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Amy L. Kiskaddon, PharmD, MBA, BCPPS, discusses how medication doses need to be adjusted for pediatric patients with obesity.
Obesity in children and adolescents is a growing global public health concern. Recent data indicate that upward of 18.5% of children and adolescents in the United States have obesity.1,2 The Centers for Disease Control and Prevention and the American Academy of Pediatrics define obesity in individuals aged 2 to 20 years as a body mass index (BMI) equal to or above the 95th percentile of the percentile range on a specific BMI-for-age growth chart.3
Given pathophysiological changes associated with a higher body proportion of fat in obesity, drug pharmacokinetics may be altered, and therefore, adjustments to medication dosing may be required.4 Furthermore, there is a risk of drug doses exceeding the recommended maximum amount if total body weight (TBW) is used for weight-based dosing of certain drugs.5
However, because of the lack of pharmacokinetic studies of individual drugs in children and adolescents with obesity, there is limited guidance for determining whether drug dose adjustments are necessary. Evaluation of pharmacokinetic changes, drug properties, and patient factors are important considerations when determining optimal doses.
Pharmacokinetic changes in obesity
Given changes in body composition and physiology that occur in the setting of obesity, alterations in drug pharmacokinetics may result in therapeutic failure or toxicity (Table 1).5-7 Children and adolescents with obesity have a higher proportion of body fat and changes in volume of distribution (Vd), although the direction and magnitude are difficult to predict. Vd is affected by physiological changes that occur in obesity, such as body mass, extracellular water, tissue perfusion, and proportions of lean and fat tissue.5
Vd is typically larger for lipophilic medications because of distribution of the drugs into adipose tissues and is often altered for hydrophilic medications as well (ie, increased or decreased). Additionally, metabolism and clearance may be affected by obesity. It is thought that individuals with obesity may have changes in hepatic clearance and increased phase 1 and 2 reactions. Increased kidney size has been noted with higher TBW, leading to increased glomerular filtration rate.5-8 Collectively, these physiological and pharmacokinetic changes may require adjustments to the loading dose, dose interval, and time to reach steady state in certain medications.
Pharmacokinetics
Obesity effect
Examples of drugs
Absorption
None
N/A
Vd
Increased Vd for highly lipophilic drugs
Altered Vd for water-soluble drugs
Benzodiazepines, opioids, propranolol
Aminoglycosidesa (ABW)
Metabolism
Reduced CYP3A4 activity, increased CYP CYP2E1 activity
Fentanyl, midazolam, carbamazepine
CL
Increased with body weight, decreased depending on drug metabolism
Aminoglycosidesa, cimetidine, some benzodiazepines, steroids
t½
Lipophilic drugs may accumulate in adipose tissue
Increased Vd and/or decreased clearance may prolong t½
Dependent on Vd and CL
ABW, adjusted body weight; CL, clearance; t½, half-life; Vd, volume of distribution.
aamikacin, gentamicin, tobramycin
Dosing in pediatric patients with obesity
Dosing regimens in pediatric patients are based on age, weight, and body surface area (BSA). Dosing based on weight and BSA is the most utilized method. However, in children and adolescents with obesity, this may lead to doses greater than the maximum dose for adults. Adjusted measures of weight have been developed to help accommodate these changes, including ideal body weight (IBW) and adjusted body weight (ABW) (Table 2).9,11 The selection of a size description for dosing is often considered when the patient TBW is greater than 120% of the IBW and prevents excess doses or accumulation of medications.11 Lean body weight may be used for maintenance dosing. BSA using the Mosteller equation for individuals aged 1 month to 14 years may also be used for certaintreatments, such as chemotherapy.10-12 Patient-specific characteristics such as underlying organ function, illness severity, and extent of obesity must also be considered. Additionally, medication characteristics including Vd, lipophilicity, hydrophilicity, and therapeutic range should be evaluated. Collectively, these factors are useful for determining appropriate loading and maintenance dosing. If a loading dose is required in pediatric patients with obesity, TBW is typically used for lipophilic drugs, ABW for partially lipophilic drugs, and IBW for hydrophilic drugs.
Weight description
Definition and calculation
ABW
Lean body mass+proportion of excess mass
IBW+prespecified cofactora× (TBW−IBW)
BSA (Mosteller)12
Square root [(height (cm)×weight (kg))/3600]
IBW10
Lean body mass in children aged 2 to 20 years
[(50th percentile BMI-for-age)×(height in m)]2
TBW10
Actual body weight
ABW, adjusted body weight; BMI, body mass index; BSA, body surface area; IBW, ideal body weight; TBW, total body weight.
aThe prespecific cofactor is medication specific.
Medication dosing adjustments in children and adolescents with obesity
Most data available to guide pediatric dosing recommendations are based on recommendations for adult patients with obesity.11 Given the limited published data to guide dosing in children and adolescents with obesity, attention should be given to dosing selected for individual medications (Table 3). To prevent potential errors, the American Academy of Pediatrics recommends that patients’ weights are appropriate for the weight-based dosing regimen and that adult doses are not exceeded. The Pediatric Pharmacy Association supports the following empiric dosing considerations for pediatric patients13:
Drug
Dosing considerations in pediatric obesity
Analgesics/sedatives
Acetaminophen14
TBW up to adult maximum dose, may consider IBW
Benzodiazepines15
TBW for loading doses, consider IBW for maintenance dosing
Dexmedetomidine17
ABW, monitor for adverse effects
Fentanyl16
IBW for maintenance dosing and adult dosing, titrate to effect
Hydromorphone15
IBW for maintenance dosing; titrate to effect, consider adult dosing
Ibuprofen16
TBW up to adult maximum dose
Ketamine15
IBW for maintenance dosing and adult dosing, titrate to effect
Ketorolac16
TBW up to adult maximum dose
Methadone15
Caution due to increased risk of adverse effects and accumulation of adipose tissue
Morphine15
IBW for maintenance dosing and adult dosing, titrate to effect
Oxycodone15
IBW for maintenance dosing and adult dosing, titrate to effect
Propofol15
Lower dose and titrate, monitor for adverse effects
Antiarrhythmics
Amiodarone18
TBW up to maximum adult dose
Lidocaine19
TBW up to maximum adult dose and monitor
Anticoagulants
Enoxaparin20,21
Therapeutic drug monitoring to ensure within goal range
Heparin22,23
Therapeutic drug monitoring, may consider using ABW
Antiepileptics
Carbamazepine24
IBW for maintenance dosing, use adult maximum dose
Levetiracetam25
Use adult maximum dose
Phenytoin/fosphenytoin26
Monitor levels, consider extent of obesity and IBW for maintenance dosing
Phenobarbital27
TBW, monitor levels
Valproic acid26
Use adult maximum dose
Antifungals
Fluconazole26
TBW up to adult maximum dose
Micafungin26
TBW up to adult maximum dose
Voriconazole28
Therapeutic drug monitoring, consider extent of obesity and using IBW
Antimicrobials/antivirals
Acyclovir26
IBW
Aminoglycosides (amikacin, gentamicin, tobramycin)26
ABW (cofactor of 0.4) and therapeutic drug monitoring
Azithromycin29
TBW up to adult maximum dose
Carbapenem28
TBW up to adult maximum dose
Cephalosporin28
TBW up to adult maximum dose
Ciprofloxacin26
TBW up to adult maximum dose
Clindamycin30
TBW up to adult maximum dose
Daptomycin28
ABW
Linezolid28
TBW up to adult maximum dose
Metronidazole26
TBW up to adult maximum dose
Penicillin28
TBW up to adult maximum dose
Sulfamethoxazole/trimethoprim28
TBW up to adult maximum dose
Vancomycin28
TBW up to adult maximum dose, therapeutic drug monitoring
Paralytics
Cisatracurium31
IBW
Rocuronium31
IBW
Vecuronium31
IBW
Vasopressors/Vasodilators
Dopamine26
TBW, titrate to effect
Dobutamine26
TBW, titrate to effect
Epinephrine26
TBW, titrate to effect
Milrinone26
TBW, titrate to effect
Nitroprusside26
TBW up to adult maximum dose
Nicardipine26
TBW up to adult maximum dose
Other
Albumin26
IBW
Digoxin26
IBW
Diphenhydramine26
TBW up to adult maximum dose
Enalapril32
TBW up to adult maximum dose
Furosemide6
TBW up to adult maximum dose
H2-receptor antagonists34
TBW up to adult maximum dose
Immunoglobulin G33
IBW or adjusted body weight
Ondansetron26
TBW up to adult maximum dose
Proton pump inhibitors34
TBW up to adult maximum dose
Steroids34
TBW up to adult maximum dose, consider extent of obesity and use of ABW
ABW, adjusted body weight; H2, histamine2; IBW, ideal body weight; TBW, total body weight.
Conclusion
Given the continued rise of obesity in children and adolescents, thought should be given to dosing when selecting medications. Pathophysiologic changes associated with obesity can predict alterations in drug pharmacokinetics and pharmacodynamics, but consideration should be given to disease state and drug-specific properties. Therapeutic drug monitoring may also be of use where feasible to assess effectiveness and safety of dosing regimens. Future research should evaluate pediatric population pharmacokinetics/pharmacodynamics in children and adolescents with obesity.
References