Azithromycin Concentrations During Long-Term Regimen in Patients With MALT Lymphoma

Abstract

IntroductionIn view of the antineoplastic effects of the macrolide clarithromycin in mucosa associated lymphatic tissue (MALT)-lymphoma, we performed a pilot study assessing levels of azithromycin in plasma, peripheral blood mononuclear cells (PBMC) and polymorphonuclear leukocytes (PMN) of MALT-lymphoma patients to determine the pharmacokinetics and potential influences of respective concentrations on the therapeutic outcome.Material and methodsIn total 16 patients with MALT-lymphoma received 1.5g of oral azithromycin once-weekly over 6 months. Blood was sampled directly prior to the following dose every 4 weeks during treatment. Drug levels were analysed by high performance liquid chromatography in plasma and intracellularly in PBMC and PMN. They were correlated with patients’ age, weight and body-mass-index and compared between patients responsive or unresponsive to treatment.ResultsMean azithromycin plasma levels of all patients were 58.97±30.48 ng/ml, remaining stable throughout the treatment period. Correlation analysis of plasma azithromycin showed no significance. Intracellular PBMC concentrations were 6648±8479 ng/ml, without any significant difference between responders and non-responders. Mean PMN levels were 39274±25659 ng/ml and significantly higher in patients unresponsive to treatment (t=2.858, p=0.017).ConclusionOur drug regime led to continuously high plasma and exceedingly high intracellular concentrations of azithromycin in PBMC and PMN. Age, weight or body-mass-index had no significant influence on plasma levels and thence should not be considered in dosage finding. High AZM levels in PBMC did not lead to a better treatment response, whereas enrichment in PMN suggested a poorer outcome. The threshold for immunomodulatory effects on lymphoma cells might not have been reached. Additionally, the finding of stable plasma and intracellular concentrations over months with high-dose azithromycin administered in intervals might also be important for the further design of azithromycin-based trials against MALT-lymphoma.

Current Status of the Spectrum and Therapeutics of Helicobacter pylori-Negative Mucosa-Associated Lymphoid Tissue Lymphoma

“…However, among 16 patients receiving azithromycin (2 with gastric and 14 with extragastric MALT lymphoma), two patients achieved CR, and two had PR (25% ORR) [ 116 ]. Furthermore, Scheibenpflug et al reported that among the 16 patients with MALT lymphoma, high intracellular concentrations of azithromycin in peripheral blood mononuclear cells were not associated with the responsiveness to azithromycin, but intracellular concentrations of azithromycin in polymorphonuclear leukocytes correlated with poor responsiveness [ 117 ].…”

Pharmacokinetics and Bioequivalence of 2 Azithromycin Tablet Formulations: A Randomized, Open‐Label, 2‐Stage Crossover Study in Healthy Volunteers

“…Moreover, the drug accumulates in the macrophages and polymorphonuclear leucocytes (up to 200 times the serum concentration) and supports their activity against infections 9,10 . This efficacy lasts for several days because of the long azithromycin half‐life of 68–79 hours 1,11 . On multiple dosing, the half‐life of azithromycin in the tissues and the tissue to serum concentration ratio increase 9 .…”

“…Conversely, its release from tissues is quite slow. 6,[9][10][11] Following an oral administration of a single dose of 500 mg, the tissue concentrations of azithromycin can reach over 100-fold the serum concentrations, especially in tonsil, lymph nodes, liver, lung, and prostate tissues. The significantly high tissue concentrations would overcome the minimum inhibitory concentration of 90% of pathogens (MIC90).…”

“…Azithromycin has an extremely rapid tissue penetration with a large volume of distribution of 23 L/kg. Conversely, its release from tissues is quite slow 6,9–11 . Following an oral administration of a single dose of 500 mg, the tissue concentrations of azithromycin can reach over 100‐fold the serum concentrations, especially in tonsil, lymph nodes, liver, lung, and prostate tissues.…”

“…9,10 This efficacy lasts for several days because of the long azithromycin half-life of 68-79 hours. 1,11 On multiple dosing, the half-life of azithromycin in the tissues and the tissue to serum concentration ratio increase. 9 Consequently, to achieve effective azithromycin concentrations at the sites of infection for several days, administration of a 500-mg dose is recommended on the first day, followed by 250 mg once daily on days 2 to 5.…”