LC–MS/MS-Based Monitoring of Pregabalin and Gabapentin Reveals Marked Pharmacokinetic Variability and Limited Exposure–Response Relationships in Neuropathic Pain Patients

This study aimed to develop and validate a liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay for the simultaneous quantification of pregabalin (PGB) and gabapentin (GBP) and to explore real-world pharmacokinetic variability. A bioanalytical LC–MS/MS method was validated using serum samples prepared by acetonitrile protein precipitation. Chromatographic separation was achieved on a C18 column with gradient elution and positive electrospray ionization. The validated method was applied to serum samples obtained from 65 patients, and associations between serum drug concentrations and clinical measures were evaluated. The assay demonstrated excellent linearity (R² > 0.998), acceptable precision and accuracy, recovery ranging from 96.9% to 101.5%, and matrix effects below 7%. Considerable inter-individual variability in serum concentrations was observed (PGB: median 700 ng/mL [IQR: 500–1000]; GBP: median 4500 ng/mL [IQR: 3200–5700]). No significant dose–concentration relationships were identified (PGB: ρ = 0.03; GBP: ρ = −0.08), and no significant associations were observed between serum concentrations and the clinical outcome measures assessed. In contrast, both drugs showed moderate inverse correlations with post-dose sampling interval (PGB: ρ = −0.46; GBP: ρ = −0.45). These findings indicate substantial pharmacokinetic variability of gabapentinoids under routine clinical conditions. Although no clear dose–concentration or exposure–response relationships were identified in this cohort, interpretation should be made cautiously because of non-standardized sampling conditions and the relatively narrow range of renal function among participants.