A joint parent-metabolite model to characterize the pharmacokinetic profile of tapentadol and its metabolites in the pediatric population and inform a model-based evaluation of a post-approval commitment pediatric trial
F Khalil1, S Buller1, K Lindauer1, M Gautrois1, S Engelen1
1Grünenthal GmbH, Aachen, Germany
Introduction:
Tapentadol (Tap) is an atypical opioid analgesic, which has been pharmacologically characterized as both a mu-opioid receptor agonist and a noradrenaline reuptake inhibitor. A prospective, open-label pediatric trial (KF5503-75) was conducted to fulfil a regulatory post-approval commitment to extend the indication of Tap hydrochloride oral solution (OS) to the pediatric population. The KF5503-75 trial assessed the pharmacokinetic (PK) profile of Tap and its two metabolites, Tap-O-glucuronide (Tap-O-G) and Tap-O-sulfate (Tap-O-Su), after administration of multiple doses of Tap OS in children aged 2 to <7 years requiring treatment with a strong analgesic. The primary and secondary endpoints of this trial were planned to be informed by means of population pharmacokinetic (popPK) modeling due to the implemented sparse PK sampling.
Objectives:
- Update a pediatric popPK model for the parent drug, Tap
- Develop a joint parent-metabolite pediatric popPK model for Tap and its two metabolites
- Perform a model-based PK evaluation for the collected PK samples in KF5503-75
Methods:
In addition to the KF5503-75, data from 4 other pediatric trials, which investigated Tap PK after the administration of a single dose given intravenously (IV) or as OS were also considered. In total, data from 5 pediatric PK trials and 158 different pediatric subjects aged from birth to <18 years old were included in this popPK analysis. The 158 subjects contributed with an average of about 4 blood samples per subject and 613, 583 and 185 quantifiable concentrations for Tap, Tap-O-G, and Tap-O-Su, respectively (1381 in total).
The popPK models were developed by means of nonlinear mixed effects modeling using the first-order method with conditional estimation and interaction using NONMEM®. Most model assumptions are detailed elsewhere[1]. The final popPK model was validated by visual predictive checks and by bootstrap. Population and individual PK parameter estimates were assessed with focus on model-based estimates of the area under the concentration-time curve for the dosing interval after single dose (AUCτ,sd) and at steady state (AUCτ,ss).
Results:
Tap PK was best described by a one compartment disposition model with linear absorption, linear elimination with allometric scaling on clearance (CL) and volume of distribution (V), as well as a maturation function on oral bioavailability (F) and CL. The popPK analysis showed that Tap mature CL and V at a reference weight of 70 kg were estimated to 93.7 L/h (= CL/F of 272 L/h) and 414 L (= V/F of 1203 L), respectively. Tap CL scaled by bodyweight with an allometric scaling exponent of 0.75 and was additionally influenced by a maturation function driven by post-menstrual age, which indicated that 80% of the maturation is achieved at about 1.9 years. Results showed also that Tap oral F gradually decreases with increasing postnatal age by an asymptotic relationship from 68.8% in neonates to 34% in older children, with a rapid decrease during the first 3-4 months after birth. Mature F was estimated at 34.4% and was achieved by the end of the first year. Tap OS absorption was rapid and showed substantial variability with a slight ALAG.
The estimated model-based primary endpoint (AUCτ,ss) values calculated for Tap in the KF5503-75 trial population ranged 142–321 h•ng/mL (median AF=1.73). These estimates were within the exposure range predicted for children aged 2 to <7 years using a popPK model [1] based on single-dose data only (138–457 h•ng/mL; 95% prediction interval). The AUCτ,ss values were also within the targeted steady state exposure range established from the adult therapeutic doses of 50–100 mg Tap immediate release tablets given every 4 h (130.7–706 h•ng/mL). The AUCτ,ss values of the two secondary trial endpoints ranged 4501–7617 h•ng/mL for Tap-O-G (median AF=1.84), and 180–590 h•ng/mL for Tap-O-Su (median AF=1.28).
Conclusions:
Modelling and simulation are very valuable tools in the planning and analysis of clinical trials especially in a vulnerable population such as the pediatrics. The joint parent-metabolite popPK model informed a model-based PK evaluation for a post-approval commitment trial but can also be used as basis to support future pediatric trials (e.g., with other formulation). The findings of KF5503-75 confirmed the linear and predictable PK profile of Tap in the pediatric population.
References:
[1] Khalil F et al. J Pain Res. 2020;13:3107-3123.