Clinical Pharmacokinetics in Kidney Disease: Application to Rational Design of Dosing Regimens

Abstract

A change in pharmacokinetics can alter drug exposure and predispose the patient to either over- or underdosing, potentially resulting in adverse drug reactions or therapeutic failure. Kidney disease is characterized by multiple physiologic effects, which induce clinically significant changes in pharmacokinetics. These vary between individuals and may be quantitated in certain instances. An understanding of pharmacokinetic concepts is, therefore, important for a rational approach to the design of drug dosing regimens for the delivery of personalized medical care. Whether kidney disease is acute or chronic, drug clearance decreases and the volume of distribution may remain unchanged or increase. AKI is defined by dynamic changes in kidney function, which complicates attempts to accurately quantify drug clearance. In contrast, changes in drug clearance progress more slowly with CKD. In general, kidney replacement therapies increase drug clearance, but the extent to which this occurs depends on the modality used and its duration, the drug's properties, and the timing of drug administration. However, the changes in drug handling associated with kidney disease are not isolated to reduced kidney clearance and an appreciation of the scale of potential derangements is important. In most instances, the first dose administered in patients with kidney disease is the same as in patients with normal kidney function. However, in some cases, a higher (loading) initial dose is given to rapidly achieve therapeutic concentrations, followed by a lower maintenance dose, as is well described when prescribing anti-infectives to patients with sepsis and AKI. This review provides an overview of how pharmacokinetic principles can be applied to patients with kidney disease to personalize dosage regimens. Patients with kidney disease are a vulnerable population and the increasing prevalence of kidney disease means that these considerations are important for all prescribers.

Keywords: Acute Kidney Injury; Drug-Related Side Effects and Adverse Reactions; Pharmacokinetics; Prevalence; Renal Insufficiency, Chronic; Renal Replacement Therapy; Sepsis; Vulnerable Populations; acute kidney injury; chronic kidney disease; clearance; dialysis; kidney disease; personalized medicine; volume of distribution.

Figure 1.

The same daily dose of metformin administered as different dosage regimens has differing effects on the concentration–time profile in a patient with CKD. Three different dosage regimens (each equivalent to 1000 mg/d) are simulated in a patient with an GFR of 20 ml/min. The concentration–time profiles are shown relative to a proposed target concentration of 2–3 mg/L. This dosage is anticipated to be an overdose on the basis of a suggested initial dose of 750 mg/d for patients with an GFR of 30 ml/min (42). Each regimen achieves steady-state concentrations within 70 hours and the same average plasma concentration, but more frequent dosing is associated with less variability in plasma concentration (the difference between Cmax and the minimum plasma concentration).

Figure 2.

A loading dose decreases the time to achieve the target concentration. When the plasma t_1/2 is prolonged (for example, because of kidney disease), the time to reach steady state or the target concentration increases proportionally. Administration of a loading dose reduces the time to achieve the therapeutic plasma concentration, and in this simulation the loading dose is double the maintenance dose.

Figure 3.

An increase in a drug’s t_1/2 prolongs the time to achieve steady-state plasma concentrations with maintenance dosing. The effect of the same dose given to three simulated patients with CKD. The increasing elimination t_1/2 are because of decreasing endogenous clearance, which is noted with increasing severity of CKD. Increasing the t_1/2 delays the time to steady-state plasma concentrations and results in higher plasma concentrations. Failure to reduce the dose or frequency in patients with the longer t_1/2 may predispose to adverse drug reactions. ^# indicates the time when steady-state conditions are achieved for the respective profile. These conditions are present when the concentration–time profile plateaus, for example, when the Cmax (maximum plasma concentrations) are no longer increasing.

Figure 4.

Dose adjustments in patients with CKD are based on the change in the concentration-time profile for the drug of interest. Compared with patients with no kidney disease, those with advanced CKD receiving oral dihydrocodeine (upper panel; substrate of CYP2D6 and CYP3A4) showed a decrease in clearance and an increase in the mean area under the concentration–time curve and Cmax of 70% and 29%, respectively. To achieve concentrations similar to those in patients without kidney disease, the dosing interval should be prolonged but the dose does not need to be changed. In contrast, for oral repaglinide (lower panel; substrate of CYP3A4, CYP2C8, and organic anion transporting polypeptide OATP1B1, in patients with advanced CKD the mean area under the concentration–time curve and Cmax increase 232% and 82%, respectively compared with patients with no kidney disease. Here, to achieve plasma concentrations similar to those in patients without kidney disease, both the dosing interval should be prolonged and a lower dose should be prescribed. Figure panels are approximate representations of data published by Barnes et al. (11) and Marbury et al. (12).

Figure 5.

The timing of gentamicin administration affects the concentration-time profile in patients using hemodialysis. Simulation on the basis of a 30-minute intravenous infusion of 200 or 80 mg gentamicin, using median values from Sowinski et al. (43) including Vd of 13.5 L, endogenous elimination t_1/2 of 39.4 hours, and elimination t_1/2 during hemodialysis (HDx) of 1.6 hours. Administration prehemodialysis maximizes the Cmax:MIC ratio (ratio of Cmax to the minimum inhibitory concentration of the bacteria; see part 1 [2]) and decreases the overall exposure. This demonstrates that a large dose can be administered immediately predialysis to take advantage of the concentration-dependent killing and postantibiotic effect of this antibiotic class. This maximizes the antibiotic concentration–time profile and drug effect, and the clearance achieved by dialysis allows for the aminoglycoside to be rapidly cleared to a less toxic concentration. Other antibiotics that also have a concentration-dependent killing and therefore may also benefit from a large dose immediately before dialysis are daptomycin (44) and the fluoroquinolones (45,46).