Hepatic Clearance of Drugs in Patients With Renal Insufficiency

Renal function can be expected to influence total clearance of drugs whose principal route of clearance is renal excretion of the intact compound.1 Dosage of such drugs and/or the interval between doses are routinely modified or adjusted in relation to impairment of renal function. Recent attention has been given to the influence of renal function on hepatic clearance of drugs that are cleared mainly by hepatic biotransformation as opposed to renal excretion. Assuming that hepatic function as such is not impaired, the notion that renal function could affect hepatic drug clearance is counter-intuitive. Nonetheless, there is ample experimental evidence from animal studies and in vitro models that renal insufficiency may lead to impaired clearance of non-renally cleared drugs.2-5 Possible mechanisms include the accumulation of uremic toxins or inflammatory cytokines which in turn impair the expression or function of gastrointestinal and hepatic drug-metabolizing enzymes, and of various transport proteins. While the experimental data as such do not predict the situation in humans, a number of clinical studies nonetheless do confirm that renal insufficiency is associated with reduced clearance and increased systemic exposure of some non-renally cleared drugs.2-7 In the context of the drug development process, the American Food and Drug Administration (FDA) has taken a position expressed in the biomedical literature6, 7 and in draft guidance dated March, 2010. The guidance states: “… a PK study in patients with renal impairment should be considered for most drugs intended for chronic use.” This applies whether or not the drug or a principal metabolite is substantially eliminated renally, “… because renal impairment can inhibit some pathways of hepatic and gut metabolism and transport.” We recommend that the FDA's position needs ongoing evaluation and possibly revision. The guidance affects the development process for essentially all drugs, regardless of the route of clearance. Pharmacokinetic studies in patients with renal insufficiency are not nearly as straightforward as in healthy subjects, and we should be convinced that the resource allocation and risk associated with these studies are justified based on the public health benefit. The published data base on drug disposition in renal failure is vast. Authors of reviews on this topic do not necessarily consider the entire data base in formulating a position on clearance of non-renally cleared drugs in patients with renal insufficiency. Studies that show little or no effect of renal function on hepatic clearance may elude citation. By way of illustration, we reviewed published studies on the clearance of benzodiazepine derivatives in patients with renal insufficiency (Table 1). These drugs undergo minimal renal clearance, and are biotransformed by Cytochrome P450 (CYP) or glucuronosyl tranferase (UGT) enzymes. An important experimental proviso is the need to consider the influence of plasma protein binding (free fraction, FF) on the interpretation of pharmacokinetic data. Reduced protein binding of drugs (increased FF) in renal insufficiency has been recognized for decades,1, 19 and drug clearance values in renal failure patients may need to be “normalized” and expressed as free clearance.20, 21 Other methodologic questions include: Are renal failure patients on hemodialysis (which may removed uremic toxins)? Are renal patients taking medications that could impair drug clearance independent of renal function? Are renal patients and control subjects matched for age? With or without the provisos, none of the nine studies show a lower total clearance of the target drug in renal patients compared to controls. FF values in patients are higher than in controls. Even after normalization for differences in FF,21 free clearance in renal patients is significantly lower than that in controls in only two of the nine studies. In some cases, values in renal patients actually are higher than controls. It is of note that the glucuronide conjugates of oxazepam and lorazepam—presumed to be pharmacologically inactive—accumulate extensively in renal failure patients compared to controls.16, 18, 19 In a follow-up study of multiple-dose oxazepam, steady-state concentrations of unbound oxazepam in renal patients were identical to those in controls.19 An earlier study of lorazepam did not report clearance or free fraction, but elimination half-life was nearly identical between controls and renal patients.23 Finally, a recent study of alprazolam in hemodialysis patients did not report clearance or FF, and did not include a control group.24 The benzodiazepine studies raise the question of whether impaired nonrenal clearance of drugs in patients with renal insufficiency is common or usual (the “rule”) as opposed to uncommon (the “exception”). Further, even a statistically significant relation of renal function to drug clearance does not imply that the effect is of clinical importance—that will depend on the magnitude of the effect, and the therapeutic range of the target drug. In any case, the modification of therapeutic plans for renal failure patients is not a matter of kinetics alone. Such patients may be taking multiple medications, be generally debilitated, or have intrinsically altered sensitivity to certain drugs. We encourage ongoing discussion of a regulatory position that both encourages drug development and assures patient welfare. There are no disclosures to declare. —David J. Greenblatt Editor-in-Chief Tufts University School of Medicine 136 Harrison Avenue, Boston, Massachusetts 02111, USA (email: [email protected])