S.Gisbert(1), V.Cosson(1), E.Fuseau(1) T. Senderovitz(2)
(1)EMF-Consulting France, (2)Ferring Pharmaceuticals Denmark
Background: Desmopressin (dDAVP) is a nonapeptide analogue of the antidiuretic hormone (ADH). In reference to previous studies the PK of dDAVP shows an absorption phase with a large inter-individual variability (30% on ka) and a disposition phase described by a 2 compartments model with a terminal half-life around 2.5h. The antidiuretic effect is mediated through the proteins G which, using the adenylate cyclase and the cyclic AMP as intermediates, will increase the aquaporine II water channels number in the collecting tubule. This complex pharmacology explains the indirect PK/PD models previously used for dDAVP. Objectives: To study the reasons of the large variability in the absorption phase of dDAVP using covariates as the food intake and the period of dDAVP administration (day/night). To built a PK/PD model for dDAVP with a standard two-stage analysis approach and, if the data allow it, transfer the model in NONMEM. Study design: 15 healthy male volunteers (55-75 years) were included in this study. In a randomised crossover design dDAVP was administered both orally (0.2 mg) and intravenously (2 mg) as single doses both during the day and the night, yielding 4 different sessions: day p.o., night p.o., day i.v. and night i.v. The sessions were separated by a wash-out period of about 3 days. Pharmacokinetic (PK) measurements: Blood samples were taken immediately before drug intake (0h) and then at 15 (only for i.v. dose), 30 and 45 minutes and 1, 1.5,2,3,4,6,8 and 12 hours after intake. Plasma dDAVP concentrations were measured with a validated radioimmunoassay. Pharmacodynamic (PD) measurements: All urine samples were collected during the 12-hour period and urine parameters as diuresis and osmolality were measured. After 11 a.m. administration of dDAVP urine was collected during the intervals: 11-14h; 14-17h; 17-20h and 20-23h. After administration of dDAVP at 22.00 pm urine was collected during the intervals: 22-08h and 08-10h and the preceding day at the intervals:08-11h; 11-14h; 14-17h and 17-18h. An ultrasound examination was performed after each voiding period to check for residual urine. PK and PK/PD analyses: PK and PK/PD analyses are currently implemented using the WinNonlin™ software ver. Pro 3.1. A PK/PD model will be developed to characterize the antidiuretic effect of dDAVP. A one-step population PK/PD model (using NONMEM) will be developed if the previous results allowed it.
Reference: PAGE 10 (2001) Abstr 273 [www.page-meeting.org/?abstract=273]
Poster: poster