Single and Multiple Dose Pharmacokinetics of a Pharmaceutical Compound in Elderly Subjects

Abstract

Single and multiple dose pharmacokinetics of a pharmaceutical compound (Compound A) have been assessed in blood, plasma, and urine from healthy elderly volunteers. Subjects were assigned to one of three treatment groups with 10 subjects/group. All three groups received a single dose of sesquifumarate salt (Compound Aa) of Compound A on Period 1; Groups I and II received a 5 mg dose and Group III received a 10 mg dose. In Period 2, Group I subjects received 5 mg b.i.d.; Group II subjects received 5 mg t.i.d., and Group III subjects received 10 mg b.i.d. Multiple dose treatment was given for seven days and Periods 1 and 2 were separated by at least seven days. Both blood (WB) and plasma (PL) concentrations were determined using LC-MS/MS. Both assays had a limit of quantitation of 0.1 ng/mL. Urine concentrations were determined with a LC-MS/MS assay having a limit of quantitation of 25 ng/mL. The AUC (0 → 24) and Cmax of Compound A increased proportionally after single and multiple doses in both matrices. Steady state was reached before the first dose on Day 7. The accumulation was well predicted across three treatment groups in both matrices. For each b.i.d. group, the average exposure to Compound A after morning dose on Day 7 was increased by approximately two-fold from Day 1. These results demonstrate that Cmax and AUC values for Compound A increased in a dose proportional fashion and that the accumulation of Compound A can be predicted based on single dose pharmacokinetics. No apparent effect of dose regimens upon the renal clearance was observed. There was also no significant difference demonstrated for the renal clearance of Compound A between single dose (Day 1) and multiple dose (Day 7). Approximately 4–7% of dose was recovered in urine as unchanged drug (Compound A).