Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation

Abstract

Abstract. This paper focuses on the retrospective evaluation of physiologically based pharmacokinetic (PBPK) techniques used to mechanistically predict clearance throughout pediatric life. An intravenous tramadol retrograde PBPK model was set up in Simcyp® using adult clearance values, qualified for CYP2D6, CYP3A4, CYP2B6, and renal contributions. Subsequently, the model was evaluated for mechanistic prediction of total, CYP2D6-related, and renal clearance predictions in very early life. In two in vitro pediatric human liver microsomal (HLM) batches (1 and 3 months), O-desmethyltramadol and N-desmethyltramadol formation rates were compared with CYP2D6 and CYP3A4 activity, respectively. O-desmethyltramadol formation was mediated only by CYP2D6, while N-desmethyltramadol was mediated in part by CYP3A4. Additionally, the clearance maturation of the PBPK model predictions was compared to two in vivo maturation models (Hill and exponential) based on plasma concentration data, and to clearance estimations from a WinNonlin® fit of plasma concentration and urinary excretion data. Maturation of renal and CYP2D6 clearance is captured well in the PBPK model predictions, but total tramadol clearance is underpredicted. The most pronounced underprediction of total and CYP2D6-mediated clearance was observed in the age range of 2-13 years. In conclusion, the PBPK technique showed to be a powerful mechanistic tool capable of predicting maturation of CYP2D6 and renal tramadol clearance in early infancy, although some underprediction occurs between 2 and 13 years for total and CYP2D6-mediated tramadol clearance.

Allometry Is a Reasonable Choice in Pediatric Drug Development

“…According to previously published information, pediatric PBPK submission to FDA accounted for 18% of 33 total PBPK submissions in 2012 . The extrapolation into pediatrics using the PBPK approach has been applied and published, eg, acetaminophen, docetaxel, sirolimus, sotalol, and tramadol …”

“…13 The extrapolation into pediatrics using the PBPK approach has been applied and published, eg, acetaminophen, 14 docetaxel, 15 sirolimus, 16 sotalol, 17 and tramadol. 18 In this research we focused on the common situation in drug development when prior PK information in adults is available and conduction of PK study in children is feasible. In order to evaluate the performance of allometric scaling in pediatric study design, we reviewed the predictability of allometric scaling in all the small-molecular drugs approved by the FDA from 1998 to 2015 and collected the evidence to support the application of the allometric scaling approach in extrapolation from adults to children as young as 2 years.…”

Development of a Physiologically Based Pharmacokinetic Model of Ethionamide in the Pediatric Population by Integrating Flavin‐Containing Monooxygenase 3 Maturational Changes Over Time

“…Until recently, CYP‐ or carboxylesterase‐specific probe substrate enzyme ontogenic profiles integrated in PBPK model were explored widely in a number of drugs, including tramadol, acetaminophen, oseltamivir, and sotalol . However, for FMO‐substrate, only itopride's PBPK model was described to evaluate the impact of FMO3 polymorphism, by incorporating FMO3 activity and abundance .…”

Oral drug absorption in pediatrics: the intestinal wall, its developmental changes and current tools for predictions

“…There are several recent examples illustrating the value of PBPK for predicting drug disposition in the pediatric population, and for supporting pediatric approval [192][193][194][195]. Often, the strategy used to predict disposition in pediatrics involves an initial step where a PBPK model is built to describe the drug pharmacokinetics in adults [195][196][197].…”