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. Author manuscript; available in PMC: 2021 Dec 14.
Published in final edited form as: J Clin Pharmacol. 2020 Jun 15;60(12):1551–1560. doi: 10.1002/jcph.1676

Dosing Recommendations for Pediatric Patients With Renal Impairment

Amer Al-Khouja 1, Kyunghun Park 2, Daijha JC Anderson 3, Caitlyn Young 4, Jian Wang 5, Shiew Mei Huang 2, Mona Khurana 6, Gilbert J Burckart 2
PMCID: PMC8670561  NIHMSID: NIHMS1761674  PMID: 32542790

Abstract

A treatment gap exists for pediatric patients with renal impairment. Alterations in renal clearance and metabolism of drugs render standard dosage regimens inappropriate and may lead to drug toxicity, but these studies are not routinely conducted during drug development. The objective of this study was to examine the clinical evidence behind current renal impairment dosage recommendations for pediatric patients in a standard pediatric dosing handbook. The sources of recommendations and comparisons included the pediatric dosing handbook (Lexicomp), the U.S. Food and Drug Administration-approved manufacturer’s labels, and published studies in the literature. One hundred twenty-six drugs in Lexicomp had pediatric renal dosing recommendations. Only 14% (18 of 126) of Lexicomp pediatric renal dosing recommendations referenced a pediatric clinical study, and 15% of manufacturer’s labels (19 of 126) described specific dosing regimens for renally impaired pediatric patients. Forty-two products had published information on pediatric renal dosing, but 19 (45%) were case studies. When pediatric clinical studies were not referenced in Lexicomp, the renal dosing recommendations followed the adult and pediatric dosing recommendations on the manufacturer’s label. Clinical evidence in pediatric patients does not exist for most renal dosing recommendations in a widely used pediatric dosing handbook, and the adult renal dosing recommendations from the manufacturer’s label are currently the primary source of pediatric renal dosing information.

Keywords: drug development, MIDD (model-informed drug development), pediatrics (PED), renal disease, special populations

Despite 800 recent labeling changes related to the care of pediatric patients,1 U.S. Food and Drug Administration (FDA)-approved labels still lack some critical information related to drug use in pediatric patients. Bioequivalence studies of pediatric dosage forms, drug-drug interaction studies, and dosing studies in renal and hepatic impairment are rarely conducted in pediatric patients.

The U.S. Congress and the FDA have advanced several pediatric regulatory initiatives over the last 25 years. The FDA Modernization Act of 1997 encouraged pediatric drug development by offering sponsors additional market exclusivity for conducting studies in pediatric populations. These established provisions were carried forward via the Best Pharmaceuticals for Children Act of 2002, and additional authority to require pediatric studies came with the Pediatric Research Equity Act of 2003, both of which were permanently reauthorized under the FDA Safety and Innovation Act in 2012. Although these legislative enhancements have been critical in improving the available therapeutic options for pediatric patients, challenges remain in pediatric drug development and have not been addressed in specific populations within pediatrics, such as those with renal impairment.2–4

The causes of renal impairment in pediatric patients are different from those in adult patients. Diabetes mellitus and long-term uncontrolled hypertension are the 2 leading causes of end-stage renal disease (ESRD) in adults in the United States.5 Congenital abnormalities of the kidneys and urinary tract are the leading cause of ESRD in children < 10 years of age, whereas acquired glomerulonephritides are the leading cause in older children and adolescents.6 According to the 2018 United States Renal Data System, the prevalence of pediatric chronic kidney disease (CKD) was estimated as 2.7 per 1000 children and adolescents among those with health care coverage.7 Pediatric patients with CKD were found to have 12 times greater hospitalization rates and approximately 7.6 times greater health care expenditures relative to those without CKD.8 At the end of 2016, the prevalence of ESRD among children and adolescents was 99.1 per million population, with approximately 28% on either hemodialysis or peritoneal dialysis.9 Drug-induced renal dysfunction can be a problem in pediatric patients just as it is in adults.

For drugs or metabolites that are renally cleared, renal impairment can significantly alter the pharmacokinetics (PK), potentially yielding increases in overall drug exposure and in the potential for toxicity.10 For the youngest pediatric patients, altered renal elimination also includes the distinction between glomerular immaturity versus tubular immaturity. Developing dosing regimens for adult patients with renal impairment is typically either dependent on the conduct of clinical and traditional PK studies in these patients or based on the application of a population PK analysis.11 However, adults with renal impairment are often excluded from clinical development to reduce heterogeneity in drug exposure, with data often lacking in those patients with the most severe forms of renal impairment.8,12

Differences because of renal morphogenesis and maturation make predictions of drug dosing in pediatric patients with impaired renal function challenging.13–15 Although equations have been developed to estimate the glomerular filtration rate (GFR) in pediatric patients,16–18 the lack of specific dosing information for pediatric patients with renal impairment underscores the importance of addressing this drug development issue. Pediatric dosing handbooks have traditionally been the primary source of this information for pediatric clinicians. As an alternative approach, if renal dosing information is available for adults on FDA labels, the pediatric dose is sometimes proportionally scaled from the normal pediatric dose based on recommended reductions in the adult dosage based on renal function (eg, cefprozil, lacosamide, ceftazidime/avibactam). The third source of renal dosing information for pediatric clinicians is publications in the medical literature.

The objective of this study was to examine the clinical evidence behind current renal impairment dosage recommendations for pediatric patients in a major pediatric dosing handbook to provide insight into generating these recommendations in the future. This objective was accomplished by identifying drugs containing specific dosing recommendations for pediatric patients with renal impairment in that handbook and to evaluate the origins of those recommendations relative to those made in drug development for renal impairment and in the published literature.

Methods

Three sources of pediatric drug dosing recommendations for renally impaired patients were reviewed and compared, and the sources of those recommendations were examined. The primary source was the drugs listed in the most current Lexicomp Pediatric & Neonatal Dosage Handbook, 25th edition (Wolters Kluwer, Hudson, Ohio), which contained specific recommendations for pediatric patients with renal impairment. Drugs that did not specify a dose adjustment, including those stating “use with caution,” were excluded from this analysis. Over-the-counter medications were also excluded. For those drugs identified in the pediatric dosing handbook, the most recent copy of the prescribing information available was located either from Drugs@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/) or from DailyMed (U.S. NLM, https://dailymed.nlm.nih.gov/dailymed/). Finally, for those drugs identified in the pediatric dosing handbook, a thorough search of the medical literature was conducted for specific clinical studies evaluating drug PK and/or pharmacodynamics in renally impaired pediatric patients.

The FDA-approved manufacturer’s labels were surveyed to evaluate whether specific dosing recommendations are made for pediatric patients with renal impairment and, if so, whether clinical studies were conducted in pediatric patients with renal impairment. Information from the manufacturer’s label was also compared with information provided in the Lexicomp Handbook, including sources referenced for particular dosage adjustments. Recommendations for adult patients on the manufacturer’s label and for pediatric patients in Lexicomp were considered the same if the creatinine clearance (CrCL) or GFR cutoffs used were the same across both populations and if the dosage adjustments were proportional based on normal dosing. When Lexicomp provided recommendations from multiple sources, including the adult recommendations as on the manufacturer’s label, this was categorized as Lexicomp having additional information.

For the references used by Lexicomp that were secondarily referenced through another renal dosing guide,19 the quality of the clinical study was assessed based on (1) whether the source was a case report, (2) the number of patients and age range covered, (3) GFR measurement technique, and (4) range of renal function included in the assessment.

A separate search of the literature via PubMed (U.S. NLM, https://www.ncbi.nlm.nih.gov/pubmed/) and Google Scholar (Google LLC, scholar.google.com) was also conducted to identify whether those drugs were studied in pediatric patients with renal impairment, including studies containing some pediatric patients with renal impairment and pediatric case studies.

Results

Of 1121 drugs listed in the Lexicomp Pediatric Handbook, 126 (11%) were identified as containing recommendations for pediatric patients with renal impairment. These 126 drugs underwent additional review as described in Methods. A summary of the information obtained from the review of these 126 drugs is provided (Figure 1 and Table S1). All drugs were classified by therapeutic area as presented in Figure 2. Anti-infectives (antibiotics, antivirals, antiretrovirals, anti-malarials, and antifungals) were the largest category of drugs with pediatric renal dosing recommendations in Lexicomp (62% or 49% of products). Seventy of the pediatric renal dosing recommendations (56%) came from a secondary reference source (Aronoff et al19; Table S1).

Figure 1.

Figure 1.

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Breakdown for the 126 drugs with dosing recommendations for pediatric populations with renal impairment, as identified from the Lexicomp Pediatric and Neonatal Dosage Handbook, 25th edition. Information was collected from a review of the FDA-approved manufacturer’s label (left), the Lexicomp Pediatric Handbook (center), and the literature (right).

Figure 2.

Figure 2.

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Therapeutic areas for drugs containing specific dosing recommendations for a pediatric population with renal impairment in either the Lexicomp Pediatric Handbook (gray) or on the manufacturer’s label (black). The number at the top of the bar is the total for that therapeutic area, and the lower number is the black bar count. Drugs listed in the “Other” class include acrivastine (antihistamine), anakinra (immunosuppressant), azathioprine (immunosuppressant), deferasirox (iron-chelating agent), gadopentetate (contrast agent), miglustat (substrate reduction therapy), and tranexamic acid (antifibrinolytic).

The recommendations for pediatric patients in Lexicomp were compared with those for renally impaired patients on the manufacturer’s label (Table 1). Of the 18 drugs with Lexicomp recommendations referencing medical literature reports of pediatric clinical information (14% of the total; Table S2), only 2 had dosing recommendations that were the same in Lexicomp and on the drug label. This was in contrast with those products not referencing pediatric clinical information in Lexicomp, for which 44 of 108 (41%) had the same dosing recommendation in Lexicomp and in manufacturers’ labeling. The risk of bias for the literature reports of these 18 products was assessed to be high for 12, unclear for 3, and low for 3 drugs (see Table S2).

Table 1.

Comparison of Whether Recommendations for Renally Impaired Pediatric Patients in Lexicomp Matches Those for Renally Impaired Adults or Pediatric Patients on the Manufacturer’s Labels and Whether Literature Clinical Studies in Pediatric Patients Are Referenced in Lexicomp

Are Literature Studies With Pediatric Patients Referenced in Lexicomp? Pediatric Recommendations in Lexicomp Versus Pediatric/Adult Recommendations on the Manufacturer’s Label
Same Lexicomp Had Additional Information Different Total
Yes 2 7 9 18
No 44 25 39 108
Total 46 32 48 126
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The FDA-approved manufacturer’s labels for all 126 drugs were evaluated, and 19 of the labels (15%) described specific recommendations for renally impaired pediatric patients. When these 19 drugs were broken down by drug class (Figure 2), 14 (74%) were classified as anti-infectives, 1 (5.3%) as cardiology/metabolic, 2 as neurology/psychiatry (11%), 1 as oncology (5.3%), and 1 (5.3%) as other.

The Lexicomp recommendations for these 126 drugs were evaluated to determine whether there were matching renal recommendations on the manufacturer’s label. Studies referenced within these Lexicomp recommendations were also identified and classified based on whether they represented studies or case reports in a pediatric population. Forty-six of the 126 drugs (37%) had recommendations for renally impaired pediatric patients from Lexicomp that matched those recommendations for renally impaired adults or pediatric patients on the manufacturer’s label (see Table 1). Of the remaining 80 drugs (63%) for which dosing information between Lexicomp and the manufacturer’s label were found to be different or for which Lexicomp had additional information, only 16 (20%) had recommendations in Lexicomp that referenced clinical studies or information gathered in pediatric populations. In total, only 14% of pediatric renal drug dosing recommendations in Lexicomp (18 of 126) referenced any form of clinical information from the medical literature that were obtained from a pediatric patient population.

The 126 manufacturers’ labels were examined for those that described or referenced clinical studies in pediatric patients with renal impairment. From the 19 drugs identified with labels that included pediatric renal dose recommendations (see Table S1), 15 reference clinical development in a pediatric population (79%). Only 1 drug label described clinical information obtained in pediatric patients with renal impairment. Eighty-four percent of these labels (16 of 19) provided proportional renal dosing recommendations for adults and pediatric patients. Two labels provided pediatric renal dosing recommendations that were not proportional to the adult renal recommendations and described pediatric clinical studies. The remaining drug also provided nonproportional renal recommendations, but without describing pediatric studies in the labeling.

Published pediatric reports related to drug dosing in renal impairment from the published literature were identified for 33% of drugs (42 of 126) identified in Lexicomp with pediatric renal dosing recommendations (Table 2, Figure 1). These studies were divided into 4 subtypes: pediatric-only studies, combined adult and pediatric studies, model development studies, and case studies. Pediatric-only studies were located for 26 of 42 drugs (62%) containing between 4 and 1703 pediatric patients. Combined adult and pediatric studies were found for 6 drugs (14%) and described information obtained in 2 to 64 pediatric patients. Modeling and simulation studies were identified for 5 drugs (12%) using information in 20 to 785 pediatric patients. Finally, case report studies were noted for 19 drugs (45%) describing clinical experience in 1 to 3 pediatric patients, although 11 drugs had only case studies published (Figure 1). Although individual studies vary, pediatric patients with a range of kidney function were represented across these studies. Clinical information obtained included patients with normal renal function, with mild or moderate renal dysfunction, with acute renal failure or kidney injury, and those patients on dialysis or with ESRD.

Table 2.

Literature Reports Describing Drug Studies in Pediatric Patients With Varying Degrees of Renal Impairment

Number of Drugsa Number of Pediatric Patients (Range) Range of Renal Function
Pediatric-only studies20–48 26 4-l703b ESRD, renal dysfunction, anephric, AKI, on renal replacement therapy, normal renal function
Combined adult and pediatric studies49–55 6 20–88 adult and pediatric (2–64 pediatric) Renal dysfunction, acute renal failure, normal renal function
Model development studies56–62 5 20–785 Renal failure to normal renal function (often based on SCr or CrCL)
Case studies63–86 19 1–3 ESRD; CKD; acute renal failure; anephric; HD, PD, CVVH; HD for drug toxicity
All 42 l-l703b ESRD to normal renal function
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AKI, acute kidney injury; CrCL, creatinine clearance; CKD, chronic kidney disease; CVVH, continuous venovenous hemofiltration; ESRD, end-stage renal disease; HD, hemodialysis; PD, peritoneal dialysis; SCr, serum creatinine.

a

Some drugs have studies in more than 1 category, which is why adding up the columns of number of drugs does not add up to the total under “All”.

b

The study describing information from 1703 pediatric patients aggregated information from 10 studies.

Discussion

Typically indications and dosing regimens granted for pediatric populations are based either on the conduct of adequate and well-controlled trials in neonates, children, and adolescents or on extrapolation of efficacy using data obtained in adults, or some combination of trials.87,88 For efficacy extrapolation, the assumptions that pediatric patients have a similar disease progression, response to intervention, and exposure-response to therapy when compared with adults is necessary.87–89 The answers to these questions guide the goals and conduct of PK and safety trials in the intended patient populations. However, matching disease etiology and exposure-response between adults and children can be challenging because of ontogenetic differences in body weight, organ function, and transporter/enzyme expression, among many other factors.90–92 Based on these differences, pediatric patients are more susceptible than adult patients to experiencing medication errors such as incorrect dosing.93 As identified in the present study, dosing recommendations for pediatric patients with renal impairment are scant and supported with varying levels of evidence. Therefore, evaluating potential therapies intended for use in a pediatric patient population is critical during a drug’s development to provide dosing recommendations.

Pediatric dosing handbooks have been the preferred source of pediatric dosing information for the past 50 years.94–96 For this study, Lexicomp was chosen as a standard pediatric dosing handbook used in many pediatric hospitals.97 Our results indicated that the renal dosing recommendations differed between Lexicomp and the FDA drug label for 48 of 126 drugs (38%; see Table 1). Those recommendations in Lexicomp that did not reference a pediatric study in the literature were more likely to have recommendations that were the same or similar to adult or pediatric recommendations in the FDA-approved drug label. For 70 of 126 products, a secondary reference source in Lexicomp was used,19 which included a general reference list in the appendix but included few pediatric-specific literature references.

Our analysis began with >1000 drugs listed in the Lexicomp Pediatric Handbook and was distilled down to 126 drugs that contained specific recommendations for pediatric patients with renal impairment. When broken down by therapeutic class, many (49%) were classified as anti-infectives. In considering information in the manufacturer’s label, anti-infectives again represented the major class in providing specific recommendations for renally impaired pediatric patients (74%) and are one of the most commonly prescribed drug classes in children.25

The objective of our analysis was to identify the evidence behind dosing recommendations in renally impaired pediatric patients. Although studies in pediatric patients were referenced in only 14% of pediatric renal dosing recommendations in Lexicomp (18 of 126), only 15% of FDA-approved labels (19 of 126) had specific pediatric renal dosing recommendations. In the absence of adequate pediatric renal impairment trials, the evaluation of adult-driven evidence appears to be a primary guiding factor toward developing and presenting dosing recommendations for renally impaired pediatric patients.

The clinical information accessed was not limited to that obtained from adequate clinical trials. As presented in Table 2, many of the recommendations were based on case studies and on clinical studies with small patient numbers. The level of evidence is not graded in a dosing handbook such as Lexicomp, so that even those drugs with pediatric dosing recommendations may have only weak support for the application of this dose to the broader pediatric population. In this situation, dosing recommendations based on well-established renal impairment clinical studies in adults provide the best support for making pediatric renal dosing recommendations.

However, even this strategy is subject to some limitations, as there are many methods of estimating renal function in adult and pediatric patients98 with variations in precision and accuracy.99,100 Recommendations identified in this study differed based on whether renal function was determined using serum creatinine, CrCL, or estimated GFR (eGFR). Use of serum creatinine or CrCL, typically presented as absolute measures, can pose a challenge, especially for pediatric patients, as serum creatinine can be affected by diet, muscle mass, and creatinine measurement technique.99 As can be seen in Table S1, Lexicomp interchangeably uses CrCL and GFR. Fortunately this does not present a problem when these values are used to stage the degree of renal dysfunction because the absolute numbers (in mL/min for CrCL and mL/min/1.73 m2 for GFR) have the same cutoff values numerically for stages 1 to 5 of renal impairment.101 This highlights the difficulty in making a single recommendation across the pediatric spectrum, where muscle mass and therefore serum creatinine are expected to change with age. In contrast, eGFR is a relative measure normalized to body surface area, which can facilitate adult-to-pediatric comparisons. However, these estimating equations are subject to imprecision and susceptible to secular trends in assay methodology impacting overall measurements.102 The literature references to pediatric clinical studies in Lexicomp refer to an early period of use of the Jaffe method for creatinine measurement for only 1 product (digoxin; see Table S2).

The use of modeling and simulation to better inform pediatric drug development programs is one approach to improving pediatric renal dosing recommendations. Model-informed drug development has increasingly been used in drug development programs across therapeutic areas to optimize dosing regimens. Using this approach, a population PK model was recently developed to predict renal clearance in neonates and infants using clinical information from both adults and newborns and infants.103 Such approaches could be used to determine renal clearance and dosing regimens in pediatric patients with renal impairment. These approaches would be very dependent on a thorough understanding of renal ontogeny.15 Despite potential large variations between adult and pediatric patients, a Bayesian statistical framework has been used to minimize this bias and enhance efficiency in designing pediatric PK studies using adult data.104 Given the wealth of available adult clinical information, translation of these data to support pediatric dosing is possible.105 If there are dosing recommendations in adult patients with renal impairment, these recommendations are also available for modeling dosing for renally impaired pediatric patients.

Additional approaches to pediatric dosing in renal impairment are possible. Therapeutic drug monitoring can be used with some drugs, especially with those drugs with a narrow therapeutic index. In those cases, drug concentrations in blood are closely monitored to avoid and/or minimize toxicity. Dosing in patients requiring hemodialysis or other forms of renal replacement therapy also require special attention and has not been evaluated in this assessment.

Conclusion

The objective of the present study was to explore the evidence behind the dosing recommendations for pediatric patients with renal impairment in a major pediatric dosing handbook (Lexicomp) compared with FDA-approved manufacturer’s labels and the published literature. One hundred twenty-six drugs in Lexicomp had pediatric renal dosing recommendations. Only 14% of Lexicomp pediatric renal dosing recommendations (18 of 126) referenced a pediatric clinical study, and 15% of manufacturer’s labels (19 of 126) described specific dosing regimens for renally impaired pediatric patients. Forty-two products had published information on pediatric renal dosing, but 19 (45%) were case studies. When pediatric clinical studies were not referenced in Lexicomp, the renal dosing recommendations were more likely to follow the adult and pediatric dosing recommendations in the manufacturer’s label. Clinical evidence in pediatric patients does not exist for most renal dosing recommendations in a widely used pediatric dosing handbook, and the adult renal dosing recommendations from the manufacturer’s label are currently the primary source of pediatric renal dosing information.

Supplementary Material

Supp Material

Acknowledgments

Dr. Al-Khouja is supported by National Institutes of Health Training Grant T32 GM066691.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Footnotes

Publisher's Disclaimer: Disclaimer

Publisher's Disclaimer: The opinions expressed in this article are those of the authors and should not be interpreted as the position of the U.S. Food and Drug Administration.

Conflicts of Interest

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Sharing

All the data for this analysis is included in the Supplemental Tables and references presented.

Supplemental Information

Additional supplemental information can be found by clicking the Supplements link in the PDF toolbar or the Supplemental Information section at the end of web-based version of this article.

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