Misdosing: More Common Than You Think

Unfortunately, even though the need for making proper dose adjustments for kidney function is well-recognized, clinicians face many challenges in doing so.

Second only to surgery complications, inappropriate treatment is the biggest risk to patients’ safety. Getting the wrong drug is dangerous, and so is getting the wrong dose. Yet, we’re not doing the research needed and care teams are left to decide for each patient without reliable guidance.

Ask any pharmacist about the most critical parts of his or her job, and they will be sure to mention the importance of proper drug dosing. The care team works hard to ensure that a patient’s medications are treating their conditions, but also being used in the safest, most effective way possible.

Drug dosing is often not as straightforward as it seems, as it must be tailored to the individual patient’s condition, age, renal and hepatic function, comorbidities, and concurrent medications. Give too much of a medication and the patient might suffer adverse effects; give too little and you risk undertreating the condition. For example, in the case of anticoagulants, which are considered medications associated with a high risk of adverse events, clinicians must work to balance the risks of causing bleeding associated with higher doses, and the potentially catastrophic consequence of the patient suffering a clot or stroke if the dose is too low.1

One common and important consideration in drug dosing is a patient’s kidney function. Kidney dysfunction is common, especially in acute care settings. Nearly 1/7 of the world’s population has chronic kidney disease (CKD) and almost 1/4 of hospitalized patients develop acute kidney injury (AKI).2,3 The risk is even higher in the intensive care unit (ICU), where more than half of patients develop AKI.4 Unfortunately, even though the need for making proper dose adjustments for kidney function is well-recognized, clinicians face many challenges in doing so.

There is no standard patient. Same with the medicine dose.

The first step in the renal dose adjustment process—estimating a patient’s kidney function (and subsequent drug clearance)—can be quite difficult. Several equations are available for estimation, with strengths and weaknesses and limited applicability to certain populations (eg those with AKI, hepatic dysfunction, etc).5-7 Hospitalized patients may have dynamic changes in kidney function, making estimation even more difficult. Additionally, if the patient needs renal replacement therapy, each type of therapy (intermittent hemodialysis, peritoneal dialysis, continuous renal replacement therapy) and its settings can affect drug removal.8

Once kidney function and drug removal is evaluated, good references for dose adjustments tailored to kidney function are often lacking.

Khanal and colleagues illustrated this point by pulling 5 different renal dosing guides and comparing recommendations for 61 commonly adjusted medications.9 Many of the sources offered ambiguous recommendations such as “increase dosing interval” or “seek specialist advice in severe impairment,” and often disagreed on the reported availability of clinical trials.

In some ways, the variability in drug dosing recommendations is not surprising. Before 1998, there was no structured regulatory guidance in the US for pharmaceutical companies regarding how, and for which drugs, such renal dosing evaluations should be conducted.9 This has improved with FDA guidance.

Still, dosing is most often based on single-dose pharmacokinetic trials and studies to quantify the impact of renal replacement therapies were only conducted for 21.6% of the 194 new chemical entities for which new drug applications were approved by the FDA between 1999 and 2010. During that time period, only 4 studies evaluated patients on peritoneal dialysis and 1 evaluated subjects on continuous renal replacement therapy (CRRT).9

With some medications, no data or only case reports are available describing how one might dose the drug. For other medications, the various pharmacokinetic studies come to different conclusions depending on the population studied. Some references have not been updated in a number of years; for example the last edition of the often-cited “Drug Prescribing in Renal Failure” by Aronoff and colleagues dates back to 2007.10

It is urgent that we address this critical gap in information.

The first step is to improve the quality of renal dosing recommendations in clinical drug references consulted every day at the point of care. To do this, the Lexicomp® editorial team at Wolters Kluwer has formed a panel of consultants—some specialized at reading and interpreting pharmacokinetic literature, some experts in caring for patients with kidney disease, and still others who know how to use the medication in question in clinical practice.

This team has been reviewing and debating gray areas in the literature to come up with the most concise, clinically helpful recommendations possible, so that the overworked clinician at the bedside can focus on safely and adequately treating their patients.

Additionally, regulatory agencies need to continue to push for well-designed studies of patients with CKD, AKI, and those receiving renal replacement therapies. Indeed, in September 2020, the FDA issued a draft guidance on the evaluation of pharmacokinetics in patients with impaired renal function. Among other things, the guidance includes advice on how to utilize population pharmacokinetics and phase 2 and 3 trials to inform dosing in patients with kidney dysfunction, and how to conduct studies in patients receiving CRRT.

Ultimately, rigorous studies should be mandated as part of the approval process, and post-marketing drug optimization research encouraged as well, not only in patients with altered kidney function but in other patient groups who may need specialized dosing; for example, individuals with obesity, children, and patients with other organ dysfunctions.

Therapeutic drug monitoring of antibiotics has also been suggested as a way to improve the care of critically-ill septic patients, who often exhibit highly variable pharmacokinetics. This type of monitoring could ensure that adequate concentrations of antibiotics are reached quickly, which could have life-saving results. Yet only about 30 hospitals are estimated to employ this approach, with the majority in European countries.10,11 The wide-spread implementation of this monitoring would ensure that dosing in our most vulnerable patients is optimized.

By pushing for these changes from regulatory and research standpoints, as well as increasing the amount of data that can be measured in real time, our clinicians would be finally equipped with the tools they need to truly individualize care for their patients.

Wolters Kluwer provides trusted clinical technology and evidence-based solutions that engage clinicians, patients, researchers, students, and the next generation of healthcare providers. With a focus on clinical effectiveness, lifelong learning, and clinical intelligence, our proven solutions drive effective decision-making and consistent outcomes across the continuum of care.

Rachel Eyler, PharmD, BCPS, is Project Clinical Lead for Lexicomp Reference Content at Clinical Effectiveness, Wolters Kluwer, Health. Prior, Eyler was Associate Clinical Professor of Pharmacy Practice and a member of the Institute for Collaboration on Health, Intervention and Policy (InCHIP) at the University of Connecticut.

Bruce Mueller, PharmD, FCCP, FASN, FNKF, is Interim Dean and Professor of Clinical Pharmacy at the University of Michigan College of Pharmacy and a senior editor for Lexicomp Reference Content at Clinical Effectiveness, Wolters Kluwer, Health.

The authors thank senior editors Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, University of Queensland, Australia, and Michael Heung, MD, MS, University of Michigan, for reviewing this article.

References

1. U.S. Department of Health and Human Services, Office of Disease Prevention and Health Promotion. (2014). National Action Plan for Adverse Drug Event Prevention. Washington, DC.Hill

2. NR, et al. Global prevalence of chronic kidney disease - A systematic review and meta-Analysis. PLoS One. 2016 Jul 6;11(7):e0158765. doi: 10.1371/journal.pone.0158765. https://pubmed.ncbi.nlm.nih.gov/27383068/​.

3. Wang HE, et al. Acute kidney injury and mortality in hospitalized patients. Am J Nephrol. 2012 May; 35(4): 349–355. https://pubmed.ncbi.nlm.nih.gov/22473149/

4. Hoste EA, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 2015 Aug;41(8):1411-23. https://pubmed.ncbi.nlm.nih.gov/26162677/

5. Jones G. Estimating renal function for drug dosing decisions. Clin Biochem Rev. 2011 May;32(2):81-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100285/

6. Raman M, Middleton RJ, Kalra PA, Green D. Int Urol Nephrol. 2017 Nov;49(11):1979-1988. https://pubmed.ncbi.nlm.nih.gov/28913589/

7. Sherman D, Fish D, Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls. Am J Kidney Dis. 2003 Feb;41(2):269-78. doi: 10.1053/ajkd.2003.50035. https://pubmed.ncbi.nlm.nih.gov/12552488/

8. Mueller BA, Smoyer WE. Challenges in developing evidence-based drug dosing guidelines for adults and children receiving renal replacement therapy. Clin Pharmacol Ther 2009;86(5):479-482. https://pubmed.ncbi.nlm.nih.gov/19844225/

9. Matzke GR, Dowling TC, Marks SA, Murphy JE. Influence of kidney disease on drug disposition: An assessment of industry studies submitted to the FDA for new chemical entities 1999-2010. J Clin Pharmacol. 2016 Apr;56(4):390-8. https://pubmed.ncbi.nlm.nih.gov/26238947/

10. Huttner A, Harbarth S, Hope WW, Lipman J, Roberts JA. Therapeutic drug monitoring of the β-lactam antibiotics: what is the evidence and which patients should we be using it for? J Antimicrob Chemother. 2015 Dec;70(12):3178-83. https://pubmed.ncbi.nlm.nih.gov/26188037/

11. Wong, G, et al. An international, multicentre survey of β-lactam antibiotic therapeutic drug monitoring practice in intensive care units. J Antimicrob Chemother. 2014 May;69(5):1416-23. https://pubmed.ncbi.nlm.nih.gov/24443514/