Pharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients: implications for combined immunotherapy with interleukin-2.

2.50
Hdl Handle:
http://hdl.handle.net/10541/80040
Title:
Pharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients: implications for combined immunotherapy with interleukin-2.
Authors:
Middleton, Mark R; Sarno, Mark; Agarwala, Sanjiv S; Glaspy, John; Laurent, Aziz; McMasters, Kelly; Naredi, Peter; O'Day, Steven; Whitman, Eric; Danson, Sarah; Cosford, Rebecca; Gehlsen, Kurt
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.
Affiliation:
Christie Hospital, Manchester, United Kingdom.
Citation:
Pharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients: implications for combined immunotherapy with interleukin-2. 2002, 42 (7):774-81 J Clin Pharmacol
Journal:
Journal of Clinical Pharmacology
Issue Date:
Jul-2002
URI:
http://hdl.handle.net/10541/80040
PubMed ID:
12092744
Type:
Article
Language:
en
ISSN:
0091-2700
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorMiddleton, Mark R-
dc.contributor.authorSarno, Mark-
dc.contributor.authorAgarwala, Sanjiv S-
dc.contributor.authorGlaspy, John-
dc.contributor.authorLaurent, Aziz-
dc.contributor.authorMcMasters, Kelly-
dc.contributor.authorNaredi, Peter-
dc.contributor.authorO'Day, Steven-
dc.contributor.authorWhitman, Eric-
dc.contributor.authorDanson, Sarah-
dc.contributor.authorCosford, Rebecca-
dc.contributor.authorGehlsen, Kurt-
dc.date.accessioned2009-09-07T14:30:01Z-
dc.date.available2009-09-07T14:30:01Z-
dc.date.issued2002-07-
dc.identifier.citationPharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients: implications for combined immunotherapy with interleukin-2. 2002, 42 (7):774-81 J Clin Pharmacolen
dc.identifier.issn0091-2700-
dc.identifier.pmid12092744-
dc.identifier.urihttp://hdl.handle.net/10541/80040-
dc.description.abstractRecent 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.en
dc.language.isoenen
dc.subjectRenal Canceren
dc.subjectKidney Canceren
dc.subject.meshAdjuvants, Immunologic-
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshCarcinoma, Renal Cell-
dc.subject.meshDrug Interactions-
dc.subject.meshDrug Therapy, Combination-
dc.subject.meshFemale-
dc.subject.meshHistamine-
dc.subject.meshHumans-
dc.subject.meshInfusions, Intravenous-
dc.subject.meshInjections, Subcutaneous-
dc.subject.meshInterleukin-2-
dc.subject.meshKidney Neoplasms-
dc.subject.meshMale-
dc.subject.meshMelanoma-
dc.subject.meshMiddle Aged-
dc.titlePharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients: implications for combined immunotherapy with interleukin-2.en
dc.typeArticleen
dc.contributor.departmentChristie Hospital, Manchester, United Kingdom.en
dc.identifier.journalJournal of Clinical Pharmacologyen

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