Abstracts

Rationale: Age-related functional declines affecting drug clearance are common findings among the elderly, particularly for drugs that are largely or primarily cleared renally. Topiramate (TPM) is one such drug in that it is not extensively metabolized, with ~70% of an administered dose eliminated unchanged in the urine. In elderly subjects receiving the original immediate-release TPM (TPM-IR) formulation (Topamax , Janssen Pharmaceuticals), TPM clearance was reduced in elderly vs younger adults only to the extent that renal function was reduced. SPN-538 (Trokendi XR, Supernus Pharmaceuticals, Inc.) is a novel extended-release, once-daily capsule formulation of TPM that may improve tolerability and enhance adherence. We evaluated the effect of subject age on the PK of a single SPN-538 dose in healthy adults stratified by age.Methods: In this open-label study, subjects received a single 100 mg capsule of SPN-538 under fasting conditions. Blood samples for PK analysis were obtained pre-dose and at specified time points through 168 hrs post-dose. TPM C_max, AUC_0-t, and AUC_inf were compared between age groups (younger adults, 18-45 yrs; elderly, age 70+ yrs). Safety and adverse events were assessed throughout the study.Results: The PK population was the entire cohort of subjects enrolled in the study (N=31). In the younger group (n=18), mean age was 33 yrs (range, 19-45 yrs); 61% were male. In the elderly group (n=13), mean age was 75 yrs (range, 71-84 yrs); 23% were male. Mean creatinine clearance (calculated) was 35% lower in elderly (77 mL/min) vs. younger (119 mL/min) adults. With acute SPN-538 dosing, TPM clearance was 29% lower in the elderly. The decrease in clearance was reflected in higher C_max, AUC_0-t, and AUC_inf (30%, 41%, and 44%, respectively) in elderly vs younger adults. Treatment-related adverse events were mild in severity, occurring more in younger (7/18, 39%) than elderly (3/13, 23%) subjects. Adverse events occurring in >1 subject were limited to headache, somnolence, and dysgeusia in younger adults. No new or unexpected safety or tolerability signals were observed.Conclusions: Following a single 100-mg dose of SPN-538, peak TPM concentration and overall drug exposures were higher in elderly than in younger adults. These changes were commensurate with the degree of reduced renal function (ie, calculated creatinine clearance). The increased TPM exposure seen in elderly subjects receiving SPN-538 is similar to that seen with TPM-IR in an elderly population. Findings suggest that dose adjustments for SPN-538 in elderly patients would follow the same recommendations for TPM-IR, ie, reduce dose according to renal function status rather than age (one-half the adult dose if creatinine clearance <70 mL/min/1.73m²). Study funded by Supernus Pharmaceuticals, Inc.