Abstracts

Rationale: Gabapentin (GBP) is indicated for both epilepsy and pain. Dosing based on GBP pharmacokinetic (PK) information in elderly nursing home (NH) patients is not available due to lack of GBP PK studies in this population. This study characterized the saturable absorption profile of GBP in NH elderly patients Methods: The study was approved by the University of Minnesota's Institutional Review Board. A prospective PK study was conducted in NH elderly patients receiving GBP for chronic pain. Residents who did not have a change in GBP dose for at least 4 weeks (steady-state), in facility for at least 2 months, and on a stable-dose of co-medications were included. Comatose subjects or those with unstable medical conditions were excluded. The study included multiple observation visits per subject (range 4- 6). At each visit, a blood sample was collected for measurement of drug level and time after dose recorded. PK analysis consisted of nonlinear mixed effects modeling (NONMEM 7). A one-compartment model fit the data. Covariates (estimated glomerular filtration rate (EGFR), age, weight, and sex) were tested for hypothesized effect on apparent drug clearance (CL) through forward inclusion (χ2, p≤0.05, df=1)/backward elimination (χ2, p≤0.01, df=1). In addition, the effect of increasing GBP dose on the extent of absorption was evaluated by testing for the significance of a saturable absorption profile. The final model was qualified through a standardized visual predictive check (SVPC) and precision of parameter estimates determined using bootstrap analysis Results: Data from 30 patients (7 men: 23 women) were available for analysis. Mean weight and age were 85 kg and 76 years (range 61-95), respectively. Median (range) EGFR was estimated to be 62.4 mL/min/1.73 m2 (13.8-109.9). Patients received a median (range) daily GBP dose of 500 mg (100-2400) divided into 3 (range 1-4) doses/day. GBP CL was significantly dependent on EGFR (change in OFV= 50, p<0.0001), while the bioavailability (F) decreased in an inhibitory sigmoidal Emax manner with increasing dose of GBP (change in OFV=11.3, p<0.01). The model estimated a maximum absolute reduction (IMAX) in F of 50% (24%, 76%) and a dose that produces 50% of the maximum saturation (ID50) of ~400 mg (95% CI 50, 700). These estimates are lower than the ID50 of 1020 mg and 1120 mg reported for healthy volunteers (Bockbrader, et al. Epilepsia 1996, 37, 159; Gidal, et al. Epilepsy Research 1998, 31, 91-99) and younger adult neuropathic pain patients (Carlsson, et al. Ther Drug Monit 2009, 31, 86-94), respectively. Visual inspection of SVPC plots demonstrated an adequate performance of the model Conclusions: A dose-dependent bioavailability and a strong association of CL on EGFR were demonstrated in NH elderly patients receiving GBP. The ID50 of saturation was estimated to be 400 mg and found to be markedly less than the reported ID50 in younger adults indicating a clinically meaningful effect of aging on the saturable absorption profile of GBP. Smaller doses given more often may be warranted in this population when using GBP for seizure reduction Funded by NIH NIA R01AG026390