Single‐ and multiple‐dose pharmacokinetic studies of tramadol immediate‐release tablets in children and adolescents

Abstract

In these combined analyzes from 3 open-label, phase-1 studies, the pharmacokinetic profile of tramadol and its metabolite (M1) following administration of tramadol immediate-release (IR) tablets in children and adolescents, 7-16 years old (studies 1 and 2: n = 38; study 3: n = 21) with painful conditions following single oral dose of tramadol IR (25-100 mg) (studies 1 and 2) or multiple oral doses of tramadol IR tablets every 6 hours for 3 days (study 3) were compared with that of healthy adults following similar treatment. Area under the curve of tramadol and its metabolite M1 in children and adolescents was lower compared with adults (Dose-normalized [DN] AUC, h ng/mL: tramadol: 1316.87 [children]; 1418.02 [adolescents];1838.29 [adults]; M1: 342.56 [children]; 475.4 [adolescents]; 636.13 [adults]) while the Cmax remained similar (DN Cmax , ng/mL: tramadol: 203.75 [children]; 165.35 [adolescents]; 226.92 [adults]; M1: 34.93 [children]; 38.42 [adolescents]; 52.14 [adults]). The DN AUC was further lower in children and adolescents with a lower body weight (<50 kg). The weight normalized oral clearance of tramadol was higher in children and adolescents compared with adults (CL/F, mL/min/kg: 12.66 [children]; 11.75 [adolescents]; 9.06 [adults]). No new safety findings emerged. Tramadol was generally safe and well-tolerated by children and adolescents with painful conditions.

Single‐Dose Pharmacokinetic Study of Tramadol Extended‐Release Tablets in Children and Adolescents

“…The PK profiles of tramadol and its metabolite M1 in children and adolescents, in single‐dose and multiple‐dose studies of immediate‐release tramadol, were low—particularly in those with a lower body weight—compared with the adult PK profile, as reported in a recent publication . The results from the current 2 studies corroborated the previously reported findings that the PK profiles resulted in a lower exposure to tramadol and its M1 metabolite in 7‐ to 11‐year‐old children.…”

Oral tramadol pharmacokinetics in pediatric subjects versus adults—Is there a role of delayed gastric emptying in pediatric subjects?

“…The interpretation of the study data using body weight adjusted and dose‐normalized pharmacokinetic parameters clearly showed that the pediatric age group tended to have differential pharmacokinetic behavior of tramadol compared with adults . The apparent oral clearance of tramadol was faster in the pediatric age group (13.14 mL/min/kg) compared with adults (9.47 mL/min/kg).…”

“…Because of ethical considerations the pediatric population in this investigation appeared to be less homogenous . The authors have emphasized caution in the interpretation of the data to enable the design of future clinical pharmacology studies because some of the children/adolescents who participated in this study had a history of surgical operation and/or had a history of painful conditions …”

“…Interestingly, it was also observed that the AUC values of children/adolescents weighing <50 kg were markedly lower after dose normalization . The authors postulated that the differences in the oral bioavailability of tramadol may have contributed for the observed differences in the pharmacokinetics between pediatric subjects and adults …”

Safety, Tolerability, and Pharmacokinetics of Therapeutic and Supratherapeutic Doses of Tramadol Hydrochloride in Healthy Adults: A Randomized, Double‐Blind, Placebo‐Controlled Multiple‐Ascending‐Dose Study

“…Tramadol is rapidly absorbed after oral administration, with an absolute bioavailability of approximately 70%, irrespective of concomitant food intake . Tramadol is extensively metabolized in the liver, resulting in many phase I and II metabolites.…”