Population Pharmacokinetics of Pregabalin Extended‐Release in Healthy Volunteers and Patients With Postherpetic Neuralgia, Fibromyalgia, and Partial‐Onset Seizures

Abstract

A population pharmacokinetic (PK) model was developed to characterize the properties of pregabalin extended‐release (ER) in healthy volunteers and was subsequently applied to patient data from efficacy/safety studies investigating pregabalin ER for postherpetic neuralgia, fibromyalgia, and partial‐onset seizures. The impact of demographic and other covariates on PK was assessed, and various dosing scenarios were simulated to inform pregabalin ER dosing/administration instructions. Phase 1 and 3 models were developed using data from 14 phase 1 studies (12 627 samples from 335 participants receiving pregabalin immediate‐release [IR] or ER) and 3 phase 3 studies (2591 samples from 1235 patients receiving pregabalin ER), respectively. Final phase 1 and 3 models adequately characterized the data. Several covariates were statistically significant, but renal function (creatinine clearance) was considered the only clinically relevant covariate. The relationship between creatinine clearance and pregabalin clearance was reasonably consistent between phase 1 and 3 models and with that reported previously with pregabalin IR data alone. Patients with moderate renal impairment who received pregabalin ER 82.5 mg once daily (QD) had similar predicted area under the plasma concentration–time curve and peak plasma concentration values as patients with normal/mild renal impairment who received 165 mg QD. Ranges in predicted PK parameters after switching from pregabalin IR administered in the morning to ER after a meal at 3, 6, or 9 pm were similar. Administration of a missed evening dose at bedtime with food or the next morning with food did not result in clinically important changes in predicted PK parameters.

Pregabalin Population Pharmacokinetic and Exposure‐Response Analyses for Focal Onset Seizures in Children (4–16 years) and Adults, to Support Dose Recommendations in Children

“…The two nominal dose levels, 2.5 and 10 mg/kg/day, were observed to deliver similar concentrations to the adult doses, 150 and 600 mg/day, respectively (Figure S3) as predicted from prior modeling, including phase I pediatric data. 18 The estimated exponent of allometric function was 0.52 for CL/F and 0.70 for V/F. This translates to ~ 40% higher CL/F for a typical child weighing 20 kg compared with a typical child weighing 40 kg.…”

“…In addition to efficacy extrapolation, we would also like to advocate for pediatric PK extrapolation to potentially replace or minimize pediatric phase I studies, an area which has been gaining credence since 2015 18,40 . The issues can be highlighted by our earlier trials, such as the phase I pediatric study investigating pregabalin, which took ~ 5 years to complete, and more specifically, the 1 month to < 2 years age group, for which it took > 2 years to recruit sufficient patients.…”

“…18,40 The issues can be highlighted by our earlier trials, such as the phase I pediatric study investigating pregabalin, which took ~ 5 years to complete, and more specifically, the 1 month to < 2 years age group, for which it took > 2 years to recruit sufficient patients. We have demonstrated that a retrospective analysis using population PK analysis 18 and physiologically-based PK modeling confirmed that the pediatric PK of pregabalin, a renally eliminated drug, could be confidently predicted using adult PK observations. 41 Merging pediatric with adult data had minimal impact on adult PK and E-R parameter estimates.…”

“…1008-003, 18 with known fed conditions, and was not used in the simulations. In contrast, the ETA-shrinkages for k a under fasted and unknown food status, as well as for CL/F, were lower (46.2% and 27.4%, respectively), consistent with more data being available to support the parameter estimates.…”

Efficacy and safety of pregabalin in eye pain: A systematic review

“…[7] It is efficient in controlling mild to moderate pain and has lower dose requirements and fewer dose-related complications. [8,9] Although many studies have evaluated the efficacy and safety of pregabalin in pain management, there has been no systematic review of eye pain management using pregabalin. This review was conducted based on existing clinical randomized controlled trials (RCTs); the primary aim was to compare the efficacy and safety of pregabalin with those of placebo in acute and chronic eye pain control, and the secondary aim was to evaluate the effect of pregabalin on the relief of dry eye symptoms after eye treatment in adults.…”