Drug Dosing Consideration in Patients With Acute and Chronic Kidney Disease

A Clinical Update From Kidney Disease: Improving Global Outcomes (KDIGO)

Gary R Matzke; George R Aronoff; Arthur J Atkinson Jr; William M Bennett; Brian S Decker; Kai-Uwe Eckardt; Thomas Golper; Darren W Grabe; Bertram Kasiske; Frieder Keller; Jan T Kielstein; Ravindra Mehta; Bruce A Mueller; Deborah A Pasko; Franz Schaefer; Domenic A Sica; Lesley A Inker; Jason G Umans; Patrick Murray

Disclosures

Kidney Int. 2011;80(11):1122-1137. 

In This Article

Drug Dosage Considerations for Patients With AKI

Critically ill patients frequently develop AKI, multiorgan dysfunction syndrome (MODS), or multisystem organ failure (MSOF).[3,68–70] Although most cases of MSOF/MODS occur secondary to shock, sepsis, and severe trauma, a multiplicity of other risk factors have been identified. Over 90% of patients who develop MSOF/MODS have early respiratory dysfunction. Cardiac dysfunction is often observed shortly thereafter, followed by hepatic dysfunction within 4–6 days and AKI in 5–7 days. Unfortunately, there are large gaps in knowledge of drug metabolism and disposition in patients with MSOF/MODS as well as AKI, and thus patients may be at significant risk for underdosing as well as overdosing.

PK and PD Data

The application of PK principles involving changes in absorption, distribution, metabolism, and excretion is the first step to optimizing drug therapies for patients with AKI, MSOF, or MODS.[71,72] Critically ill patients typically have minimal oral intake of food and liquids and rely upon intravenous fluids for fluid maintenance and nutrition. In addition, H2-antagonists and proton pump inhibitors are used for stress ulcer prophylaxis and they significantly increase the gut pH. Any orally administered drug needing an acidic environment for dissolution may thus not be readily absorbed. Other absorption-altering conditions such as slow gastrointestinal motility, prolonged intestinal transit times, bacterial colonization, and necrotizing enterocolitis (seen in neonates) have also been noted in these patients. Thus, intravenous administration of drugs may need to be considered to assure appropriate absorption.

Drug distribution is one of the most important, yet the most complicated, physiologic variable to quantify for patients with AKI, MSOF, or MODS. There is a fine balance between detrimental fluid overload and adequate hydration to preserve kidney perfusion. Numerous studies in both adult and pediatric patients have concluded that critically ill patients should early on be managed in a slightly negative fluid balance after initial adequate fluid resuscitation.[68,73–75] However, in patients prone to low blood pressure, this may not be prudent. Careful and frequent reassessment of volume status is mandatory in this patient situation.

Multiple animal[57,76–78] and a few human studies[57,79–82] have demonstrated a reduction in the transcription and/or metabolic activity of hepatic and intestinal CYP450 in CKD patients. The impact of AKI, MSOF, and MODS on drug metabolism is delayed in onset or minimal in the majority of studies,[83–85] whereas nine studies did not demonstrate any impact on hepatic metabolic activity.[86–94] The remaining four studies revealed either an increase or a decrease in hepatic metabolic activity.[95–98] Definitive conclusions on the PK of metabolized medications in AKI remain hampered by the clinical complexity and potential confounders in the critically ill patients. Hypoxia, decreased protein synthesis, competitive inhibition from concomitant medications, and decreased hepatic perfusion could also be explanations for the reduced clearance.

Patient Assessment

Hyperfiltration and massive overhydration are often evident early in the course of MSOF/MODS, especially in those with burns or trauma, and can lead to the use of inappropriately low doses of medication, treatment failure, and even death.[99] Hypofiltration and GFR may be especially challenging to quantify in those with rapidly changing function.[8,51] Finally, estimation or measurement of GFR may not provide an accurate measure of the contribution of the kidney to the excretion of all drugs, especially those that are extensively secreted and/or metabolized in the kidney or other organs.[100,101] Several new quantitative techniques and assessment protocols have been developed and utilized in patients with 'stable' CKD, liver disease, and some other conditions.[102–104] The potential benefits of these methods include an improvement in dosage individualization and identification of the mechanisms responsible for nephrotoxic injury. Although both methods have been validated, there has been no subsequent published data regarding their application in patients with CKD, AKI, or MSOF/MODS.

Assessment of kidney function in patients with AKI or MSOF/MODS is challenging.[105–107] Any endogenous filtration marker, such as creatinine, needs to be measured at steady state before it can provide a reliable estimate of GFR. Hence, no estimating equations can provide an accurate estimate of GFR in AKI. The rate of change of SCr or eGFR may provide some insight but this cannot be used as a quantifiable measure, and such values cannot be applied to individual patient situations as multiple events are typically happening concurrently. Another strategy to estimate GFR in AKI is to measure creatinine clearance with incorporation of the mean of the beginning and ending Scr value as an estimate of GFR. Shorter time periods than 24 h may be appropriate in patients with rapidly changing levels of kidney function. For patients with MSOF/MODS without AKI, Scr and all related estimating equations are likely to overestimate the GFR or creatinine clearance because of the influence of non-GFR determinants in these clinical scenarios.

There is a paucity of dosing algorithms to guide pharmacotherapy, derived from investigations of the PK/PD of medications, in patients with AKI or MSOF/MODS.[64,72,108] Indeed, most of the critical care literature and almost all FDA or EMEA product labeling contains drug dosage recommendations that were derived from observations in patients with CKD or those receiving RRT. The limited data from these populations that are available have predominantly been developed by clinicians who have gained experience with a given drug after it has been approved for marketing, and rarely, if ever, is this information incorporated into official product labeling. Thus, it is challenging for clinicians to individualize therapy when the available PK/PD information is so scant. It is near impossible to provide the best dosage regimen for AKI or MSOF/MODS patients because of their fluctuating kidney function, volume status, and potentially metabolic activity.

Drug Dosing Approaches

The principles of drug dosage regimen modification previously described for use in CKD patients are the foundation for those with AKI or MSOF/MODS.

Loading Dose As the V D of many drugs, especially hydrophilic antibiotics, including β-lactams, cephalosporins, and penems, are significantly increased in the presence of AKI, the administration of aggressive loading doses (25–50% greater than normal) are highly recommended.

Maintenance dose Clinical judgment is paramount and forecasting the degree and rate of change in kidney function and fluid volume status is fraught with uncertainty. Because of the preservation of nonrenal clearance for some agents such as vancomycin, imipenem, and ceftizoxime, as well as the tendency to attain a positive fluid balance in the early stages of AKI, the dosing regimen for many drugs, especially antimicrobial agents, should be initiated at normal or near-normal dosage regimens.

Therapeutic Drug Monitoring Prospective measurement of serum drug concentrations and the subsequent use of sound PK/PD therapeutic drug monitoring approaches should be used whenever possible, especially for drugs with a narrow therapeutic range. When this is not a possibility because of the unavailability of rapid specific analytical methods for the determination of serum drug concentrations, the development of excessive pharmacologic effect or toxicity may be the primary indicator of a need for dosage adjustment. Finally, there are currently very limited data to guide drug dosing for AKI or MSOF/MODS patients receiving one of the multiple variants of RRT (Table 5).[64,72,108]

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