CKD

CKD is a progressive decline in GFR such that kidney function is reasonably stable over weeks or months. Drug absorption from the gastrointestinal tract may be highly variable in patients with CKD. Although it is commonly thought that absorption decreases in edematous states because of gut wall edema, animal and human studies indicate that drug absorption may actually increase because of impairment of the gut wall barrier function or a decrease in function and/or expression of efflux transporters, such as P-glycoprotein (10). Furthermore, for drugs with a low bioavailability because of hepatic first-pass metabolism, the decrease in cytochrome-P (CYP) 450 enzyme and transporter activity (see part 1 [2]) may increase bioavailability. For example, significant increases in both the area under the concentration-time curve and Cmax have been demonstrated for both dihydrocodeine and repaglinide in patients with advanced CKD (Figure 4) (11,12). It is important to be cognizant of this phenomenon when prescribing these and other drugs. However, it is not clear how applicable these data are to other patients, so increased monitoring is required. The complexities of interpreting changes in area under the concentration-time curve and Cmax with regards to reduced clearance or increased bioavailability are discussed in part 1 of this series (2).

An expansion in Vd is reported with advanced CKD because of subsequent fluid retention, hypoalbuminemia, and decreased protein binding. However, Vd may also decrease in the context of sarcopenia, which is more common with advanced CKD. Overall, the change in Vd from interdialytic weight gain is low relative to total body water and is not clinically significant. The effect of severe edema on Vd is inconsistent, with studies finding that Vd could either double (13) or remain unchanged (14) in the setting of marked extracellular fluid expansion. Fluid overload is more likely to affect the Vd of hydrophilic drugs (for example, aminoglycoside, β-lactam, and glycopeptide antibiotics) compared with lipophilic drugs, but these rules are not always applicable.

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The decrease in GFR with CKD decreases kidney drug clearance. A practical approach to adjusting drug doses in CKD is to assume that kidney drug clearance will decrease in proportion to GFR, and that nonkidney clearance is unchanged (see Figure 2 in part 1 [2]). However, this otherwise convenient approach is limited by changes to nonkidney clearance that occur with kidney disease and are difficult to quantify at the individual level (2). It also ignores the role of intact kidney tubules in the handling of many drugs and that tubular elimination likely increases relative to glomerular clearance in some types of kidney disease. For example, kidney clearance is 25% lower in patients with CKD involving tubular dysfunction relative to those with isolated GN (15).

In patients with GN, proteinuria, and hypoalbuminemia but creatinine clearance (CrCL) >90 ml/min, apparent clearance of fexofenadine (substrate of P-glycoprotein and other transporters) is decreased 40% compared with healthy controls with a comparable GFR (16). Further, the elimination t1/2 of fexofenadine is prolonged in patients with GN compared with patients with ESKD and healthy controls, suggesting an increased Vd with GN (16). Yet, flurbiprofen (CYP2C9 substrate) had similar pharmacokinetics in patients with GN and CrCL>90 ml/min as in patients with ESKD. Rosiglitazone clearance is increased three-fold in patients with FSGS and nephrotic-range proteinuria despite normal eGFR, compared with healthy controls (17). Therefore, it is not possible to generalize these findings of altered pharmacokinetics to patients with different GFRs, kidney diseases, or other drugs, but the general principles are summarized in Tables 2 and ​and33.

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