13 minute read
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
Pharmacists 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 DrugPrescribing 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 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.
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. 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 fi nancial disclosures other than their stated employment.
OPIOIDS/HAV/HBV
continued from page 15
have had two or more doses of HAV vaccine, as have 17.7% of international travelers and 20.8% of adults with chronic liver disease.
Can’t Blame the Kids Anymore
Children used to drive outbreaks of HAV, but in 2007, recommendations from ACIP to vaccinate children were implemented. “We don’t see a lot of cases among children anymore,” Foster said.
Vaccination coverage for children is around 86% for one dose, and 60% for the required two doses, he said.
Treatment “is mainly supportive care,” Foster said. Most people with healthy immune systems expunge the virus, and antibodies provide lifelong protection. In rare cases, fulminant hepatic failure requires transplantation.
Hepatitis B
Like HAV, HBV has been increasing, due to many of the same risk factors, notably from injecting opioids. “One thing we should be doing that we don’t do enough is treating pregnant women with chronic hepatitis B,” Jhaveri said. “The literature has shown that if [such women] meet criteria for high replication of the virus, we providers should treat those women with an antiviral through the middle of their pregnancy until just after delivery. The real deficit is many women don’t get the additional testing they need to identify them as higher risk for transmitting to the baby,” Jhaveri said, adding that the CDC, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America are pushing to get the systems in place to ensure automatic follow-up testing. He also said Kaiser Permanente in Northern California has put such systems in place.
Worldwide, vaccines are becoming routine throughout much of Asia. Southern Africa has high rates of HBV,
but little routine vaccination at birth, according to Jhaveri.
Hepatitis D
Hepatitis D requires machinery from HBV to cause infection, Jhaveri noted. Hepatitis D, although uncommon in the United States, can “cause a severe worsening of symptoms if you already have chronic hepatitis B,” he said. Hepatitis D is spread by contact with infected blood or other bodily fluids. There is no vaccine for hepatitis D; hepatitis B vaccine is the best protection. Protection is given because only people infected with HBV can become infected with hepatitis D virus, according to the CDC.
Ravi Jhaveri, MD
—David C. Holzman
PharmacyPracticeNews.com/eNews
Get the latest news from the most widely read hospital pharmacy publication in the United States, including multimedia and web-only content, delivered directly to your inbox!
Articles from the current month’s issue Articles ahead of print • Web-exclusive content
Brought to you by the same people who publish
Glucarpidase Keeps CNS Lymphoma Rx on Track
A new outpatient treatment regimen allowed patients with central nervous system (CNS) lymphoma to continue infusions during the height of the COVID-19 pandemic, and could change the way patients receive care after the current crisis subsides.
Researchers at Memorial Sloan The researchers also analyzed the cereKettering Cancer Center (MSKCC) in brospinal fluid of seven patients and New York City found methotrexate could found potentially cytotoxic methotrexbe coupled with repeated doses of glu- ate concentrations remained in the fluid carpidase (Voraxaze, BTG Internation- one hour and six hours after patients glucarpidase and additional hydration. an outpatient setting likely will involve al), and patients could safely receive the received glucarpidase. No glucarpidase None of the patients required hospital- surmounting some logistical hurdles, two treatments in an outpatient setting, was detected in the cerebrospinal fluid ization, and in each case, methotrexate Holle said. Many smaller institutions according to a study presented at the of the seven patients tested. levels dropped to less than 100 nmol/L 48 don’t have the laboratory capacity to 2020 Society for Neuro-Oncology virtual To Schaff and her team, these findings hours after the dose. Two patients expe- process their own methotrexate, she annual meeting. demonstrated the glucarpidase treat- rienced grade 1 elevation of aspartate noted. In addition, a new treatment like
While the pandemic was surging in ment was safe and did not cross the aminotransferase/alanine aminotrans- this could require additional training for New York last spring, many patients blood–brain barrier to interfere with ferase levels over three treatments, and infusion center staff, and the costs and with CNS lymphoma canceled treat- the methotrexate response. They also one had a grade 2 creatinine increase that cost-effectiveness of the treatment also ments because they were afraid to come noticed that patients who received glu- was remedied with additional hydration. need to be determined, she added. to the hospital, missing potentially curay cura tive infusions, said Lauren Schaff, MD, ff, MD, a neuro-oncologist and neurologist at gist at MSKCC and lead investigator on the on the research. “We just felt like that was not was not in the best interest of our patients and ts and really not acceptable,” she said.
Before the pandemic began, an, Schaff and her team had started ed examining the safety and efficacy cy of low-dose glucarpidase to clear ear methotrexate from patients who who received both medications in the hoshe hospital (abstract CTNI-61). Schaff and ff and her team wanted to see whether gluer glucarpidase could be given multiple times e times and stay effective for patients with new th new or recurrent CNS lymphoma without without systemic involvement and renal failure. failure.
In the study, 12 patients received a i d total of 65 doses of methotrexate (28 carpidase could go home earlier than Patients really appreciated the outpa- For now, the MSKCC researchers are doses of 3 g/m2, 26 doses of 6 g/m2 they would have been able to otherwise, tient option, Schaff said. “Every patient continuing to study the safety and effiand 11 doses of 8 g/m2). Twenty-four Schaff said. who received this treatment opted to cacy of this approach. They are treating hours after each methotrexate infusion, When COVID-19 hit in March and continue the outpatient treatment as patients who need access to outpatient patients received glucarpidase, at 1,000 April 2020, Schaff and her team quickly long as feasible.” treatment as a result of the continuing (20 doses) and 2,000 units (45 doses). reconceived a follow-up study already in pandemic and have started enrolling
The researchers found that glucarpi- the works to accommodate patients who Some Centers Likely to Face patients into a prospective study of this dase led to a more than 95% reduction were unable to continue their inpatient Logistical Hurdles treatment approach in the outpatient in serum methotrexate levels within treatment because of the pandemic. “It’s very interesting and exciting to see setting. Schaff predicted, “I think cer15 minutes 97.7% of the time after They opened the study to patients who what researchers and clinicians are doing tainly there’s going to be a place for this administration of 2,000 units of glucar- had isolated CNS lymphoma and previ- to try to move patients from an inpa- post-pandemic.” pidase and 75% of the time after admin- ously tolerated high-dose methotrex- tient setting to an outpatient setting in a istration of 1,000 units. ate. The study enrolled four patients way that’s safe,” said Lisa Holle, PharmD,
Four of 11 analyzed patients had who received a total of 10 methotrexate BCOP, an associate clinical professor at anti-glucarpidase antibodies that were treatments (3.5 g/m2) in the outpatient the University of Connecticut School of associated with reduced methotrexate setting with hydration. Patients came Pharmacy, in Storrs. clearance and methotrexate rebound. back 24 hours later for 2,000 units of However, moving these treatments to
—Lisa Holle, PharmD, BCOP
Glucarpidase yielded 95%+
reduction in serum methotrexate 97.7%
of time after dose of 2,000 units; 75%
after 1,000 units
Source: MSKCC
—Jillian Mock
Holle reported no relevant fi nancial disclosures. Schaff has her name on a patent pending for a lower dose of glucarpidase. BTG Specialty Pharmaceuticals provided the glucarpidase for this study.
