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Pediatric obesity presents complexities in medication dosing

Contemporary PEDS Journal, November/December 2022,

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

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:

  • Fewer than 18 years of age and less than 40 kg: utilize weight-based dosing
  • Fewer than 18 years of age and greater than or equal to 40 kg: utilize weight-based dosing with adult maximum doses or total daily doses for the specific indication
  • Therapeutic drug monitoring as indicated to ensure effective and safe therapy

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

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