Paul Healy1, Oscar Della Pasqua1,2
1 Clinical Pharmacology & Therapeutics Group, School of Pharmacy, University College London, London, UK. 2 Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Uxbridge, UK.
Objectives: Neuropathic and chronic pain in children has been considered rare although in recent years the diagnosis and prevalence of this syndrome seems to be increasing. Often, the drugs used for treating pain in adults are used off-label in children[1]. The GAPP consortium was set up to establish the dose rationale and assess the efficacy of gabapentin in paediatric patients aged between 3 months and ≤18 years, who have been diagnosed with chronic pain, as compared to tramadol. Given the challenges to generate efficacy data in this group of patients, particularly in younger patients, in whom pain assessment relies upon non-verbal measurements, pharmacokinetic (PK) bridging is used to optimise exposure to gabapentin and tramadol, scaling drug disposition characteristics from adults to children. The primary objective of our investigation was to establish the dose rationale for gabapentin and tramadol in paediatric patients with chronic pain to be enrolled in a prospective non-inferiority study including 94 paediatric patients. A secondary objective was to optimise the titration phase and sampling schemes for the evaluation of pharmacokinetics and pharmacodynamics (i.e. pain response) of gabapentin and tramadol, considering effects of clinical and demographic covariates on PK.
Methods: Nonlinear mixed effects modelling was used to scale the PK of gabapentin and tramadol assuming comparable exposure-response relationships between adults and children. A one-compartment model for gabapentin[1] and a two-compartment model for tramadol[2] was integrated into a clinical trial simulation framework for evaluating paediatric exposure to a range of dosing regimens based on body weight as the main covariate factor affecting the disposition of both drugs. Analysis included extrapolation of drug disposition parameters from adults to children using allometric scaling principles and PK data from published literature[3]. Clinical trial simulations were performed to optimise study protocol procedures, focussing on suitable titration and maintenance phases. In addition, attention was given to the optimisation of blood sampling for PK evaluation, to ensure minimum invasiveness and patient burden.
Results: Simulations showed that efficacious mean steady-state exposure (area under the concentration vs. time curve, AUC0-8) of 32.8 µg*h/mL and mean steady-state concentrations of 200-300 ng/mL can be achieved during maintenance phase of treatment with gabapentin and tramadol, respectively. These levels are preceded by titration steps, with doses ranging from 7-63 mg/kg in patients between 5-15 kg and 5-45 mg/kg in patients >15kg. For tramadol, the target exposure was associated with a maximum daily intake of 8 mg/kg preceded by the similar titration steps, with doses ranging of 1-8 mg/kg t.i.d. An evaluation of the feasibility of sparse blood sampling for the analysis of pharmacokinetics revealed that a minimum of four samples per patient was required to allow estimation of the parameters of interest.
Conclusions: In contrast to evidence generation based on empirical protocols, the GABA-1 study illustrates how quantitative clinical pharmacology principles can be used during the design phase of a study to ensure a robust dose rationale. Moreover, use of clinical trial simulations has provided an opportunity to identify suitable titration steps for subsequent characterisation of underlying pharmacokinetic-pharmacodynamic relationships for gabapentin and tramadol in the target paediatric population.
References:
[1] Ouellet D, Bockbrader H N, Wesche DL, Shapiro D Y, Garofalo E. Population pharmacokinetics of gabapentin in infants and children. Epilepsy Res. 2001; 47:229–41.
[2] Garrido, M. J., Habre, W., Rombout, F., & Trocóniz, I. F. (2006). Population Pharmacokinetic/Pharmacodynamic Modelling of the Analgesic Effects of Tramadol in Pediatrics. Pharmaceutical Research, 23(9), 2014–2023.
[3] Payne K. A., Roelofse J. A., Shipton E. A. Pharmacokinetics of Oral Tramadol Drops for Postoperative Pain Relief in Children Aged 4 to 7 Years – A Pilot Study, Anesth Prog. 2002; 49(4): 109–112.
Reference: PAGE 28 (2019) Abstr 9100 [www.page-meeting.org/?abstract=9100]
Poster: Drug/Disease Modelling - Paediatrics