Population pharmacokinetics meta-analysis of plitidepsin (Aplidin®) in cancer subjects

Nalda-Molina, Ricardo; Valenzuela, Belén; Ramon-Lopez, Amelia; Miguel-Lillo, Bernardo; Soto-Matos, Arturo; Pérez‐Ruixo, Juan José

doi:10.1007/s00280-008-0841-4

Cited by 27 publications

(23 citation statements)

References 31 publications

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“…In plasma and whole blood, mean half-lives ranged from 21 to 44 hours. Plitidepsin is widely distributed, with apparent volumes of distribution at steady state ( V ss) ranging from 500 to 1,350 L. Approximately 97.3% of the human plasma protein was bound 26. Mean clearance values in plasma range from 45 to 49 L/h.…”

Section: Designmentioning

confidence: 99%

“…Plitidepsin was evaluated as a single agent in six trials (one of them in children), in which it consistently showed limited efficacy (Table 2). 26–34 Overall, in 252 patients, two confirmed partial responses (PRs) and four unconfirmed PRs were found from all Phase I studies of plitidepsin. Clinical benefit, defined as stable disease (SD) lasting more than 3 months (time to progression [TTP] >3 months) was observed in 30 adult patients (range of clinical benefit, 3.0–9.7 months) and six children (range, 3.5–13.0 months).…”

Section: Developmentmentioning

confidence: 99%

“…The primary dose-limiting toxicities (DLTs) found in the dose-finding Phase I studies with single-agent plitidepsin were musculoskeletal adverse events (AEs) 26–30,36,41. The most common were myalgia, muscle weakness, and increase in serum CPK (noncardiac fraction) levels.…”

Section: Developmentmentioning

confidence: 99%

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Plitidepsin: design, development, and potential place in therapy

Alonso‐Álvarez

Pardal

Sánchez-Nieto

et al. 2017

DDDT

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Plitidepsin is a cyclic depsipeptide that was first isolated from a Mediterranean marine tunicate (Aplidium albicans) and, at present, is manufactured by total synthesis and commercialized as Aplidin®. Its antitumor activity, observed in preclinical in vitro and in vivo studies has prompted numerous clinical trials to be conducted over the last 17 years, alone or in combination with other anticancer agents. Single-agent plitidepsin has shown limited antitumor activity and a tolerable safety profile in several malignancies, such as noncutaneous peripheral T-cell lymphoma, melanoma, and multiple myeloma. In patients with relapsed or refractory multiple myeloma, plitidepsin activity seems to be enhanced after addition of dexamethasone while remaining well tolerated, and a Phase III trial comparing plitidepsin plus dexamethasone vs dexamethasone alone is underway. Additional studies are required to better define the role of plitidepsin in combination with other active agents in these indications. Results of plitidepsin activity in other hematological malignancies or solid tumors have been disappointing so far. Further studies analyzing its mechanisms of action and potential biomarkers will help select patients who may benefit most from this drug. In this review, we critically analyze the published studies on plitidepsin in hematological malignancies and solid tumors and discuss its current role and future perspectives in treating these malignancies. We also review its design, pharmaceutical data, and mechanism of action.

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Section: Designmentioning

confidence: 99%

Section: Developmentmentioning

confidence: 99%

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Plitidepsin: design, development, and potential place in therapy

Alonso‐Álvarez

Pardal

Sánchez-Nieto

et al. 2017

DDDT

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“…The data revealed that breast, melanoma, and non-small-cell lung cancer appear to be sensitive to low concentrations of Aplidine [27], [28]. Aplidin has entered into phase II clinical trials in Europe and Canada for the treatment of renal, head and neck, and medullary thyroid tumors [29]. Didemnin B, a branched N -methylated cyclic peptolide, was originally isolated from the Trididemnum genus of marine tunicates.…”

Section: Resultsmentioning

confidence: 99%

Isolation and Characterization of Marine Brevibacillus sp. S-1 Collected from South China Sea and a Novel Antitumor Peptide Produced by the Strain

et al. 2014

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A Gram-positive, rod-shaped bacterium, designated as S-1, was isolated from a marine sediment sample collected from South China Sea. Phylogenetic analysis based on 16S rRNA gene sequence showed that S-1 belongs to the genus Brevibacillus. A novel cytotoxic peptide was isolated from the fermentation broth of the marine-derived bacterium Brevibacillus sp. S-1, using ion-exchange chromatography and reverse-phase HPLC chromatography. The molecular weight of this peptide was determined as 1570 Da by MALDI-TOF mass spectrometry, and its structure was proposed as a cyclic peptide elucidated by MALDI-TOF/TOF mass spectrometry and de novo sequencing. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay showed that this peptide exhibited cytotoxicity against BEL-7402 human hepatocellular carcinoma cells, RKO human colon carcinoma cells, A549 human lung carcinoma cells, U251 human glioma cells and MCF-7 human breast carcinoma cells. Additionally, SBP exhibited low cytotoxicity against HFL1 human normal fibroblast lung cells. The result suggested that the cytotoxic effect of the peptide is specific to tumor cells.

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“…This same model was defined for plitidepsin in a population PK meta-analysis of data from 283 patients with advanced solid tumors who received the drug as monotherapy at doses ranging from 0.13 to 8.0 mg/m 2 and at different schedules, one of which was the one evaluated in the present study. 26 In conclusion, single-agent plitidepsin has shown antitumor activity and a tolerable safety profile in patients with relapsed/refractory non-cutaneous PTCL. These results therefore support the conduct of further clinical trials to evaluate plitidepsin-containing combined therapies in this disease setting.…”

Section: Studymentioning

confidence: 99%

Multicenter phase II study of plitidepsin in patients with relapsed/refractory non-Hodgkin's lymphoma

et al. 2012

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This phase II clinical trial evaluated the efficacy, safety and pharmacokinetics of plitidepsin 3.2 mg/m 2 administered as a 1-hour intravenous infusion weekly on days 1, 8 and 15 every 4 weeks in 67 adult patients with relapsed/refractory aggressive non-Hodgkin's lymphoma. Patients were divided into two cohorts: those with non-cutaneous peripheral T-cell lymphoma (n=34) and those with other lymphomas (n=33). Efficacy was evaluated using the International Working Group criteria (1999). Of the 29 evaluable patients with non-cutaneous peripheral T-cell lymphoma, six had a response (overall response rate 20.7%; 95% confidence interval, 8.0%-39.7%), including two complete responses and four partial responses. No responses occurred in the 30 evaluable patients with other lymphomas (including 27 B-cell lymphomas). The most common plitidepsin-related adverse events were nausea, fatigue and myalgia (grade 3 in <10% of cases). Severe laboratory abnormalities (lymphopenia, anemia, thrombocytopenia, and increased levels of transaminase and creatine phosphokinase) were transient and easily managed by plitidepsin dose adjustments. The pharmacokinetic profile did not differ from that previously reported in patients with solid tumors. In conclusion, plitidepsin monotherapy has clinical activity in relapsed/refractory T-cell lymphomas. Combinations of plitidepsin with other chemotherapeutic drugs deserve further evaluation in patients with non-cutaneous peripheral

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Population pharmacokinetics meta-analysis of plitidepsin (Aplidin®) in cancer subjects

Cited by 27 publications

References 31 publications

Plitidepsin: design, development, and potential place in therapy

Plitidepsin: design, development, and potential place in therapy

Isolation and Characterization of Marine Brevibacillus sp. S-1 Collected from South China Sea and a Novel Antitumor Peptide Produced by the Strain

Multicenter phase II study of plitidepsin in patients with relapsed/refractory non-Hodgkin's lymphoma

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