Intranasal and Intravenous Administration of Desmopressin: Effect on F VIII/vWF, Pharmacokinetics and Reproducibility

Summary

A comparison was made of intranasal administration of 300 μg desmopressin (DDAVP) by spray, with intravenous administration of 0.2, 0.3 and 0.4 μg DDAVP/kg in 10 healthy volunteers. The effect of DDAVP was measured on F VIII/vWF complex and on plasminogen activator release. In addition, plasma levels of DDAVP were determined using a specific and sensitive radioimmunoassay. Moreover, the reproducibility of the spray effect in 10 healthy volunteers was tested after administration of 300 μg DDAVP intranasally by spray on 5 different occasions.

Plasma levels of DDAVP showed a clear dose-response with the maximum levels at 0.4 μg/kg i.v. The effect of the spray approximated the 0.2 μg/kg response. However, the maximum response in both F VIII/vWF complex and plasminogen activator release was obtained after 0.3 μg/kg i. v. The response to 0.4 μg/kg i. v. was not significantly different from the response to 0.3 μg/kg indicating that maximum stimulation was reached with 0.3 μg/kg. There was no correlation between plasma levels of F VIII/vWF and DDAVP indicating that the biological response to DDAVP is subjected to saturation kinetics.

The reproducibility of the effect of the spray dose on VIII : C was 21% (c.v.) and 27% for the intra-individual and interindividual variation, respectively, and compared favorably with intravenous administration.

Intranasal DDAVP (300 μg) is as effective as 0.2 μg/kg intravenously and provides an accurate, reproducible and convenient alternative to parenteral administration.

Keywords

DDAVP - Intranasal - Intravenous - Pharmacokinetics - F VIII

• References

• 1 Mannucci PM, Åberg M, Nilsson IM, Robertson B. Mechanism of plasminogen activator and factor VIII increase after vasoactive drugs. Br J Haematol 1975; 30: 81-92
• 2 Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. l-deamino-8-D-arginine vasopressin: A new pharmacological approach to the management of haemophilia and von Willebrand’s disease. Lancet 1977; I: 869-872
• 3 Mannucci PM, Canciani MT, Rota L, Donovan BS. Response of factor VIII/von Willebrand factor to DDAVP in healthy subjects and patients with haemophilia A and von Willebrand’s disease. Br J Haematol 1981; 47: 283-293
• 4 Äberg M, Nilsson IM, Vilhardt H. The release of fibrinolytic activator and factor VIII after injection of DDAVP. In: Davidson JF. (ed) Progress in Chemical Fibrinolysis and Thrombolysis. pp. 92-97 1979
• 5 Nilsson IM, Vilhardt H, Holmberg L, Ästedt B. Association between factor VIII related antigen and plasminogen activator. Acta Med Scand 1982; 211: 105-112
• 6 Kobayashi I. Treatment of hemophilia A and von Willebrand’s disease patients with an intranasal dripping of DDAVP. Thromb Res 1979; 16: 775-779
• 7 Nilsson IM, Walter H, Mikaelsson M, Vilhardt H. Factor VIII concentrate prepared from DDAVP stimulated blood donor plasma. Scand J Haematol 1979; 22: 42-46
• 8 Mikaelsson M, Nilsson IM, Cedergren B, Jonsson S, Rydberg L, Wiechel B. The use of Desmopressin (DDAVP) in the preparation of improved Factor VIII concentrate. Scand J Haematol 1984; Suppl. 40 (33) 93-101
• 9 Köhler M, Hellstern P, Miyashita C, von Blohn G, Wenzel E. Comparative study of intranasal, subcutaneous and intravenous administration of desamino-D-arginine vasopressin (DDAVP). Thromb Haemostas 1986; 55: 108-111
• 10 Köhler M, Hellstern P, Reiter B, von Blohn G, Wenzel E. The subcutaneous administration of the vasopressin analogue 1-desamino-8-D-arginine vasopressin in patients with von Willebrand’s disease and hemophilia. Klin Wochenschr 1984; 62: 543-548
• 11 De Sio L, Mariani G, Muzzocconi MG, Chistolini A, Tirindelli MC, Mandelli F. Comparison between subcutaneous and intravenous DDAVP in mild and moderate hemophilia A. Thromb Haemostas 1985; 54: 387-389
• 12 Streit A, Furlan M, Beck EA. Desamino-8-D-Arginin-Vasopressin-Nasentropfen zur Behandlung der milden Hämophilie A und des Morbus von Willebrand. Schweiz med Wschr 1984; 114: 1389-1393
• 13 Grossman A, Fabbri A, Goldberg PL, Besser GM. Two new modes of desmopressin (DDAVP) administration. Br Med J 1980; 280: 1215
• 14 Harris AS, Nilsson IM, Wagner Z-G, Alkner U. Intranasal administration of peptides: Nasal deposition, biological response, and absorption of desmopressin. J Pharm Sei 1986; 75: 1085-1088
• 15 Lethagen S, Ostergaard H, Nilsson IM. Clinical application of the chromogenic assay of factor VIII in haemophilia A, and different variants of von Willebrand’s disease. Scand J Haematol 1986; 37: 448-453
• 16 Holmberg L, Borge L, Ljung R, Nilsson IM. Measurement of antihaemophilic factor A antigen (VIIIC:Ag) with a solid phase immunoradiometric method based on nonhaemophilic antibodies. Scand J Haematol 1979; 23: 17-24
• 17 Zimmerman TS, Ratnoff OD, Powell AE. Immunologic differentiation of classical hemophilia (factor VIII deficiency) and von Willebrand’s disease. J Clin Invest 1971; 50: 244-254
• 18 Holmberg L, Kristoffersson A-C, Lecander I, Wallen P, Astedt B. Immunoradiometric quantification of tissue plasminogen activator secreted by fetal organs. Comparison with urokinase. Scand J clin Lab Invest 1982; 42: 347-354
• 19 Nilsson IM, Felding P, Lecander I, Lenner C, Astedt B. Different types of plasminogen activator inhibitors in plasma and platelets in pregnant women. Br J Haematol 1986; 62: 215-220
• 20 Kobrinsky NL, Doyle JJ, Israels ED, Winter J SD, Cheang MS, Walker RD, Bishop AJ. Absent factor VIII response to synthetic vasopressin analogue (DDAVP) in nephrogenic diabetes insipidus. Lancet 1985; I: 1293-1294
• 21 Harris AS. Biopharmaceutical aspects on the intranasal administration of peptides. In: Delivery Systems for Peptide Drugs. Davis SS, Ilium L, Tomlinson E. (eds), pp 191-204 Plenum Press; New York: 1986