Introduction
Methods
Generalities on the methods proposed for dosing drugs in children with obesity
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weight-based dosing should be used in patients aged < 18 years who are < 40 kg,
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weight-based dosing should be used for children who are ≥40 kg, unless the patient’s dose or dose per day exceeds the recommended adult dose for the specific indication,
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familiarity with adult dosage regimens is needed to avoid exceeding the recommended maximum adult dose,
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Clinicians should consider the occurrence of modifications of PK parameters for adjusting drug dosage whenever possible in children with overweight/obesity to ensure the most effective and safe regimen [11].
Body Descriptor/ Equation/ Population | Remarks |
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TBW TBW: drug dose *kg Pediatric (up to 40 kg and 12 Years) | Not recommended for lipophilic drugs. For unfractionated heparins a lower dose is recommended [12]. |
BSA BSA (m2) = square root of (height (cm) x weight (kg)/3600) Children and adults | This method is used for both adults and children especially for dosing chemotherapy drugs. |
IBW IBW = [50th percentile weight (age)*height(cm)] Age 2-20 years | Accurate determination of IBW is important for the proper dosing of medications, such as acyclovir, digoxin, and morphine. There is no consensus on the most accurate calculation in children. The growth chart-based Moore’s method determines IBW by looking at the same weight percentile line as the child’s height percentile for that age. |
BMI BMI chart for age (weight in kilograms divided by the square of height in meters). Age 2–20 years | A high BMI can be an indicator of high body fatness. Pediatric BMI should be correlated with growth curves and percentiles. |
Allometric scale Dose in children = adult dose * (TBW of a child/70)0.75 Age 2–20 years | Drug dose is predicted using allometry, depending on the properties of the drug such as free fraction in adults, pharmacodynamics and binding proteins [13]. |
Fat Free Mass FFM = weight [kg] * [1 - (body fat [%]/ 100)] Adults | Fat-Free Mass (FFM) refers to all body components except fat. It includes water, bone, organs and muscle content with different measure for males and females. |
Age scaling The dose is selected according to the child’s age using charts. Over six months age. | This method does not take into account the changes due to developmental growth that occurs within each age group (e.g., the hepatic metabolic capacity of an infant child is different from that of a neonate) |
Physiologically Based Dosing | Based on pathophysiology and changes in obesity, drug binding or distribution volume. The adipose tissue succeeds in getting the lipophilic molecules, making them less available for therapeutic effect. The increase in the blood volume and cardiac output of the child affected by obesity and the alteration of plasma proteins create alterations in the distribution of drugs [13, 14] |
Clearance Based Scaling • Dose for the child = adult dose *(CL in the child/CL in adults) • CL in the child = CL in adults * (TBW of a child/70) exp The fixed exponent of 0.75 is commonly used and predicts reasonably well for children older than 2 years of age (as used generally in allometric scaling) [15]. | A. Clearance is a measure of the drug metabolism in the gut and liver and/or their renal elimination. B. Obesity is a predisposing factor for liver steatosis in both adults and children, involving reactions that require modification and therefore the elimination of drugs. CYP3A4 activity is reduced in obese patients. The Clearance based method takes into account renal function too in terms of Volume of distribution and clearance. Obesity can affect kidney enzyme functions |
Common-use and sub-specialty drugs dosing in pediatric patients with obesity
Drug | TBW (Total Body Weight) | Use In Children Affected By Obesity |
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ANTIBIOTICS | ||
Amoxicillin/clavulanic acid (combination of amoxicillin, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor) | 25–70 mg/Kg/die | |
Azithromycin (macrolide) | 10 mg/kg/day | Underdosing the TBW: risk of overdose due to difficult elimination [19]. |
Cefazolin (first generation cephalosporine) | 25-100 mg/kg/day | |
Ceftazidime (cephalosporine) | 40 mg/kg IV q6h | The administration maximized the model-based probability of target attainment PTA in children and adolescents with obesity and GFR ≥ 80 mL/min/1.73 m2 [20] |
Clindamycin (lincosamide) | 20-40 mg/kg/day in three or four equal doses. | |
Ceftriaxone (third-generation cephalosporin) | 50-100 mg/kg/day | TBW dosing has proven safe and effective in childhood obesity [23]. |
Linezolid (oxazolidinones) | 10 mg/kg day, max 600 m | Weight-based dosing in children remains unclear. Data from adult patients suggest risks of linezolid underdosing in empirical antibiotic therapy of most resistant bacteria [19]. |
Meropenem (carbapenem) | 20 mg/kg IV every 8 hours | |
Trimethoprim/sulfamethoxazole (cotrimoxazole) | 8 mg/kg/day trimethoprim | |
Vancomycin (glycopeptide) | 20-40 mg/kg/day | No dose adjustment for obesity [20]. |
ANALGESICS AND ANESTHETICS | ||
Acetaminophen/Paracetamol | 10–15 mg/kg/day every 4-6 h <12y | No significant differences in circulating acetaminophen concentrations after a 5-mg/kg (up to 325 mg) single oral dose administration in children with NAFLD In adults there are higher concentrations of hepatotoxic CYP2E1-mediated acetaminophen metabolites. Adults with obesity may not tolerate high doses due the overproduction of hepatotoxic acetaminophen metabolites [2]. |
Dexmedetomidine (selective a2-agonist) | 1 μg/kg | No differences in the dosage required for sedation in children suffering from obesity and those with normal weight [27]. Rolle et al. have found in their study that lean body mass (LBM) is an appropriate dosing scalar for size in adult patients with obesity [18]. |
Fentanyl (opiate agonist) | 1–2 μg/kg/dose IM | Lipophilic. Adjusted Body Weight (cofactor of 0.25) has been recommended [28]. Mortensen et al. recommended TBW for induction and lean body weight (LBW) for maintenance of anesthesia [28]. |
Midazolam (benzodiazepine) | 0.1–0.3 mg/kg, max 5 mg IV,IM | Potential need for higher initial drug dose administration for continuous infusion [29]. |
Morphine (opiate agonist) | 0.1–0.15 mg/kg/dose every 4 h IM or 0.2–0.4 mg/kg/dose every 4 h OD | Dosing morphine is based on IBW because it is a hydrophilic opioid [28]. TBW not recommended. |
Propofol (short-acting, lipophilic intravenous general anesthetic) | 1–2 mg/kg pro dose | Diepstraten et al. proposed TBW-based dosing to achieve maintenance anesthesia [30]. |
OTHER DRUGS | ||
Amlodipine (Calcium channel blocker) | 0.1 mg/kg/day | TBW [31] |
Angiotensin-Converting Enzyme Inhibitor (Ramipril) | 0.05–0.15 mg/kg/day max 40 mg/day | |
Antipsychotics (e.g. haloperidol, thioridazine, risperidone, aripiprazole) | ||
Atorvastatin (statins) | > 10y: 10-20 mg/day | Due to the correlation of statins with the genotypic variability of SLCO1B1, cases of statin overtreatment may occur [36]. |
Antineoplastic drugs | Depending on the drug and protocols | Doses of chemotherapy are commonly calculated based on a patient’s Body surface area, using TBW. Baillargeon et al. by studying children with leukemia found that 7% of those with obesity received less than the protocol-specified dose [37]. |
Inhaled corticosteroids (e.g. beclomethasone, budesonide, flunisolide, fluticasone) | Depending on the drug | |
Liraglutide (analogous to glucagon-like peptide) | Same dose of adults (i.e. 3 mg, s.c.). | Children over 10 years of age with an indication of type 2 diabetes mellitus not correctly compensated with metformin indications also for the treatment of obesity in patients aged> 12 years weighing > 60 kg |
Low-molecular weight Heparin | Depending on the drug and indication | |
Metformin (biguanide) | 500 mg day, max 2 g/day | TBW dosing: higher drug doses than patients without obesity [2] Use of adult doses of metformin in older children and adolescents with obesity [41] |
PPIs e.g., Pantoprazole | 10–20 mg/day | |
Steroids | Depending on indication | Need for standardization of drug dosing guidelines for children with obesity to avoid risk of harm [38]. |
Vitamin D | 1000 and 2000 IU 25(OH)D /day | The highest percentages of patients affected by obesity with values ≥20 ng/ mL were seen only among the 2000-IU group, implying therefore the superiority in effectiveness of this dose in comparison to the lower ones [43] |