Authors' response to the letter from Dr. Srinivas.

Abstract

We welcome the comments by Nuggehally R. Srinivas and appreciate his interest in our article, “Single- and multiple-dose pharmacokinetic studies of tramadol immediate-release tablets in children and adolescents.” First, we would like to clarify that the pharmacokinetic data in adults came from 1 internal published and 3 internal unpublished clinical studies with well-documented study design details. It is unlikely that the observed lower levels of M1 in the children are due to design elements such as differences in blood sampling or differences in dosing. The last sampling time was 36 hours in the adult studies and 24 hours in the pediatric study. The lower level of quantitation of M1 in adults was between 2 and 5 ng/mL compared with 5 ng/mL observed in children. The plasma levels of M1 metabolite were undetectable 24 hours postdose in 10 of 13 children, whereas in adults, M1 levels could be detected in 63 of 67 participants at 24 hours. It is less likely that the observed lower levels of M1 in children would be due to a difference in design between studies. This is clear from Figure IB in the article, in which it can be observed that in children the plasma levels of M1 were lower from the initial sampling times onward. Nuggehally R. Srinivas commented that a systemic circulating amount of tramadol higher than 1 mg/kg may cause delayed gastric emptying and decrease oral absorption in children. The tramadol dose administered in the adult studies was 75 or 112.5 mg of tramadol, corresponding to a dose of 1–1.5 mg/kg and hence similar to the pediatric study doses. Although, no data on absolute bioavailability are available for the pediatric population, the absolute bioavailability in adults is approximately 70%. Therefore some children could have been exposed to a circulating amount of 1 mg/kg of tramadol. Nuggehally R. Srinivas also commented on possible delayed gastric emptying in children that may cause incomplete oral absorption of tramadol and the higher apparent oral clearance in children. Peripheral μ-opioid effects are believed to play a predominant role in the inhibition of gastric emptying by opioids1 The μ-opioid effect of tramadol is mainly due to its M1 metabolite.2 This metabolite is only formed after first pass in the liver through the CYP2D6 pathway. A comparison of the tmax values after single-dose administration demonstrates that it was 1.9 hours for tramadol and 2.7 hours for the M1 metabolite in children, whereas it was 1.9 hours for tramadol and 2.8 hours for the M1 metabolite in adults. Furthermore, as demonstrated in Figure IA in our article, a child with slower absorption does have higher plasma tramadol at later times, suggesting good absorption throughout the entire gastrointestinal tract. After multiple-dose administration in children, the tmax was 1.7 hours for tramadol and 1.8 hours for M1, which is similar to that seen in adults (tramadol, 2.1 hours; M1 metabolite, 2.9 hours).3 This is consistent with the absence of an impact on the pharmacokinetic profile of acetaminophen after coadministration of acetaminophen and tramadol as a fixed-dose combination versus administration as a single agent.3 Therefore, the data do not suggest a major difference in the rate and extent of absorption between both populations after single and multiple dosing.