Drug Dosing and Pharmacokinetics in Children With Obesity: A Systematic Review

Abstract

Importance: Obesity affects nearly one-sixth of US children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxic side effects. The depth of available literature regarding obesity's effect on drug safety, pharmacokinetics, and dosing in obese children is unknown.

Objective: To perform a systematic literature review describing the current evidence of the effect of obesity on drug disposition in children.

Evidence review: We searched the MEDLINE, Cochrane, and EMBASE databases (January 1, 1970-December 31, 2012) and included studies if they contained data on drug clearance, volume of distribution, or drug concentration in obese children (aged ≤18 years). We compared exposure and weight-normalized volume of distribution and clearance between obese and nonobese children. We explored the association between drug physicochemical properties and clearance and volume of distribution.

Findings: Twenty studies met the inclusion criteria and contained pharmacokinetic data for 21 drugs. The median number of obese children studied per drug was 10 (range, 1-112) and ages ranged from newborn to 29 years (1 study described pharmacokinetics in children and adults together). Dosing schema varied and were either a fixed dose (6 [29%]) or based on body weight (10 [48%]) and body surface area (4 [19%]). Clinically significant pharmacokinetic alterations were observed in obese children for 65% (11 of 17) of the studied drugs. Pharmacokinetic alterations resulted in substantial differences in exposure between obese and nonobese children for 38% (5 of 13) of the drugs. We found no association between drug lipophilicity or Biopharmaceutical Drug Disposition Classification System class and changes in volume of distribution or clearance due to obesity.

Conclusions and relevance: Consensus is lacking on the most appropriate weight-based dosing strategy for obese children. Prospective pharmacokinetic trials in obese children are needed to ensure therapeutic efficacy and enhance drug safety.

Figure 1

Study Outline of Systematic Literature Search and Inclusion of Identified Articles

Figure 2. Relationship Between Obesity-Related Changes in Pk and Drug Physicochemical Properties

V and CL ratios plotted by measured logP and BDDCS class. Ratios displayed as obese/controls. CL and V are weight-normalized (e.g., V in L/kg). If authors did not report weight-normalized values (antipyrine, carbamazepine, and caffeine), then weight-normalized parameters were calculated by dividing reported values by individual or study mean weight values. A: V by measured logP; B: V by BDDCS class; C: CL by measured logP; D: CL by BDDCS class. V, volume of distribution; Cl, clearance; logP, lipophilicity; BDDCS, Biopharmaceutical Drug Disposition Classification System; ace, acetaminophen; ant, antipyrine; caf, caffeine; cbz, carbamazepine; dox, doxorubicin; eto, etoposide; gen, gentamicin; mer, mercaptopurine; mtx, methotrexate; ten, teniposide; the, theophylline; tob, tobramycin; van, vancomycin.

Figure 2. Relationship Between Obesity-Related Changes in Pk and Drug Physicochemical Properties

V and CL ratios plotted by measured logP and BDDCS class. Ratios displayed as obese/controls. CL and V are weight-normalized (e.g., V in L/kg). If authors did not report weight-normalized values (antipyrine, carbamazepine, and caffeine), then weight-normalized parameters were calculated by dividing reported values by individual or study mean weight values. A: V by measured logP; B: V by BDDCS class; C: CL by measured logP; D: CL by BDDCS class. V, volume of distribution; Cl, clearance; logP, lipophilicity; BDDCS, Biopharmaceutical Drug Disposition Classification System; ace, acetaminophen; ant, antipyrine; caf, caffeine; cbz, carbamazepine; dox, doxorubicin; eto, etoposide; gen, gentamicin; mer, mercaptopurine; mtx, methotrexate; ten, teniposide; the, theophylline; tob, tobramycin; van, vancomycin.