Pharmacokinetics and antidiuretic effect of a new vasopressin analogue (F992) in overhydrated male volunteers

Objective: The aim of the present study was to study the pharmacokinetics, the antidiuretic effects and the safety of [D-Phe(2), Thi(3), alpha-Me-Abu( 4); Hyp(7), D-Arg(8)]-dC(1)-vasopressin, a new antidiuretic peptide (F992, Ferring, Sweden), administered as intravenous infusion to orally overhydrat ed male volunteers. Methods: Eight healthy male volunteers participated in this open study cons isting of two parts: a dose titration study and a safety study. In the dose titration study ascending doses of F992 were administered to volunteers in pairs in order to find a dose that within 1 h after the infusion, in both subjects, caused a reduction of the urine flow rate to below 5 ml . min(-1) (target dose). Subsequently, this target dose was administered to all volu nteers. In the safety study the target dose was doubled and given to all vo lunteers. On each study occasion, in both study parts, the subjects were or ally overhydrated with water. F992 was administered as i.v. infusion approx imately 1.5 h after the start of the hydration procedure. Throughout the st udy days, blood was sampled for determination of plasma concentrations of F 992 and for safety evaluation. Urine was collected at intervals in order to estimate flow rate and osmolality. Results: The target dose was found to be 4.0 mu g as this dose fulfilled th e criteria regarding antidiuretic effect, consequently 8.0 mu g was adminis tered to all subjects in the safety study. After infusion of 4.0 and 8.0 mu g, the median half-lives of elimination were 4.72 (range 3.99-.53)h and 3. 85 (range 3.04-11.08) h, respectively. The plasma clearance and the volume of distribution at steady state were estimated to be 0.88 (SD 0.24) ml . mi n(-1) . kg(-1) and 326 (SD 68) ml . kg(-1) after infusion of 4 mu g. After the highest dose (8 mu g), the corresponding estimates were 0.86 (SD 0.32) ml . min(-1) . kg(-1) and 299 (SD 81) ml . kg(-1), respectively. Significan tly(P = 0.033) different maximum mean urine osmolalities were produced afte r infusion of 4.0 and 8.0 mu g of F992 (534 (SD 318) vs 732 (SD 189) mOsmol . kg(-1)). The median times to reach these values showed some tendency to be longer for the highest dose, however statistical significance was not re ached. No serious adverse events were observed during the study. Conclusion: We found it safe to administer F992 as infusion to overhydrated male volunteers. The results suggest that F992 has a longer half-life and a lower potency than the widely used peptide desmopressin.