Drug dosage in obese children a weighty challenge

Obesity in children and adolescents is a big problem, affecting at least 124 million children and carrying significant comorbidity [1]. Childhood obesity is defined by the World Health Organization (WHO) as having a body mass index (BMI, kg/m2) above the 95th percentile of individuals the same age and sex in children aged 5–18 years inclusive, and above the 99th percentile in those aged up to 5 years [1]. Other organizations, such as the American Academy of Pediatrics [2], include “late adolescents” aged 18–21 years in the paediatric population. For simplicity, “children” and “paediatric” in this review refers to all paediatric age groups, including adolescents.

Although paediatric obesity is common, there are few pharmacokinetic or other studies on the best approach to use for drug dosage adjustment in this patient population [3]. Total body weight (TBW), the scalar most commonly used in the overall paediatric population, may be inappropriate for those who are obese. Their bodyweight (BW) may equate to or exceed that of adults, but aspects of their anatomy and physiology may differ [4,5,6,7]. The paucity of data results in inadequate or excessive drug levels in a huge percentage of obese children, with up to two-thirds being susceptible to either toxicity or treatment failure [3]. This article summarises current information on obesity-related dosage adjustment for commonly prescribed paediatric drugs, including those prescribed for obesity-related comorbidities, as reviewed by Kyler et al. [8].

Start with size, but be aware of pharmacokinetics

While paediatric dosage adjustments have traditionally been size-related, an all-round view that also considers patient physiology and drug physiochemical properties may be more clinically relevant [5]. Aside from TBW, proposed allometric or size-based measures include: normal fat mass scaled for volume, BW or body surface area (BSA); ideal BW (IBW); lean BW (LBW); and BMI or BSA alone [5].

Size-based measures are complicated by obese children’s abnormal vertical growth. In childhood and/or puberty, overweight children grow taller than normal-weight peers [9], but by adulthood they are shorter or the same height [8]. Nomographs, which show relationships between ≥ 3 variables [4], or obesity-specific dose curves [8] may eventually provide better dose-adjustment models.

Size aside, obese children may display variations in pharmacokinetics and possibly even disease phenotypes relative to normal-weight children (Table 1) [10]. Drug absorption, distribution, metabolism and excretion all tend to differ between the two groups due to differing anatomy and physiology (Table 1) [7], but specifics are ill-defined, because of the limited physiological data for obese children (Table 1). Although more information is available for obese adults, such data can provide only a broad context regarding pharmacological changes, as physiology, hepatic function and other pharmacokinetic parameters differ between children and adults [8].

Table 1 Physiological changes potentially affecting pharmacokinetics in obese children and adolescents
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Physiochemical drug properties, such as lipophilicity, suggest another possible path to optimal drug dosages [8]. In theory, highly lipophilic drugs have a higher volume of distribution (Vd) in obesity, suggesting that higher dosages, especially initially, are needed. However, while this seems logical, inconsistent relationships between lipophilicity and Vd have been observed, with factors such as unpredictable sequestering in, and release from, adipose tissue potentially affecting the correlation [7, 17, 19]. The pharmacokinetic profiles of hydrophilic drugs in obese individulals also require clarification [19].

Adjust dosages cautiously then monitor carefully

Clear guidelines on dosage adjustments in obese children are lacking, but pharmacokinetic studies and analyses in this patient population provide pointers to dosage adjustment for some commonly used drugs (Table 2). Studies to date focus on the in-hospital acute or intensive care setting, as well as on drugs with a narrow therapeutic index and serious potential toxicity [21]. As no paediatric data are yet available for many commonly used drugs, some adult information is included in Table 2; such data should be considered with caution and not just simply extrapolated to children. As information is sparse or uncertain, clinicians need to carefully monitor obese children’s responses to treatment, and watch for signs of toxicity [8].

Table 2 Evidence underlying suggested dosage adjustments for selected drugs used in the treatment of obese children and adolescents
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Use available data in common comorbidities

Obese children and adolescents are prone to the metabolic and cardiovascular disorders frequently seen in obese adults and, therefore, may require medications usually prescribed to adults. Information on appropriate dosage adjustment for these drugs is also scant [8]. Available information regarding some of the drugs commonly used to treat comorbid conditions in obese children suggests the following:

  • Metformin Consider increasing dosages in line with increased TBW and LBW to compensate for increased clearance and perhaps Vd [51, 52]. Of note, metformin acts as a substrate for OCT1, a hepatic uptake transporter that increases in obese patients, potentially leading to interactions between metformin and other OCT1 drug substrates (e.g. cimetidine, tramadol).

  • Calcium channel blockers May need to increase dosages if clinically required, possibly due to secondary increases in Vd [53, 54].

  • ACE inhibitors and ARBs Do not adjust dosage unless clinically required, as both classes of antihypertensives appeared equally effective at standard dosages in a study in three obese and three non-obese paediatric patients with renal disease [53].

  • β-blockers Do not adjust dosage to allow for an increase in Vd on the basis of lipophilia unless clinically appropriate, as these antihypertensives may preferentially target lean body tissue [8].

  • Statins Systemic exposure to statins is not simply a function of BMI, as two- to fivefold increases in exposure to pravastatin were observed due to genetic variations in some obese children’s hepatic uptake [55, 56].

  • Proton pump inhibitors (PPIs) The treatment of GORD is a particular concern, as GORD is six times more common in obese children than in non-obese children, and the use of PPIs is associated with infections, osteopenia and other adverse drug events in children [57]. Base the dosage of pantoprazole on LBW to avoid systemic overexposure, as total CYP2C19-mediated clearance of the PPI from plasma may be reduced [58,59,60].

Take home messages

  • Be aware that obese children often require pharmacological treatment for comorbid conditions, such as T2D and hypertension.

  • Realize that adjusting the dosage based on treatment effect may be the best option for many commonly prescribed drugs, as adjustment based on TBW, as for normal-weight children, is hampered by a lack of reliable data for most drugs.

  • Recognize the urgent need for pharmacokinetic studies in obese children to provide clearer dosage adjustment guidelines.