolism. A triple blind (double blind to treatment assignment and blind to biology) empirical statistician might try this to 'test' if renal function describes differences in clearance with this model: CL = THETA(1)*CLCRCG * EXP(ETA(1)) Because CLCRCG is actually CLCRstd*WT/70 then the random differences in CLCRstd which do not explain CL will be added to the between subject variability defined by the distribution of ETA(1). The WT/70 part of CLCRG is then equivalent to writing: CL = THETA(1)*WT/70 * EXP(ETA(1)) Because CL necessarily increases with size then this model will improve the objective function value because of the inclusion of WT as a fixed effect covariate. There will also be an increase in the variance of ETA(1) because ETA(1) is now describing the BSV not related to renal function plus the variability in renal function which is also not related to CL. This will probably also improve the OFV. > 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. Your approach makes the assumption that the clearance defined by CLCR is appropriate for drug clearance. Recall that clearance is a proportionality factor that depends on concentration. If CLCR is predicted relative to serum (the usual case) then it will not be appropriate to predict CL which is being described in terms of say blood clearance or unbound clearance, especially if there are concentration dependent differences in the ratio between blood conc and serum or unbound conc and serum. In my opinion a better approach is to transform covariate effects into dimensionless quantities whenever possible so that the fundamental parameters of the model are not confounded with the units of the covariate. Your approach may seem straightforward but it mixes apples with oranges. The same approach using WT has led to generations of clinicians thinking that clearance is higher in children than in adults because they did not understand that using a linear function of WT to predict clearance is biologically wrong. > 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] -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 mobile:NZ +64(21)46 23 53 FR +33(7)85 36 84 99 email:[email protected] http://holford.fmhs.auckland.ac.nz/ Holford NHG. Disease progression and neuroscience. Journal of Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 http://link.springer.com/article/10.1007/s10928-013-9316-2 Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013: http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html Holford NHG. Clinical pharmacology = disease progression + drug action. British Journal of Clinical Pharmacology. 2013: http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract