title: Pharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients: implications for combined immunotherapy with interleukin-2.
abstract: Recent clinical trials in melanoma and leukemia have demonstrated potential for increased survival time and improved remission when histamine dihydrochloride is added to cytokine monotherapy. In the present study, the pharmacokinetics of subcutaneous histamine (1 mg) in 21 healthy subjects and 12 melanoma patients was determined via model-dependent methods. Drug-drug interactions with subcutaneous interleukin-2 (1.1 mg) were evaluated in a combined cohort of patients with melanoma (n = 8) or renal cell carcinoma (n = 4). Histamine dihydrochloride administered over 10 minutes in healthy subjects peaked at 18 minutes (Cmax 38 nmol/L), attained a distribution volume of 59 L, and was eliminated at 6%/min. The results were similar in a 20-minute infusion in melanoma patients. No gender effects were observed (p > 0.05). Interleukin-2 injected either 10 minutes prior to or 10 minutes following histamine dihydrochloride had no effect on histamine kinetics. Histamine dihydrochloride administered 10 minutes prior to injection of interleukin-2 also had no effect on interleukin-2 kinetics. Maximal concentration of interleukin-2 (2,442 pg/ml) occurred at 2.5 hours with an elimination half-life of 1.7 hours, area under the curve (AUC) of 15,746 pg x h/ml, and volume of distribution and plasma clearance of 194 L and 74 L/h, respectively. However, interleukin-2 Cmax (1,758 pg/ml) and AUC (12,448 pg x h/ml) were reduced when histamine dihydrochloride was infused 10 minutes following interleukin-2, likely due to the pharmacodynamic effects of histamine, including increased heart rate and reduced blood pressure. It is concluded that histamine dihydrochloride and interleukin-2 can be safely coadministered with minimal interaction.
authors.affiliation: Christie Hospital, Manchester, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Middleton
authors.forename: Mark
authors.initials: M
authors.lastname: Sarno
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Agarwala
authors.forename: John
authors.initials: J
authors.lastname: Glaspy
authors.forename: Aziz
authors.initials: A
authors.lastname: Laurent
authors.forename: Kelly
authors.initials: K
authors.lastname: McMasters
authors.forename: Peter
authors.initials: P
authors.lastname: Naredi
authors.forename: Steven
authors.initials: S
authors.lastname: O'Day
authors.forename: Eric
authors.initials: E
authors.lastname: Whitman
authors.forename: Sarah
authors.initials: S
authors.lastname: Danson
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cosford
authors.forename: Kurt
authors.initials: K
authors.lastname: Gehlsen
mesh_terms: D000276:Adjuvants, Immunologic / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006632:Histamine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000493:pharmacokinetics*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D007376:Interleukin-2; D006632:Histamine