Pharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients

Implications for combined immunotherapy with interleukin-2

Mark Middleton, Mark Sarno, Sanjiv S. Agarwala, John Glaspy, Aziz Laurent, Kelly McMasters, Peter Naredi, Steven O'Day, Eric Whitman, Sarah Danson, Rebecca Cosford, Kurt Gehlsen

Research output: Contribution to journalArticle

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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·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·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.

Original languageEnglish (US)
Pages (from-to)774-781
Number of pages8
JournalJournal of Clinical Pharmacology
Volume42
Issue number7
DOIs
StatePublished - Jul 2 2002

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Immunotherapy
Histamine
Interleukin-2
Healthy Volunteers
Pharmacokinetics
Neoplasms
Melanoma
Area Under Curve
Plasma Volume
Drug Interactions
Renal Cell Carcinoma
Half-Life
Leukemia
Heart Rate
Clinical Trials
Cytokines
Blood Pressure
Injections
Survival
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Middleton, Mark ; Sarno, Mark ; Agarwala, Sanjiv S. ; Glaspy, John ; Laurent, Aziz ; McMasters, Kelly ; Naredi, Peter ; O'Day, Steven ; Whitman, Eric ; Danson, Sarah ; Cosford, Rebecca ; Gehlsen, Kurt. / Pharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients : Implications for combined immunotherapy with interleukin-2. In: Journal of Clinical Pharmacology. 2002 ; Vol. 42, No. 7. pp. 774-781.
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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·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·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.",
author = "Mark Middleton and Mark Sarno and Agarwala, {Sanjiv S.} and John Glaspy and Aziz Laurent and Kelly McMasters and Peter Naredi and Steven O'Day and Eric Whitman and Sarah Danson and Rebecca Cosford and Kurt Gehlsen",
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Middleton, M, Sarno, M, Agarwala, SS, Glaspy, J, Laurent, A, McMasters, K, Naredi, P, O'Day, S, Whitman, E, Danson, S, Cosford, R & Gehlsen, K 2002, 'Pharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients: Implications for combined immunotherapy with interleukin-2', Journal of Clinical Pharmacology, vol. 42, no. 7, pp. 774-781. https://doi.org/10.1177/009127002401102713

Pharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients : Implications for combined immunotherapy with interleukin-2. / Middleton, Mark; Sarno, Mark; Agarwala, Sanjiv S.; Glaspy, John; Laurent, Aziz; McMasters, Kelly; Naredi, Peter; O'Day, Steven; Whitman, Eric; Danson, Sarah; Cosford, Rebecca; Gehlsen, Kurt.

In: Journal of Clinical Pharmacology, Vol. 42, No. 7, 02.07.2002, p. 774-781.

Research output: Contribution to journalArticle

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T1 - Pharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients

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AU - Middleton, Mark

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AU - Glaspy, John

AU - Laurent, Aziz

AU - McMasters, Kelly

AU - Naredi, Peter

AU - O'Day, Steven

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AU - Cosford, Rebecca

AU - Gehlsen, Kurt

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N2 - 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·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·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.

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