Single and Multiple Dose Pharmacokinetics of a Pharmaceutical Compound in Elderly Subjects
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Drug Information Journal, Vol. 31. pp. 1227-1235, 1997 Printed in the USA. All rights reserved.
SINGLE AND MULTIPLE DOSE PHARMACOKINETICS OF A PHARMACEUTICAL COMPOUND IN ELDERLY SUBJECTS* H. JANG, D. BUHRMAN, J. BURTON,B. JOSHI, M. MUMERT,P. PRICE, J. SHI,D. SMALLWOOD, R. VAN HORN,M. DROZD,D. Wu, J. MOSSER, J. NEWTON,G. WEI, G. LOCKWOOD, AND F. CATTELIN Sanofi Research, a Division of Sanofi Pharmaceuticals Inc.. Malvem, Pennsylvania
Single and multiple dose phannacokinetics 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 subjectslgroup. A11 three groups received a single dose of sesquifumarate salt (Compound Aa) of Compound A on Period I ; Groups I and II received a 5 mg dose and Group I l l 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 I l l subjects received 10 mg b.i.d. Multiple dose treatment was given for seven days and Periods I 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 C,, 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-foldfrom Day 1. These results demonstrate that C,, 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 dase phannacokinetics. No apparent effect of dose regimens upon the renal clearance was observed. There was also no signijicant difference demonstrated for the renal clearance of Compound A between single dose (Day I ) and multiple dose (Day 7). Approximately 4 7 % of dose was recovered in urine as unchanged drug (Compound A). Key Words: Single dose; Multiple dose; Elderly subject; Alzheimer’s disease
INTRODUCTION COMPOUND Aa (the sesquifumarate salt of Compound A, an amino 3 pyridazine deriva-
*ms paper presented s a pharmacoki,,etics, phamacodynamics. and thug Metabolism poster in the 1996 American Association of Pharmaceutical Scientists Annual Meeting, Seattle, WA. Reprint address: Hai-Shan C. Jang, MS, Senior Research Scientist, Clinical Pharmacokinetics and Metabolism, Sanofi Pharmaceuticals, Inc.. 9 Great Valley Parkway, Malvern, PA 19355.
tive [l]) is a partial agonist of the M, muscarinic receptor (2-6). Compound Aa has therapeutic potential in the symptomatic treatment of cognitive disorders (memory and attention impairment) associated with patients suffering from Alzheimer’s disease (AD) (7-10). Earlier single and multi
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