Elena Soto (1), Jing Liu (2), Scott Marshall (1)
(1) Pfizer R&D UK Limited, United Kingdom (2) Pfizer, USA
Introduction: Pregabalin is an alpha-2-delta ligand that has analgesic, anxiolytic, and anticonvulsant activity. It is approved for management of neuropathic pain (NeP) associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, NeP associated with spinal cord injury, and as adjunctive therapy for the treatment of POS in patients 4 years of age and older. Pregabalin pharmacokinetics are linear and predictable and is primarily eliminated by renal excretion as unchanged drug.
A study to evaluate 2 pregabalin doses, administered three times daily (TID) as adjunctive therapy in patients 1 month to
Objectives:
To extend the current PopPK model for pregabalin to paediatric subjects 1 month to
To provide population pharmacokinetic simulations to support dosing recommendations for paediatric subjects 1 month to
Methods:
PopPK Model
Pharmacokinetic (PK) data from older paediatric (4 to 16 years of age) and adult patients, healthy volunteers and adults with renal impairment together with PK data from younger paediatric subjects (1 months to
The model previously described, consisting of a 1-compartment model with first-order elimination and absorption with a lag time [2], was applied to the current data using NONMEM 7.3 [3]. This base model included creatinine clearance (CrCL mL/min/1.73 m2), body weight and sex as covariates for pregabalin apparent clearance (CL/F) and body weight and sex as covariates in pregabalin volume of distribution. It also included food status in absorption rate constant and lag time.
Simulations
Pregabalin PK profiles for subjects 1 month to
To account for renal maturation in infants, two simulation approaches were tested.
In Approach 1; for younger subjects scaled predictions of CrCL from glomerular filtration rate (GFR) estimates, derived utilising the equation described by Rhodin et al [4] were simulated. Pregabalin CL was then estimated based on the established relationship with CrCL.
In Approach 2, Rhodin’s maturation equation [4] was included in the PopPK model to describe the renal maturation-related pregabalin CL/F in infants (
Paediatric demographics for simulations were bootstrapped from available study data (> 12 months of age) or created based on CDC Growth Charts [5].
Results:
A total of 1082 subjects including 358 paediatric (<=16 years of age) subjects and 724 adults contributing to 5562 plasma concentrations were included in the PopPK analysis. The youngest subject was 3 months old.
Data from patients
Simulations showed:
Pregabalin exposures for subjects 1 to
In Approach 1, the 12 mg/kg dose led to lower exposures in infants 1 to
For both approaches, the simulated average and maximum concentration at steady state in infants at the proposed maximal dose of 14 mg/kg/day did not exceed the adult exposures following the highest recommended dose in adults of 600 mg/day.
Conclusion:
The simulations demonstrated that pregabalin doses of 14 mg/kg/day administered TID in paediatric subjects 1 month to
References:
[1] Mann D et al. 2014, Safety, tolerability, and pharmacokinetics of pregabalin in children with refractory partial seizure: A phase I, randomized controlled study. Epilepsia 55(12):1934-1943.
[2] Chan et al., Population pharmacokinetics of pregabalin in pediatric and adult subjects with partial onset seizures (POS) and healthy volunteers to support dosing in pediatric subjects. Presented in ASCPT 2018 Annual Meeting.
[3] Beal SL et al. 1989-2011. NONMEM Users Guides. Icon Development Solutions, Ellicott City, Maryland, USA.
[4] Rhodin MM et al. 2009, Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatric nephrology vol.24: 67
[5] 2000 CDC Growth Charts for the United States: Methods and development, Data from the national Health Examination Surveys and the National Health and Nutrition Examination Surveys, Series 11, Number 246, 2002, Vital and health statistics.
Reference: PAGE 28 (2019) Abstr 8898 [www.page-meeting.org/?abstract=8898]
Poster: Drug/Disease Modelling - Paediatrics