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Specialty Pharmacy Continuum • March/April 2021
CLINICAL
The Hidden Pandemic of Misdosing Rachel Eyler, PharmD, BCPS Project Clinical Lead Lexicomp Reference Content at Clinical Effectiveness Wolters Kluwer Health Ann Arbor, Michigan
Bruce Mueller, PharmD, FCCP, FASN, FNKF Interim Dean and Professor of Clinical Pharmacy University of Michigan College of Pharmacy Senior Editor Lexicomp Reference Content at Clinical Effectiveness Wolters Kluwer Health Ann Arbor, Michigan
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harmacists and clinicians adjust drug doses for patients every day. Yet determining the correct dosage is one of the most difficult aspects of the prescribing process. This is due in part to the complexity involved in tailoring dosage to an individual patient’s condition, age, organ function, comorbidities, and concurrent medications. Kidney dysfunction, in particular, presents unique challenges that clinicians calculating medication dosages.
Renal Dosing: A Common Yet Complex Task About 14% of the world’s population has chronic kidney disease (CKD)1 and almost one-fourth of hospitalized patients develop acute kidney injury (AKI).2 The risk is even greater in the ICU, where more than half of patients develop AKI.3 Accurate dosing and monitoring in these patients is complex and crucial. Dosing of anticoagulants provides a clear example. Anticoagulants are high-risk medications. Clinicians must carefully balance the risks for causing bleeding associated with higher doses with the potentially catastrophic consequence of the patient suffering a clot or stroke if the dose is too low.4 Estimating a patient’s kidney function and subsequent drug clearance is the first step in the renal dose adjustment process and can be quite difficult. Several equations are available for estimation, but there are strengths and weaknesses in each formula and limited applicability to certain populations (eg, those with AKI, hepatic dysfunction, and other conditions).5-7 Hospitalized patients may experience dynamic changes in their kidney function, making dose estimation even more difficult. For patients who require renal replacement therapy, each type of therapy (intermittent hemodialysis, peritoneal dialysis, continuous renal replacement therapy) can affect drug removal.8 Once kidney function and drug removal are evaluated, the next step is tailoring
dose adjustments to kidney function. This step also is lacking in good references to assist pharmacists and clinicians in making the proper dose recommendations. Khanal et al highlighted this dynamic in their study that pulled 5 different renal dosing guides and compared recommendations for 61 commonly adjusted medications.9 According to their review, 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. The variability in drug dosing recommendations is not surprising. Before 1998, the United States did not provide structured regulatory guidance to pharmaceutical companies about how, and for which drugs, such renal dosing evaluations should be conducted.10 This has improved somewhat with guidance from the FDA. One ongoing problem is the lack of pharmacokinetic trials and studies that thoroughly evaluate dosing implications for patients with kidney dysfunction. Many dose recommendations are based on single-dose pharmacokinetic trials and studies to quantify the impact of renal replacement therapies that were conducted for only 21.6% of the 194 new chemical entities for which new drug applications were approved by the FDA between 1999 and 2010. Only 4 of those studies evaluated patients on peritoneal dialysis and 1 evaluated patients receiving continuous renal replacement therapy.10 That means that for some medications, there are no data or only case reports available to advise clinicians about how to dose these drugs. For other medications, the various pharmacokinetic studies draw different conclusions based on the population studied. Some references have not been updated in over a decade. For example, the last edition of the oftencited Drug Prescribing in Renal Failure, by Aronoff et al, was published in 2007.11
Addressing the Critical Information Gap There is a clear need to improve the quality of renal dosing recommendations in clinical drug references that clinicians consult every day at the point of care. Teams behind evidence-based
References 1. US Department of Health and Human Services. Office of Disease Prevention and Health Promotion. National Action Plan for Adverse Drug Event Prevention. 2014. Accessed January 29, 2021. http://bit.ly/3pAnn3Y 2. Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease—a systematic review and meta-analysis. PLoS One. 2016;11(7):e0158765.
medicine tools should consist of a panel of consultants that include experts specialized in reading and interpreting pharmacokinetic literature, experts in caring for patients with kidney disease, and others who know how to use the medication in question in clinical practice. These teams should review and debate gray areas in the literature to develop concise, clinically helpful recommendations, so overworked clinicians at the bedside can provide safe, effective, patient-centered care. Regulatory agencies also need to continue to push for well-designed studies of patients with CKD, AKI, and those receiving renal replacement therapies. Rigorous studies should be mandated as part of the approval process, and postmarketing drug optimization research should be encouraged to include patients with altered kidney function. The FDA has signaled its intention to address some of these concerns. In September 2020, the FDA issued a draft guidance on the evaluation of pharmacokinetics in patients with impaired renal function.12 The guidance includes advice on how to use population pharmacokinetics and phase 2 and 3 trials to inform dosing in patients with kidney dysfunction and how to conduct studies in patients receiving continuous renal replacement therapy. Addressing the challenges in proper renal dose adjustments will require regulatory changes and new approaches to scientific research to include access to real-time data. Once this is achieved, our clinicians will be equipped with the tools they need to truly individualize care for their patients.
3. Wang HE, Muntner P, Chertow GM, et al. Acute kidney injury and mortality in hospitalized patients. Am J Nephrol. 2012;35(4):349-355. 4. Hoste EA, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41(8):1411-1423. 5. Jones GR. Estimating renal function for drug dosing decisions. Clin Biochem Rev. 2011;32(2):81-88. 6. Raman M, Middleton RJ, Kalra PA, et al. Estimating renal function in old people: an in-depth review. Int Urol Nephrol. 2017;49(11):1979-1988. 7. Sherman D, Fish DN, Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls. Am J Kidney Dis. 2003;41(2):269-278. 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. 9. Khanal A, Castelino RL, Peterson GM, et al. Dose adjustment guidelines for medications in patients with renal impairment: how consistent are drug information sources? Int Med J. 2014;44(1):77-85. 10. Matzke GR, Dowling TC, Marks SA, et al. Influence of kidney disease on drug disposition: an assessment of industry studies submitted to the FDA for new chemical entities 19992010. J Clin Pharmacol. 2016;56(4):390-398. 11. Aronoff GR, Brier ME. Drug Prescribing in Renal Failure. 5th ed. American College of Physicians; 2007. 12. FDA. Pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labeling. September 2020. Accessed January 29, 2021. http://bit.ly/3otVxFa The authors thank Jason Roberts, PhD, BPharm (Hons), B App Sc, University of Queensland, Australia, and Michael Heung, MD, MS, University of Michigan, for reviewing this article. Drs Eyler and Mueller reported no financial disclosures other than their stated employment.
