Improving Pediatric Dosing Through Pediatric Initiatives: What We Have Learned
OBJECTIVE. The goal was to review the impact of pediatric drug studies, as measured by the improvement in pediatric dosing and other pertinent information captured in the drug labeling.
METHODS. We reviewed the pediatric studies for 108 products submitted (July 1998 through October 2005) in response to a Food and Drug Administration written request for pediatric studies, and the subsequent labeling changes. We analyzed the dosing modifications and focused on drug clearance as an important parameter influencing pediatric dosing.
RESULTS. The first 108 drugs with new or revised pediatric labeling changes had dosing changes or pharmacokinetic information (n = 23), new safety information (n = 34), information concerning lack of efficacy (n = 19), new pediatric formulations (n = 12), and extended age limits (n = 77). A product might have had ≥1 labeling change. We selected specific examples (n = 16) that illustrate significant differences in pediatric pharmacokinetics.
CONCLUSIONS. Critical changes in drug labeling for pediatric patients illustrate that unique pediatric dosing often is necessary, reflecting growth and maturational stages of pediatric patients. These changes provide evidence that pediatric dosing should not be determined by simply applying weight-based calculations to the adult dose. Drug clearance is highly variable in the pediatric population and is not readily predictable on the basis of adult information.
- pediatric dosing
Efforts to ensure that drug therapies for the pediatric population are studied with the same level of scientific and clinical rigor as adult therapeutic agents have a long history. These efforts have advanced over the years through the commitment of many organizations, including the American Academy of Pediatrics, the National Institutes of Health, and the Food and Drug Administration (FDA).1–5
Originally, pharmaceutical companies were reluctant to study drugs in children because of the complexity, difficulty, and expense of such trials. In addition, most physicians erroneously assumed that children with conditions or diseases similar to those of adults would consistently respond comparably to adults. This assumption perpetuated empiric use of medications without evidence-based efficacy and safety studies in the relevant pediatric populations.6 Without appropriate safety and efficacy studies in children, pediatricians and other health professionals are often forced to treat children on a trial-and-error basis, through the off-label use of drugs. The outcomes of such off-label treatment can range from beneficial to ineffective or harmful.6
Two legislative initiatives, the FDA Modernization Act in 1997 and the Best Pharmaceuticals for Children Act in 2002, authorized an incentive program for manufacturers who conducted pediatric clinical trials in response to an FDA written request. The Pediatric Research Equity Act in 2003 codified the authority of the FDA to require pediatric studies of certain drugs and biological agents. These 3 laws have resulted in improvements in pediatric information in drug labeling as a result of studies conducted to determine proper dosing and to identify the risks of therapies in pediatric patients.7–11
During pediatric development, physiologic and biochemical processes governing drug absorption, distribution, metabolism, and excretion undergo significant maturation.12 Although adjustment of drug pharmacokinetic parameters according to body weight or body surface area (BSA) can occasionally explain the observed exposure differences between adult and pediatric patients, the direction and extent of these differences across age groups, in general, are not predictable. Some drugs are eliminated more rapidly or more slowly in younger pediatric patients, compared with older pediatric patients. Therefore, weight-based methods for determining pediatric doses, such as the rule of Clark and Young,13 may not account accurately for all variables related to the different stages of maturation and are unlikely to predict consistently the correct dose for each pediatric age group.
In 2003, we reported our experience with the first 33 drugs that received labeling changes as a result of the exclusivity incentive. Twelve of those drugs had dosing and/or safety information that was considered important from a public health perspective.14 This article provides an update on dosing and safety information in drug labeling, with emphasis on significant aspects of pharmacokinetics such as clearance and pharmacodynamic findings, as well as the resulting labeling changes.
We reviewed the pediatric studies for 108 products (including the first 33 drugs, reported previously14) submitted in response to a FDA written request for pediatric studies, as part of a new drug application or supplement, and the subsequent labeling changes through October 28, 2005. Approximately 92000 pediatric patients (including ∼42000 from a large safety study) were enrolled in the ∼250 studies conducted for these 108 products. The studies included safety, clinical effectiveness or clinical outcome, and clinical pharmacology assessments. Although the sponsors were asked by the FDA to submit information on race and ethnicity, we chose not to include that information in this communication because of the variability in interpretation of the information collected by the sponsors.
To assess the overall impact of pediatric efforts, we reviewed the data to determine trends and outcomes across studies that resulted in improved dosing recommendations and new labeling or labeling changes. Pediatric studies were defined as representing ≥1 clinical investigation, including pharmacokinetic studies, conducted in pediatric patients in the age groups in which the drug is anticipated to be used.9 The numbers of pediatric patients in the clinical pharmacology studies in this article are comparable to those in similar publications. Patients’ ages ranged from those of the neonatal period through 17 years, depending on the individual study. Approximately 9500 patients participated in studies of the 23 drugs with dosing changes or new pharmacokinetic information. The numbers of participants in the pharmacokinetic and/or pharmacokinetic/pharmacodynamic studies ranged from 22 to 357 patients per drug studied. The patient numbers were dependent on study design and data analysis considerations. A smaller number of patients participated in studies in which traditional pharmacokinetic approaches were used, relative to the number of patients who participated in population pharmacokinetic and/or pharmacodynamic studies. In addition, demographic features of the target patient population were taken into account for their adequate and appropriate representation in these clinical pharmacology studies, such that pharmacokinetic and/or pharmacodynamic studies were often conducted with a subset of the patients in the clinical outcome studies, to ensure that the demographic features of the target population were represented adequately and appropriately.
For ease of reference and for linkage to the relevant clinical pharmacology information in the product labeling, we discuss several representative examples, to illustrate the scope of observations related to drug clearance in pediatric patients and, as a result, the pediatric doses. The examples are taken from the approved product labeling. Each label represents the data from the clinical trial and is the end product of a negotiation between the FDA and the owner of the label, the pharmaceutical company. We acknowledge that representation of information such as pharmacokinetic parameters and/or units varies in drug labels, as in literature publications, and is considered reflective of current practices. Because we chose to present the information as available in the individual labels, the units and parameters were not further standardized. Also, the available strengths and the range of safe and effective doses for rapidly growing children are taken into consideration when the doses according to weight range or age group are negotiated between the sponsor and the FDA.
Clearance as a Focus
Traditionally, choosing the correct pediatric dose has been empirical. However, as the number of pediatric studies increases, the necessity of basing dose selection on the appropriate drug exposure/dose and the clinical outcome becomes more evident. Because of this prominent relationship, this article focuses on drug clearance as 1 of the 2 key parameters (clearance and bioavailability) describing drug exposure. Because most of these studies were not designed to characterize drug bioavailability, clearance was determined to be most suitable for exploration of general trends and differences in drug exposure in the pediatric population. In addition to the general robustness of this parameter (because it is based on multiple measurements), drug clearance is influenced by the maturation processes. As evident in the specific examples in this article, the emerging pattern supports the observation that drug clearances in pediatric patients, unlike adults, reflect the parameters of growth and maturation in children.
Clearance (also referred to as total clearance) represents both renal and nonrenal clearance of drugs, reflecting maturation (age)-related changes. After oral administration, the clearance parameter described is apparent oral clearance, a composite value that represents a net estimate of drug clearance and the fraction of the dose absorbed. In this article, clearance calculations are based on drug concentrations measured in plasma or serum. Because of the inverse relationship between clearance and elimination half-life, changes in clearance (in the absence of changes in distribution volume) are indicative of changes in drug elimination half-life (eg, a reduction in clearance would indicate a prolonged elimination half-life), which may necessitate an alteration in dose and/or dosing frequency.
To capture the emerging trends in these examples, observations of drug clearance (or apparent oral clearance, as applicable) are grouped as being lower or higher in younger patients, compared with older patients or adults, with “influencing” factors such as body weight or BSA as predictors of changes in clearance estimates. For ease of reading, observations related to clearance and apparent oral clearance are listed in the same sections. Unique to the pediatric population, drug clearance is occasionally reported with normalization according to body weight. This approach is used to address the wide body weight range observed in the pediatric patient population.
The 108 products with new pediatric labeling represent ∼250 studies submitted by 42 sponsors in response to 108 FDA written requests. These 108 labeling changes included, among others, new or revised pediatric information such as new dosing, dosing changes, or pharmacokinetic information (n = 23) listed in Table 1, new and/or enhanced safety data (n = 34), information on lack of efficacy (n = 19), new formulations (n = 12), and dosing instructions extending the age limits in the pediatric populations (n = 77) (a product could have ≥1 pediatric labeling change). Seven of these applications were for new molecular entities.
Significant Pharmacokinetic and/or Pharmacodynamic Findings and Dosing Changes in Labeling
Pharmacokinetic findings yielded new dosing recommendations in children for one fifth (n = 23) of the products studied (see Table 1 for list and indications). Several examples are discussed in detail because they illustrate important pharmacokinetic findings and dosing recommendations. A representative set of drugs (n = 16) that highlight considerations pertinent to pediatric dosing is listed in Table 2, with a summary of the key pharmacokinetic findings.
Lower Drug Clearance (or Apparent Oral Clearance) in Younger Patients
Luvox (Fluvoxamine Maleate)
The multiple-dose pharmacokinetics of fluvoxamine (Luvox, Sandoz, Princeton, NJ) were determined in male and female children (age: 6–11 years) and adolescents (age: 12–17 years). After administration of a 100-mg fluvoxamine dose, the apparent oral clearance (mean ± SD) of fluvoxamine normalized according to body weight was 0.449 ± 0.261 L/hour per kg in the younger patients and 0.884 ± 0.737 L/hour per kg in the adolescents. The steady-state plasma fluvoxamine concentrations were approximately twofold higher in the younger patients than the adolescents. As in adults, fluvoxamine pharmacokinetics in younger patients and adolescents were nonlinear, that is, the systemic drug exposure increased disproportionately with dose.
Although gender differences were not detected for adolescents, fluvoxamine mean body weight-normalized apparent oral clearance values for the 3 dose groups (25-mg, 50-mg, and 100-mg doses) in the younger female pediatric patients were approximately one half the values seen in male pediatric patients. Titration of dosing to the desired clinical effect, as recommended in the labeling, addresses these differences. Consequently, therapeutic effects in female patients may be achieved with a lower dose. The recommended starting dose for fluvoxamine tablets in pediatric populations (age: 8–17 years) is 25 mg, administered as a single daily dose at bedtime. The dose should be increased in 25-mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved. The maximum dose should not exceed 200 mg/day in patients up to 11 years of age and 300 mg/day in adolescents.15
In pharmacokinetic studies, famotidine clearance after intravenous administration of 0.5 mg/kg famotidine doses in pediatric patients <1 year of age was lower than that in older pediatric patients (age: 1–15 years) and adults. After intravenous administration of a 0.5 mg/kg dose, famotidine clearance (mean ± SD) was 0.13 ± 0.06 L/hour per kg in infants 0 to 1 month of age and 0.21 ± 0.06 L/hour per kg in those 0 to 3 months of age, ∼25% and ∼50%, respectively, of the values seen in 1- to 15-year-old pediatric patients and adults. Famotidine clearance was 0.54 ± 0.34 L/hour per kg in pediatric patients 1 to 11 years of age and 0.48 ± 0.14 L/hour per kg in 11- to 15-year-old patients. In adults, famotidine clearance after a 20-mg intravenous dose was 0.39 ± 0.14 L/hour per kg.
Similar trends were observed in famotidine distribution volume. In pediatric patients 0 to 1 month, 0 to 3 months, >3 to 12 months, and 1 to 11 years of age, famotidine distribution volume (mean ± SD) was 1.4 ± 0.4 L/kg, 1.8 ± 0.3 L/kg, 2.3 ± 0.7 L/kg, and 2.07 ± 1.49 L/kg, respectively. Famotidine distribution volumes were comparable in 11- to 15-year-old patients and adults, with mean ± SD values of 1.5 ± 0.4 L/kg and 1.3± 0.2 L/kg, respectively.
Bioavailability of famotidine after administration of famotidine oral suspension (Pepcid, Merck and Co, Inc, Whitehouse, NJ) was similar in pediatric patients <1 year of age, compared with pediatric patients 1 to 15 years of age and adults. Therefore, on the basis of lower famotidine clearance in pediatric patients <1 year of age, lower famotidine doses are recommended. The recommended oral starting dose is 0.5 mg/kg once daily for infants <3 months of age and 0.5 mg/kg twice daily for children 3 months to <1 year of age.
For pediatric patients 1 to 16 years of age, famotidine dose varies depending on the indication, as described in the drug labeling (peptic ulcer: 0.5 mg/kg per day, orally, at bedtime or divided at twice per day, up to 40 mg/day; gastroesophageal reflux disease with or without esophagitis including erosions and ulcerations: 1.0 mg/kg per day, orally, divided at twice per day, up to 40 mg twice per day). As described in the drug label, treatment duration and dose should be individualized on the basis of clinical response and/or pH determination (gastric or esophageal) and endoscopic findings.
Pharmacokinetic information from 36 neonates given lamivudine at up to 1 week of age demonstrated that the clearance of Epivir (lamivudine) (GlaxoSmithKline, Research Triangle Park, NC) was substantially reduced in 1-week-old neonates, compared with patients >3 months of age. Although there was insufficient information to characterize the time course of changes in lamivudine clearance between 1-week-old neonates and infants for the period up to 3 months of age, lamivudine clearance was higher in patients 4 months to 14 years of age than in younger infants, and the clearance in older children (adolescents) became comparable to adult values. Unlike the observation in neonates, lamivudine clearance (normalized according to body weight) was approximately twofold higher in 1-year-old patients than in older pediatric patients. As illustrated in the drug labeling, systemic clearance of lamivudine was ∼0.75 L/hour per kg for 1-year-old patients and ∼0.4 L/hour per kg for 14-year-old patients in a pharmacokinetic study.
In pediatric patients (n = 11) 4 months to 14 years of age, 4 mg/kg twice-daily doses resulted in lamivudine exposures comparable to those in adults after a daily dose of 4 mg/kg per day. In combination with other antiretroviral agents, the recommended oral dose of lamivudine for HIV-infected pediatric patients 3 months up to 16 years of age is 4 mg/kg twice daily (up to a maximum of 150 mg twice per day), administered in combination with other antiretroviral agents. No dosing recommendation is available in the label for infants <3 months of age.
Concerta (Methylphenidate HCl)
In a multiple-dose study, the apparent oral clearance of methylphenidate (mean ± SD) after administration of a 36-mg oral dose of methylphenidate extended-release tablets (Concerta, ALZA Corporation, Mountain View, CA) was 372 ± 137 L/hour in healthy adolescents with attention-deficit/hyperactivity disorder (ADHD). This mean apparent oral clearance of methylphenidate in the younger group (age: 6–12 years) was ∼40% lower in comparison with adolescents and 50% lower in comparison with adults. Starting with methylphenidate HCl immediate-release tablets (Ritalin), the therapeutic dose in pediatric patients ≥6 years of age is 5 mg twice daily, whereas the average adult dose is considerably higher, 20 to 30 mg daily, administered in 2 or 3 divided doses. For adolescents naive to methylphenidate, higher maximum methylphenidate doses are recommended, compared with children 6 to 12 years of age. Dose recommendations are based on current dosing regimens and clinical judgment. A dose-conversion table is provided in the Concerta labeling for switching to a single daily dose of methylphenidate.16
Adderall XR (d-Amphetamine and l-Amphetamine Neutral Sulfate Salts, 3:1)
Systemic exposure to amphetamines is higher in younger pediatric patients (age: 6–12 years) than adolescents or adults for a given dose of Adderall XR (Shire US Inc, Wayne, PA). Comparison of the pharmacokinetics of d- and l-amphetamine after oral administration of Adderall XR to pediatric patients and adolescent and healthy adult volunteers indicated that body weight is the primary determinant of apparent differences in the pharmacokinetics of d- and l-amphetamine. The d-amphetamine apparent oral clearance (mean ± SD) after a 20-mg oral dose was 377 ± 87.7 mL/min in adolescents weighing ≤75 kg (≤165 lb) and 436 ± 77.3 mL/min in adolescents weighing >75 kg (>165 lb). The l-amphetamine apparent oral clearance was 331 ± 94.4 mL/min in adolescents weighing ≤75 kg (≤165 lb) and 389 ± 83.8 mL/min in adolescents weighing >75 kg (>165 lb). The mean elimination half-life for d-amphetamine was 9 hours in pediatric patients (age: 6–12 years), 11 hours in adolescents weighing ≤75 kg (≤165 lb), and 10 hours in adults. The mean elimination half-life for l-amphetamine was 11 hours in pediatric patients (age: 6–12 years), 13 to 14 hours in adolescents weighing ≤75 kg (≤165 lb), and 13 hours in adults.
For pediatric patients (age: 6–12 years) with ADHD, the starting dose is 10 mg of Adderall XR once daily in the morning for first-time patients or those switching from another medication. The daily dosage may be adjusted in increments of 5 mg or 10 mg at weekly intervals. The maximum recommended dose for pediatric patients (age: 6–12 years) is 30 mg/day; doses of >30 mg/day Adderall XR have not been studied in pediatric patients. In adolescents with ADHD, the recommended Adderall XR dose starts at 10 mg/day. The dose may be increased to 20 mg/day (a dose similar to adults) after 1 week if ADHD symptoms are not adequately controlled.
Increasing Drug Clearance (or Apparent Oral Clearance) With Increasing Body Weight (Up to Adult Values)
Drugs in this group are similar to those in the first group (lower drug clearance in the youngest or younger patients) with a primary distinction that adjustments to accommodate differences in body weight are adequate to explain differences in drug clearances and exposures across all age groups. Optimal dosing recommendations for this group are influenced primarily by patient body weight.
Malarone (Atovaquone/Proguanil HCl)
The elimination half- life of atovaquone after administration of atovaquone/proguanil is shorter in pediatric patients (1–2 days), compared with adults (2–3 days). The elimination half-life of proguanil is 12 to 21 hours in pediatric and adult patients. Although longer elimination half-lives in older patients or adults, compared with pediatric patients, may seem paradoxical with increasing clearance in older patients, compared with younger patients, this observation was found to be mostly attributable to differences in body weight. The clearance of each component increased with increasing body weight for patients who weighed <40 kg. Body weight was found to be the primary factor describing the differences in the apparent oral clearances of atovaquone and proguanil. Atovaquone apparent oral clearance (mean ± SD) was 1.34 ± 0.63 L/hour for patients weighing 11 to 20 kg, 1.87 ± 0.81 L/hour for patients weighing 21 to 30 kg, 2.76 ± 2.07 L/hour for patients weighing 31 to 40 kg, and 6.61 ± 3.92 L/hour for patients weighing >40 kg. For proguanil, apparent oral clearance was 29.5 ± 6.5 L/hour for patients weighing 11 to 20 kg, 40.0 ± 7.5 L/hour for patients weighing 21 to 30 kg, 49.5 ± 8.30 L/hour for patients weighing 31 to 40 kg, and 67.9 ± 19.9 L/hour for patients weighing >40 kg. As a result, atovaquone/proguanil HCl daily doses, as fixed-dose Malarone (GlaxoSmithKline) tablets, are recommended according to a patient's body weight (ie, higher doses with increasing body weight). For example, for pediatric patients with body weights within the 11- to 20-kg range and for patients who weigh >40 kg, fixed-dose Malarone (atovaquone/proguanil) tablets of 62.5 mg/25 mg and 250 mg/100 mg, respectively, are recommended for prevention of malaria. Body weight-based dosing information for prevention and treatment of malaria in pediatric patients weighing 11 to 20 kg, 21 to 30 kg, and 31 to 40 kg is stated in the drug labeling. Adult doses are recommended for pediatric patients who weigh >40 kg.
Prozac (Fluoxetine HCl)
After daily 20-mg fluoxetine oral dosing, the average steady-state concentrations of Prozac (Fluoxetine HCl, Eli Lilly and Co, Indianapolis, IN) and its active metabolite norfluoxetine in pediatric patients (age: 6 to <13 years) were 2- and 1.5-fold higher, respectively, than those in adolescents (age: 13–18 years) with major depressive disorder or obsessive-compulsive disorder. The mean steady-state fluoxetine concentrations in the younger group (age: 6 to <13 years) and in adolescents were 171 ng/mL and 86 ng/mL, respectively. Similarly, the mean norfluoxetine steady-state concentrations in the younger group and in adolescents were 195 ng/mL and 113 ng/mL, respectively. Because a fixed daily dose was administered to the younger group and the adolescents, exposure values corrected for body weight suggested that the observed differences in exposure among the 2 groups could be explained almost entirely by differences in body weight. As in adults, steady-state concentrations were achieved within 3 to 4 weeks of daily dosing. In adults, after administration of 40 mg/day for 30 days, the plasma concentrations of fluoxetine and norfluoxetine ranged from 91 to 302 ng/mL for fluoxetine and from 72 to 258 ng/mL for norfluoxetine. Although concentration ranges were comparable between adult and pediatric patients, these concentrations were achieved at twofold higher fluoxetine doses in adults, compared with pediatric patients. A lower starting dose (10 mg daily, compared with 20 mg in adults) is recommended in the labeling for children, particularly for those with lower weight, compared with adults.
The safety and efficacy of Arava Leflunomide (Sanofi-Aventis US LLC, Bridgewater, NJ) in pediatric patients with polyarticular juvenile rheumatoid arthritis have not been fully evaluated. Leflunomide is metabolized to 1 primary active metabolite (metabolite 1) and several minor metabolites. The parent compound is rarely detectable in plasma. The mean clearance of metabolite 1 from orally administered leflunomide is ∼30% lower in pediatric patients (age: 3–17 years) with polyarticular course juvenile rheumatoid arthritis weighing ≤40 kg, compared with those weighing >40 kg. In a 16-week multicenter study in which the loading dose and maintenance dose of Arava were based on 3 weight categories (<20 kg, 20 to ≤40 kg, and >40 kg), the clinical response to Arava in pediatric patients weighing <40 kg was less robust than that in pediatric patients weighing ≥40 kg. The reason for this outcome is unknown and may be related to suboptimal dosing in lower-weight pediatric patients and/or other clinical differences in responses in this group of patients.
Zofran (Ondansetron HCl)
Zofran (GlaxoSmithKline) is approved for prevention of postoperative nausea and vomiting in adults and pediatric patients 1 month to 12 years of age (0.1 mg/kg dose) and for prevention of chemotherapy-induced nausea and vomiting in adults and pediatric patients 6 months to 18 years of age (0.15 mg/kg per dose every 4 hours up to 4 doses). In the studies conducted in response to the FDA written request, ondansetron was studied in younger pediatric patients (age: 1–24 months) for postoperative induced nausea and vomiting and in 6- to 48-month-old patients for chemotherapy-induced nausea and vomiting. When the drug was administered intravenously on a weight basis to pediatric surgical patients 1 to 24 months of age, the clearance of ondansetron was lower and the half-life was longer in the 1- to 4-month-old patients, compared with the older pediatric patients (5 and 24 months of age). The mean half-life of ondansetron was 6.7 hours in patients 1 to 4 months of age and 2.9 hours in the older age groups (5–24 months and 3–12 years). In healthy adult volunteers given a single 24-mg tablet dose, the ondansetron half-life was ∼5 hours. According to a population pharmacokinetic analysis, ondansetron clearance and volume of distribution were dependent on body weight and age. Because body weight and age are highly correlated in pediatric patients, ondansetron dosing was based on body weight. For prevention of postoperative induced nausea and vomiting, ondansetron dosing is a single 0.1 mg/kg dose for patients weighing ≤40 kg or a maximum single dose of 4 mg for patients weighing >40 kg. For prevention of chemotherapy-induced nausea and vomiting, based on similarity of exposures, the intravenous ondansetron dose is 0.15 mg/kg every 4 hours for 3 doses in pediatric patients with cancer 6 to 48 months of age, as well as older pediatric patients with cancer (age: 4–18 years).
For prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy, the Zofran oral dosage for pediatric patients ≥12 years of age is the same as that for adults. The recommended adult oral dose is one 8-mg Zofran tablet, one 8-mg Zofran orally disintegrating tablet (ODT), or 10 mL (2 teaspoonfuls, equivalent to 8 mg of ondansetron) of Zofran oral solution given twice per day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. The second dose should be followed by one 8-mg Zofran tablet, one 8-mg Zofran ODT, or 10 mL of Zofran oral solution administered twice per day (every 12 hours) for 1 to 2 days after completion of chemotherapy.
For pediatric patients 4 through 11 years of age, the dosage is one 4-mg Zofran tablet, one 4-mg Zofran ODT, or 5 mL (1 teaspoonful, equivalent to 4 mg of ondansetron) of Zofran oral solution given 3 times per day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. Then one 4-mg Zofran tablet, one 4-mg Zofran ODT, or 5 mL of Zofran oral solution should be administered 3 times per day (every 8 hours) for 1 to 2 days after completion of chemotherapy.
Higher Apparent Oral Drug Clearance in Younger Patients (ie, Pediatric and Adult Clearance Values Become Comparable After a Certain Age Range)
The experience with the anticonvulsant Neurontin (Parke Davis Pharmaceuticals, Vega Baja, PR) oral solution provides another important example of age-related differences in drug clearance. The pharmacokinetics of gabapentin were characterized in 48 pediatric patients who were 1 month to 12 years of age, after administration of a ∼10 mg/kg dose. The apparent oral clearance normalized according to body weight was higher in younger children (age: 1 month to <5 years) and resulted in ∼30% lower gabapentin exposure (area under the drug concentration-time curve) than that observed in older children (≥5 years). The body weight-normalized apparent oral clearance values in pediatric patients ≥5 years of age were similar to values observed in adults (∼225 mL/min). Therefore, higher doses are required in the younger pediatric age group. Patients 3 to 4 year of age should be given 40 mg/kg per day gabapentin in 3 divided doses, whereas patients 5 to 12 years of age should receive 25 to 35 mg/kg per day administered in 3 divided doses. For the entire age span of 3 to 12 years, gabapentin should be administered starting at a dose of 10 to 15 mg/kg per day in 3 divided doses, reaching the effective dose through upward titration over a period of ∼3 days.
Lotensin (Benazepril HCl)
With repeated multiple daily oral doses of Lotensin (Benazepril HCl, Novartis Pharmaceuticals Corporation, Suffern, NY) ranging from 0.1 to 0.5 mg/kg, the clearance of benazeprilat, the active metabolite, was 0.35 L/hour per kg in 6- to 12 year-old, hypertensive, pediatric patients and 0.17 L/hour per kg in hypertensive adolescent patients, ∼50% and 27% higher, respectively, than the values seen in healthy adults (0.13 L/hour per kg) receiving a single dose of 10 mg. The terminal elimination half- life of benazeprilat in pediatric patients is ∼5 hours, approximately one third of that observed in adults. In pediatric patients, the recommended starting dose of benazepril is 0.2 mg/kg once per day as monotherapy. Doses of >0.6 mg/kg (or >40 mg daily) have not been studied in pediatric patients (age: 6–16 years). Benazepril is not recommended for children <6 years of age or pediatric patients with glomerular filtration rates of <30 mL/min, because there are insufficient data available to support a dosing recommendation for those groups.
Oxcarbazepine is rapidly metabolized to its 10-monohydroxy metabolite, which is primarily responsible for its antiepileptic effect. Weight-adjusted 10-monohydroxy metabolite clearance is higher in younger pediatric patients, compared with older pediatric patients and adults, and, with increasing age and body weight, approaches adult values for patients ≥13 years of age. After a single dose of 5 or 15 mg/kg Trileptal (Oxcarbazepine, Novartis Pharmaceuticals Corporation), the dose-adjusted area under the concentration-time curve values for the 10-monohydroxy metabolite were 30% to 40% lower in children <8 years of age, compared with children >8 years of age. Children >8 years of age had clearance values similar to adult values of 0.043 L/hour per kg.
Although the population pharmacokinetic model identified BSA as a predictor of clearance, the clinical studies were conducted on the basis of weight-adjusted dose. Given the relationship between BSA and body weight, as well as for practical purposes and ease of calculation, oxcarbazepine dosing recommendations are based on body weight.
Patients first are exposed to oxcarbazepine as adjunctive therapy and then are converted to monotherapy. Specifically, as adjunctive therapy (for patients 2–16 years of age), oxcarbazepine treatment should be initiated at a daily dose of 8 to 10 mg/kg generally, not to exceed 600 mg/day, given in a twice-daily regimen. Detailed instructions for adjunctive therapy and conversion to monotherapy from adjunctive therapy and the doses according to body weight (20–70 kg) are described in the Trileptal labeling.
The pharmacokinetics of single-dose Keppra (Levetiracetam, UCB Inc, Smyrna, GA) (20 mg/kg) were evaluated in 24 pediatric patients (age: 6–12 years). The body weight-adjusted apparent oral clearance of levetiracetam was ∼40% higher than that in adults (mean clearance in adults: 0.96 mL/minute per kg). The half-life of levetiracetam was ∼5 hours in pediatric patients (age: 4–12 years) and 7 hours in adults.
In population pharmacokinetic analyses, body weight was shown to have a significant effect on both apparent oral clearance and apparent oral distribution volume of levetiracetam. Body weight-based dosing recommendations are made for pediatric patients weighing <40 kg. In 4- to 16-year-old pediatric patients, levetiracetam treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg, 2 times per day). The daily dose should be increased every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg, 2 times per day). Patients with body weights of ≤20 kg should be treated with oral solution, whereas patients with body weights of >20 kg can be treated with either tablets or oral solution. Keppra labeling provides detailed dosing information for pediatric patients weighing between 20.1 and 40 kg and for those who weighed >40 kg (ie, up to the adult dose of 60 mg/kg per day 2 times per day, or 3000 mg/day).17
In adults, treatment should be initiated with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg, 2 times per day). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg.
BSA and Response Relationship
The study of Betapace (sotalol HCl) in pediatric patients demonstrated that BSA was the most important covariate and was more relevant than age in describing the exposure-response relationship for sotalol. Smaller children (BSA: <0.33 m2) showed a tendency for a larger change in QTc and an increased frequency of prolongation of the QTc interval, as well as greater β-receptor-blocking effects. Therefore, the best approach is individualized dosing based on BSA and close monitoring of the patients, particularly pediatric patients whose BSA values are ≤0.33 m2.
Other Significant Pharmacokinetic and/or Pharmacodynamic Findings
Ultiva (Remifentanil HCl)
In pediatric patients (age: 5 days to 17 years), the clearance of Ultiva (Remifentanil HCl, Abbott Park, IL) was higher in the younger patients and approached adult values as the patients grew older. In patients <2 months of age, the remifentanil clearance (mean ± SD) was ∼90.5 ± 36.8 mL/minute per kg; in adolescents (age: 13–16 years), the value was 57.2 ± 21.1 mL/minute per kg. The volume of distribution of remifentanil was greater in patients <2 months of age and approached adult values in adolescents, with steady-state distribution volume values (mean ± SD) of 452 ± 144 mL/kg and 223 ± 30.6 mL/kg, respectively. The differences in distribution volume in patients <2 months of age are most likely attributable to the higher fat content in that population and the greater lipid solubility of the drug, The adult remifentanil clearance and distribution volume estimates are 40 mL/minute per kg and 350 mL/kg, respectively. The half-life of remifentanil was similar in neonates and in adolescents. The clearance of remifentanil was highly variable in neonates and approximately twice that observed in healthy young adults. Because of high variability in neonatal pharmacokinetics, starting with a fixed remifentanil infusion rate of 0.4 μg/kg per minute may be appropriate for some neonates but a higher infusion rate may be necessary for others to maintain adequate surgical anesthesia, and additional bolus doses may be required. Careful titration of individual doses for each patient is recommended.
Viracept (Nelfinavir Mesylate)
Although pharmacokinetic information for Viracept (Nelfinavir Mesylate, Agouron Pharmaceuticals, Inc, La Jolla, CA) is available for pediatric patients from birth through 13 years, the highly variable drug exposure and responses represent a significant problem in the dosing of pediatric patients, especially those <2 years of age. In adult clinical pharmacology studies, food high in fat and/or energy content increases nelfinavir exposure and reduces the variability in its exposure; as a result, taking nelfinavir with food is recommended. In pediatric patients, however, food seems to increase the variability in nelfinavir exposure. This difference may be attributable to eating habits and inconsistent food intake in pediatric patients and may be more significant for those <2 years of age (because of different food exposures such as formula and pureed foods, frequency of eating, and gastric motility). A reliable effective dose could not be established for those <2 years of age because of the large variability in nelfinavir exposure and response.
The approval of the muscarinic antagonist for adults was based on the improvement in clinical and urodynamic parameters. When Detrol (Tolterodine, Pfizer Pharmaceuticals, Inc, New York, NY) was studied in pediatric patients to determine pediatric doses for treatment of urinary urge incontinence, urgency, and frequency in a pediatric population, the pharmacokinetic/pharmacodynamic and efficacy/safety trials did not show efficacy at the selected dose estimated from the adult studies. Although study resulted in invaluable pediatric safety information for labeling, the trial also highlighted the importance of dose selection and the need to consider possible differences in drug pharmacokinetics and pharmacodynamics in pediatric and adult patients. Therefore, it is important to note that, in some instances, when the dose selection is based on assumptions of similar exposure-response relationships in pediatric patients and adults (ie, similar drug concentrations), the selected dose may not be efficacious.
Recent legislation and the efforts of the FDA, as well as those of many investigators, willing parents and pediatric patients, and the pharmaceutical industry, have resulted in a significant increase in the number of pediatric studies conducted to evaluate the safe and effective use of drugs in pediatric patients. These efforts have resulted in significant changes in drug labeling for pediatric patients and have shown that unique pediatric dosing, reflecting growth and maturation stages, is often necessary. Before these initiatives, most therapies given to children were “off-label” (ie, studies of safety and efficacy had not been conducted and the drug labels did not include dosing, efficacy, or safety information for pediatric use). The pediatric trial designs are being modified as we continue to gain knowledge from the submitted studies regarding pharmacologic intervention in pediatric diseases and as our assumptions (such as similarity in responses) are being confirmed or challenged.
Depending on the drug therapeutic index, differences in drug exposure may result in modified dosing recommendations in drug labeling for various age groups. All pharmacokinetic studies may not result in dose or dosing adjustments; they may confirm the selected dose or serve to identify areas that deserve additional attention. The examples presented above highlight differences in drug pharmacokinetics in pediatric patients and the factors that are important for pediatric dosing. Changes in drug clearance in pediatric patients cannot always be explained by changes in body weight and should not simply lead to body weight-adjusted dosing. Increasing body weight, particularly for younger patients, correlates strongly with growth and maturation, as reflected in traditional growth charts.
In the examples provided, drug clearance was lower in younger patients than in older pediatric patients and/or adults for some drugs, necessitating dose reductions for fluvoxamine, famotidine, lamivudine, methylphenidate, and d- and l-amphetamine. In contrast, drug clearance was higher in younger patients for gabapentin, benazepril, oxcarbazepine, and levetiracetam, leading to recommendations for higher doses in those patients, compared with older patients. Body weight-related differences can account for differences in drug exposure in pediatric patients for some therapies, with dosing recommendations incorporating adjustments for body weight. This situation has been observed particularly when fixed doses (due to dosage forms) are administered to children and adolescents. Examples include atovaquone/proguanil, fluoxetine, and leflunomide. For other drugs, adjustment based on BSA leads to desired exposure, and BSA is the primary factor accounting for the differences in exposure and the subsequent response (eg, sotalol). Some of the significant findings (in indications, drug safety, and efficacy) that have been incorporated into the drug labeling are available.11 Overall, these differences in drug pharmacokinetics in pediatric patients may be explained by differences in maturation of drug-metabolizing enzymes and/or organs of elimination and changes in body composition, leading to changes in the distribution volumes of drugs. Because of the complexity of the factors involved, the magnitude and the direction of the differences are not always readily predictable. Furthermore, interpatient variability in pharmacokinetic and pharmacodynamic studies seems to be greater in pediatric patients, compared with adults. The volume of distribution also changes with age in many instances (the remifentanil labeling provides an example of this). This greater variability may be partly attributable to inherent differences, including variability in doses, which may be associated with difficulties related to age-appropriate formulations.
The findings from these pediatric trials support the need to continue studying drugs in this population. The dosing, efficacy, and safety information incorporated into pediatric labeling provides practicing pediatricians and generalists with the data that support a pragmatic safe approach to prescribing drugs for this vulnerable patient population. The translation of this information into improved prescribing therapies for children is critical to ensure the safety and efficacy of therapy.
We recognize the value of harmonized and innovative methods that incorporate unique patient and disease characteristics, leading to greater understanding and greater patient benefit. These approaches may include modeling and simulation of exposure-response and/or risk-benefit data and robust statistical methods supporting data analyses from often-small studies. Harmonized study designs, enabling information-sharing across studies through standardized approaches to data collection and interpretation, are needed to optimize the information from these pediatric studies, such that the sum becomes greater than the total of its parts. Harmonization of end points should permit greater learning from multiple studies (for example, through meta-analysis of studies), whereas innovative methods could incorporate unique growth and maturation characteristics of the pediatric patients and include pharmacogenomic and biomarker information. All of these efforts combined could facilitate efficient pediatric drug development and bring advancement in this field. A long-term commitment, starting in early drug development, to gaining and optimizing knowledge for pediatric patients is of utmost importance for developing therapies for this unique and vulnerable patient population.
We thank Jim Angel for his technical assistance throughout the various phases of development of this communication.
- Accepted August 9, 2007.
- Address correspondence to William J. Rodriguez, MD, PhD, Food and Drug Administration, 5600 Fisher Lane, Parklawn Building, Room 13B-45, Rockville, MD 20850. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
The views expressed are those of the authors. No official support or endorsement by the US Food and Drug Administration is provided or should be inferred.
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- Pediatric Research Equity Act of 2003, S 650, 108th Congress. Available at: http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=108_cong_bills&docid=f:s650enr.txt. Accessed November 20, 2006
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