Gabapentin CNS exposure and analgesic response are modulated by OCT2 genotype in patients with chronic neuropathic pain

TL;DR

This study shows that a genetic variant in OCT2 affects how gabapentin enters the brain and its pain-relieving effects in patients with chronic neuropathic pain.

Contribution

The study demonstrates that OCT2 genotype influences gabapentin's CNS exposure and analgesic response, supporting genotype-guided dosing.

Findings

The SLC22A2 c.808G>T variant reduces gabapentin's influx rate to the CNS by 10-fold.

GT carriers experience reduced pain relief at maximum approved doses compared to GG homozygotes.

Renal impairment increases systemic exposure but does not improve CNS penetration.

Abstract

Gabapentin (GBP) is commonly used for chronic neuropathic pain, yet its therapeutic response varies widely across individuals. As a substrate of the organic cation transporter 2 (OCT2), encoded by the SLC22A2 gene, GBP’s penetration into the central nervous system (CNS) may be influenced by genetic variability. This study aimed to characterize the impact of SLC22A2 c.808G>T polymorphism on GBP pharmacokinetics (PK) and pharmacodynamics (PD) and inform genotype-guided dosing strategies.

Data from two clinical studies (n = 94) were pooled, including single and multiple oral dose regimens of GBP. Population PK/PD modeling was performed using nonlinear mixed-effects modeling.

A two-compartment PK model with first-order absorption and linear elimination best described GBP disposition, with estimated apparent clearance (CL/F) significantly influenced by renal function (eGFR). Pain scores revealed delayed pain relief relative to peak plasma levels, requiring an effect compartment to link PK to an Imax model. The SLC22A2 c.808G>T (OCT2) variant was associated with a 10-fold reduction in the influx rate constant (ke1) to the effect site, suggesting impaired CNS drug delivery. Simulations demonstrated that GT carriers experienced markedly reduced pain relief, even at the maximum approved doses, compared to GG homozygotes. Renal impairment increased systemic exposure but did not alter CNS penetration.

These findings highlight the importance of the OCT2 genotype in modulating GBP’s analgesic efficacy. Incorporating transporter pharmacogenetics into PK/PD models may enhance individualized therapy for neuropathic pain, particularly in identifying poor responders who may benefit from alternative dosing or adjunct treatments.

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