Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain

Abstract

Despite off-label use, the efficacy and safety of gabapentin and tramadol in pediatric patients (3 months to <18 years old) diagnosed with chronic pain has not been characterized. However, generating evidence based on randomized clinical trials in this population has been extremely challenging. The current investigation illustrates the use of clinical trial simulations (CTSs) as a tool for optimizing doses and protocol design for a prospective investigation in pediatric patients with chronic pain. Pharmacokinetic (PK) modeling and CTSs were used to describe the PKs of gabapentin and tramadol in the target population. In the absence of biomarkers of analgesia, systemic exposure (AUC, Css) was used to guide dose selection under the assumption of a comparable exposure-response (PKPD) relationship for either compound between adults and children. Two weight bands were identified for gabapentin, with doses titrated from 5 to 63 mg/kg. This yields gabapentin exposures (AUC_0-8 ) of approximately 35 mg/L*h (1200 mg/day adult dose equivalent). For tramadol, median steady state concentrations between 200 and 300 ng/mL were achieved after doses of 2-5 mg/kg, but concentrations showed high interindividual variability. Simulation scenarios showed that titration steps are required to explore therapeutically relevant dose ranges taking into account the safety profile of both drugs. Gabapentin can be used t.i.d. at doses between 7-63 and 5-45 mg/kg for patients receiving gabapentin weighing <15 and ≥15 kg, respectively, whereas a t.i.d. regimen with doses between 1 and 5 mg/kg can be used for tramadol in patients who are not fast metabolisers.

Keywords: dose rationale; extrapolation; gabapentin; pediatric chronic pain; pharmacokinetics; tramadol.

FIGURE 1

Upper panels: Simulated concentration versus time profiles of gabapentin (A) and tramadol (B) on the last day of each titration step. Data are shown stratified by weight band for gabapentin. Solid line shows the median, shaded area indicates the 95% confidence interval. Lower panels: Whisker‐box plots showing the predicted AUC for gabapentin (C) and predicted AUC for tramadol (D) for each titration step, based on a t.i.d. regimen. Gabapentin results are compared to the observed AUC values after doses of 1.2–3.6 g to adult subjects. Dotted red line shows the putative target exposure range for gabapentin (32.8–75.1 mg/L*h) and tramadol (1600–2400 ng/mL*h). Lower and upper hinges of the box‐plots correspond to the first and third quartiles. The upper whisker extends from the hinge to the highest value that is within 1.5*IQR of the hinge, where IQR is the inter‐quartile range, or distance between the first and third quartiles. The lower whisker extends from the hinge to the lowest value within 1.5*IQR of the hinge. Data beyond the end of the whiskers are outliers and plotted as points. IQR, interquartile range.