Arturo Soto-Matos

PharmaMar, Madrid, Madrid, Spain

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Publications (24)105.57 Total impact

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    ABSTRACT: In this study, we characterize the population pharmacokinetics of kahalalide F (KF), a novel marine anticancer drug, after intravenous (i.v.) administration in advanced cancer patients. Data from 240 patients included in three Phase I and three Phase II trials receiving i.v. weekly and every 3 weeks infusions of KF, at doses ranging 266-6650 µg/m(2), were analyzed using NONMEM™ VII. The effect of demographics and/or pathophysiologically relevant factors on KF pharmacokinetic parameters was evaluated. Model evaluation was conducted using nonparametric bootstrap and visual predictive check (in both internal and external datasets). An open two-compartment model with linear distribution and elimination from central compartment was suitable to describe the data. Volume of distribution at steady state and its between-subject variability (CV%) was estimated to be 6.56 L (28 %). Plasma clearance was estimated to be 6.25 L/h (43 %). Within the range of covariates evaluated, age, weight, body surface area, gender, ECOG performance status, presence of liver metastases, creatinine clearance, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total protein and serum albumin did not contribute to explain KF pharmacokinetic variability to a significant extent. The developed model was deemed appropriate to describe the time course of KF plasma concentrations and its variability in advanced cancer patients. The integration of pharmacokinetic data from six clinical studies demonstrated KF linear elimination from plasma, dose-proportional exposure and time-independent pharmacokinetics. Based on analyzed data, no clinically relevant covariates were identified as predictors of KF pharmacokinetics.
    No preview · Article · Jun 2015 · Cancer Chemotherapy and Pharmacology

  • No preview · Article · Nov 2014 · European Journal of Cancer

  • No preview · Conference Paper · Sep 2014
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    ABSTRACT: Background: We wanted to evaluate the impact of peritoneal dialysis on trabectedin therapy in terms of side effects, response and levels in the blood and dialysate of a patient on peritoneal dialysis for end-stage renal failure caused by previous ifosfamide therapy. This has not yet been reported in the medical literature. Methods: We measured the levels of trabectedin in the blood and peritoneal dialysate at different time points before and after the administration of a 3rd cycle of trabectedin (1.5 mg/m(2) over 24 h). Toxicity from the treatment was recorded and the response status was evaluated on a CT scan after the 3rd and 6th cycles. Results: Serum creatinine clearance (Cockcroft-Gault formula) was 8.31 ml/min. The patient had a World Health Organization performance status score of '0' and did not suffer any significant side effects except for grade 2 anaemia. There was no difference in the plasma level of trabectedin just before and after a 3-hour session of peritoneal dialysis. The amount of trabectedin in the peritoneal dialysates was undetectable (limit of quantification: 25.9 pg/ml). The patient achieved stable disease after 3 cycles, and progressive disease was observed after 6 cycles on CT scan. Conclusion: Our patient did not suffer undue side effects from trabectedin, and peritoneal dialysis did not appear to have an impact on the clearance of the drug.
    No preview · Article · Aug 2014 · Chemotherapy
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    ABSTRACT: Background and objective: PM00104 (Zalypsis(®)) is a novel marine-derived compound that has shown antineoplastic activity against a number of human tumour cell lines. Myelosuppression was found to be a PM00104 dose-limiting toxicity during phase I studies. The objective of this study was to characterize the time course of neutropenia after intravenous PM00104 administration in cancer patients. Methods: Absolute neutrophil counts (ANCs) and pharmacokinetic data from 144 patients receiving PM00104 doses ranging from 0.053 to 5 mg/m(2) were used to estimate the system-related (baseline ANC [Circ(0)], mean transit time [MTT], feedback on proliferation [γ] and maturation [δ]) and drug-specific (first-order elimination rate constant from effect compartment [k(e0)] [α and β]) parameters of a modified Friberg's model. The concentrations in the effect compartment (C(e)) were assumed to reduce the proliferation rate of the progenitor cells according to the function [Formula: see text] Model evaluation and simulations were undertaken to evaluate the effect of dose intensity, dose density and the intravenous infusion duration on severe neutropenia incidence. Results: The typical values (between-subject variability [%]) of the Circ(0), MTT, γ, δ, k(e0), α and β were estimated to be 5.66 × 10(9) cells/L (13 %), 149 h (29 %), 0.136, 0.191, 0.00639 h(-1) (32 %), 0.332 L/µg (24 %) and 1.47, respectively. Age, bodyweight, sex, serum albumin, total protein, liver metastases, number of previous chemotherapy lines and performance status were not associated with model parameters. The model evaluation evidenced an accurate prediction of the neutropenia grade 3 and/or 4 incidence. Simulations indicated that PM00104 dose and dosing interval, but not infusion duration, were the main determinants of the neutropenia severity and duration. Conclusions: The time course of neutropenia following PM00104 was well characterized by the model developed. The model-predicted time course of the ANCs and its variability confirmed that neutropenia is reversible, of short duration and non-cumulative.
    No preview · Article · Oct 2012 · Clinical Pharmacokinetics
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    ABSTRACT: Background AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. HSP90 is a chaperone of client proteins relevant in NSCLC pathogenesis, including ALK and EGFR. Oncogenic fusion genes giving constitutive ALK activity (ALK+) occur in up to 6% of NSCLCs, and EGFR mutation (mut) occurs in 10–20% of cases. We report data from a Phase II study of AUY922 in patients (pts) with previously treated, advanced NSCLC, stratified by molecular status.
    Preview · Article · Sep 2012 · Annals of Oncology
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    ABSTRACT: Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) of elisidepsin. Methods: Eligible patients with refractory, advanced solid tumors received elisidepsin as 24-h intravenous infusion every 3 weeks. Pharmacokinetic profiles were analyzed during cycles 1 and 2. Results: Forty-two patients received elisidepsin at doses from 0.5 to 6.8 mg/m(2). The MTD was 6.8 mg/m(2), and the RD was 5.5 mg/m(2). Cohort expansion at the RD was done at a fixed dose (FD) of 10 mg, considered equivalent to 5.5 mg/m(2). DLTs (reversible grade 3 transaminase increases) occurred at 6.8 mg/m(2) (n = 2 patients), 5.5 mg/m(2) (n = 1), and 10 mg FD (n = 1). One patient with esophageal adenocarcinoma achieved complete response for >38 months, and 12 patients had disease stabilization (8 for ≥3 months). Median time-to-progression for these 12 patients was 4.8 months. Plasma elisidepsin concentrations increased with dose. No drug accumulation between cycles was found. No correlation was observed between body surface area (BSA) and plasma clearance; therefore, elisidepsin was given as flat dose (in mg) in the expansion cohort at the RD and in ongoing clinical trials. Conclusions: Elisidepsin is well tolerated with predictable reversible transaminase increases. Encouraging preliminary evidence of antitumor activity was observed.
    No preview · Article · Aug 2012 · Cancer Chemotherapy and Pharmacology
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    ABSTRACT: PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly. Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data. A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23-3.6 mg m(-2)) and 20 patients on the 3-h schedule (1.8-3.5 mg m(-2)). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m(-2). With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m(-2). Common PM00104-related adverse events at the RP2D comprised grade 1-2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ≥6 months. PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.
    Full-text · Article · Apr 2012 · British Journal of Cancer
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    ABSTRACT: This analysis determined the incidence of serious rhabdomyolysis events reported during trabectedin treatment since the first phase I clinical trial in April 1996 up to September 2010. Search was done in the Yondelis(®) Pharmacovigilance and Clinical Trials databases using a list of terms according to the Medical Dictionary for Regulatory Activities (MedDRA, v. 13.1), followed by a medical review of all cases retrieved. Total estimated sample was 10,841 patients: 2,789 from clinical trials; 3,926 from compassionate use programs; and 4,126 treated in the marketplace. Two groups were identified: (1) rhabdomyolysis and (2) clinically relevant creatine phosphokinase (CPK) increases without acute renal failure (ARF). Descriptive analysis included demographic, clinical/laboratory data, and contributing/confounding factors. Potential predictive factors were evaluated by multivariate stepwise logistic regression analysis. Possible changes of pharmacokinetics (PK) in patients with rhabdomyolysis were explored using a population PK model. The global incidence of rhabdomyolysis was 0.7%, and most cases occurred in Cycle 2 of treatment. The incidence of fatal cases was 0.3%. None of the variables evaluated to detect potential risk factors of rhabdomyolysis were predictive. Additionally, CPK increases (without ARF) were detected in 0.4% of patients as an incidental finding with good prognosis. Rhabdomyolysis is an uncommon event during trabectedin treatment. Multivariate analyses did not show any potential factor that could be predictive or represent a significantly higher risk of developing rhabdomyolysis. Nevertheless, close patient monitoring and adherence to drug administration guidelines may help to limit the incidence of this event.
    Full-text · Article · Apr 2012 · Cancer Chemotherapy and Pharmacology
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    ABSTRACT: Plitidepsin is a cyclic depsipeptide of marine origin in clinical development in cancer patients. Previously, some depsipeptides have been linked to increased cardiac toxicity. Clinical databases were searched for cardiac adverse events (CAEs) that occurred in clinical trials with the single-agent plitidepsin. Demographic, clinical and pharmacological variables were explored by univariate and multivariate logistic regression analysis. Forty-six of 578 treated patients (8.0%) had at least one CAE (11 patients (1.9%) with plitidepsin-related CAEs), none with fatal outcome as a direct consequence. The more frequent CAEs were rhythm abnormalities (n = 31; 5.4%), mostly atrial fibrillation/flutter (n = 15; 2.6%). Of note, life-threatening ventricular arrhythmias did not occur. Myocardial injury events (n = 17; 3.0%) included possible ischemic-related and non-ischemic events. Other events (miscellaneous, n = 6; 1.0%) were not related to plitidepsin. Significant associations were found with prostate or pancreas cancer primary diagnosis (p = 0.0017), known baseline cardiac risk factors (p = 0.0072), myalgia present at baseline (p = 0.0140), hemoglobin levels lower than 10 g/dL (p = 0.0208) and grade ≥2 hypokalemia (p = 0.0095). Treatment-related variables (plitidepsin dose, number of cycles, schedule and/or total cumulative dose) were not associated. Electrocardiograms performed before and after plitidepsin administration (n = 136) detected no relevant effect on QTc interval. None of the pharmacokinetic parameters analyzed had a significant impact on the probability of developing a CAE. In conclusion, the most frequent CAE type was atrial fibrillation/atrial flutter, although its frequency was not different to that reported in the age-matched healthy population, while other CAEs types were rare. No dose-cumulative pattern was observed, and no treatment-related variables were associated with CAEs. Relevant risk factors identified were related to the patient's condition and/or to disease-related characteristics rather than to drug exposure. Therefore, the current analysis supports a safe cardiac risk profile for single-agent plitidepsin in cancer patients.
    Full-text · Article · Dec 2011 · Marine Drugs
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    ABSTRACT: This dose-escalating phase I clinical trial was designed to determine the recommended dose (RD) and to assess the safety and feasibility of weekly plitidepsin (1-hour i.v. infusion, Days 1, 8 and 15) combined with carboplatin (1-hour i.v. infusion, Day 1, after plitidepsin) in 4-week (q4wk) cycles given to patients with advanced solid tumors or lymphomas. Twenty patients were enrolled and evaluable for both safety and efficacy. The starting dose was plitidepsin 1.8 mg/m(2) and carboplatin area under the curve (AUC) = 5 min*mg/ml; dose escalation proceeded based on worst toxicity in the previous cohort. The maximum tolerated dose (MTD) was plitidepsin 3.0 mg/m(2) and carboplatin AUC = 5 min*mg/ml, with grade 3 transaminase increases as the most common dose-limiting toxicities (DLTs). The RD for phase II studies was plitidepsin 2.4 mg/m(2) and carboplatin AUC = 5 min*mg/ml, with fatigue, myalgia and nausea as the most common drug-related adverse events (AEs). No unexpected toxicity was seen. Twelve patients (60%), ten of whom were heavily pretreated (≥2 previous chemotherapy lines) showed stable disease (SD), with a median time to progression (TTP) of 4.4 months. In conclusion, plitidepsin 2.4 mg/m(2) and carboplatin AUC = 5 min*mg/ml is a safe dose for future phase II studies evaluating the use of this combination in cancer patients potentially sensitive to platinum-based therapy.
    No preview · Article · Dec 2011 · Investigational New Drugs
  • Mirela Cartoafa · Carmen Kahatt · Arturo Soto-Matos · Elena Roy · Pilar Lardelli
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    ABSTRACT: No abstract available.
    No preview · Article · Sep 2011 · Acta Haematologica
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    ABSTRACT: The pharmacokinetics of trabectedin has never been reported in patients with impaired renal function or in patients on hemodialysis. We examined trabectedin PK in a patient on hemodialysis, starting trabectedin therapy at a standard dose for recurrence of a retroperitoneal myxoid liposarcoma that had occurred under immunosuppressive drugs for kidney transplant. As compared with a population with normal renal function, the study patient presented a higher C (max) and AUC, with lower clearance, terminal half-life, and volume of distribution. The low dialysis clearance, accounting for a minor part of the total body clearance and the absence of detectable trabectedin in the dialysate samples, suggests that hemodialysis does not efficiently clear trabectedin. Trabectedin tolerance was good. This case reports for the first time the feasibility of trabectedin therapy in a hemodialyzed patient. Given the rising incidence of cancer in patients with end-stage renal disease, it is crucial to provide data that improve the management of anticancer drugs in dialyzed patients.
    Full-text · Article · Aug 2011 · Cancer Chemotherapy and Pharmacology
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    ABSTRACT: Maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics (PK) were evaluated for trabectedin 3-h every-3-weeks schedule in 33 cancer patients stratified according to liver dysfunction degree as per baseline alkaline phosphatase (AP). Stratification was as follows: stratum I [upper limit of normal (ULN) < AP ≤ 1.5 × ULN; n = 16], stratum II [1.5 × ULN < AP ≤ 2.5 × ULN; n = 12], and stratum III [AP >2.5 × ULN; n = 5] (bilirubin <2.5 × ULN for all 3 strata). In each stratum, patients were treated in sequential cohorts at escalating doses. Dose-limiting toxicities (DLTs) were grade 3 transaminase increases not recovering baseline values on day 21, febrile neutropenia/grade 4 neutropenia lasting >5 days and AP increase more than twice over baseline. The MTD and RD for stratum I (mild baseline AP) was 1.3 mg/m(2). Recruitment was stopped early in strata II/III (moderate/severe baseline AP) without reaching the MTD due to slow accrual and difficulty in finding patients. Biochemical parameters other than AP (bilirubin, AST or ALT) were similar between strata. No relevant PK differences were found between strata. In conclusion, the MTD and RD (1.3 mg/m(2)) were confirmed only for stratum I. Stratification criteria based on baseline AP apparently did not segregate the patients according to their liver dysfunction degree. Antitumor activity was found in patients with pretreated ovarian cancer.
    Full-text · Article · Jun 2011 · Medical Oncology
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    ABSTRACT: The aim of this study was to characterize the population pharmacokinetics of PM00104 (Zalypsis(®)) in cancer patients. A total of 135 patients included in four phase I clinical trials who receive intravenous PM00104 at doses ranging from 53 to 5,000 μg/m(2) and administered as 1-, 3-, or 24-h infusion every 3 weeks or as 1-h infusion on days 1, 8, and 15 of a 28-day cycle, or 1-h infusion daily during 5 consecutive days every 3 weeks were included in the analysis. Pharmacokinetic data were analyzed with non-linear mixed effect model using NONMEM VI software. The effect of selected patient covariates on PM00104 pharmacokinetics was investigated. Model evaluation was performed using predictive checks and non-parametric bootstrap. An open four-compartment catenary linear model with first-order elimination was developed to best describe the data. Plasma clearance and its between-subject variability was 43.7 L/h (34%). Volume of distribution at steady state was 822 L (117%). Within the range of covariates studied, age, sex, body size variables, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, lactate dehydrogenase, creatinine clearance, albumin, total protein, hemoglobin, performance status, liver metastases, dose-limiting toxicity, and stable disease for 3 months were not statistically related to PM00104 pharmacokinetic parameters. Bootstrap and posterior predictive check evidenced the model was deemed appropriate to describe the time course of PM00104 plasma concentrations in cancer patients. The integration of phase I pharmacokinetic data demonstrated PM00104 linear elimination from plasma, dose proportionality up to 5,000 μg/m(2), and time-independent pharmacokinetics. No clinically relevant covariates were identified as predictors of PM00104 pharmacokinetics.
    No preview · Article · May 2011 · Cancer Chemotherapy and Pharmacology
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    ABSTRACT: Spisulosine is a marine compound that showed antitumor activity in preclinical studies. We report results of a phase I trial performed in patients with advanced solid tumors with the marine compound, with the aim to determine the maximum tolerated dose (MTD) of a weekly 3-h intravenous (iv.) infusion, and to evaluate the safety, efficacy, and pharmacokinetics (PK) of the compound. Two centers contributed 25 patients to the trial, and 7 dose levels were explored. In dose levels ranging from 4 to 128 mg/m²/day, no dose-limiting toxicities (DLT) were observed. One patient had DLT at 200 mg/m², a reversible grade 3 ALT increase. The MTD was not reached due to early termination of the Spisulosine trial program but is considered to be likely in the range of 200 mg/m² for this schedule. Drug-related adverse reactions included mild to moderate nausea, pyrexia, injection site reactions, and vomiting. One case of grade 4 peripheral motor and sensory neuropathy associated with general weakness and pain was observed during treatment cycle 4 and possibly contributed to the death of the patient. Grade 3 laboratory abnormalities included anemia and lymphopenia and increases in liver enzymes (alkaline phosphatase, transaminases, and bilirubin). Objective responses were not observed, and only four patients had short-lasting stable disease (<3 months). The PK data indicated a wide distribution, a long residence time, and dose proportionality of the agent. Hepato- and neuro-toxicity are schedule independent dose-limiting adverse events for this marine compound, as illustrated by this and other early clinical trials.
    Full-text · Article · Apr 2011 · Cancer Chemotherapy and Pharmacology
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    ABSTRACT: This analysis provides a cross-study evaluation of the cardiac safety of trabectedin. Drug-related cardiac adverse events (CAEs) were retrieved from phase I-III clinical trials, pharmacovigilance databases, and spontaneously reported cases. Left ventricular ejection fraction (LVEF) was monitored in combination phase I studies with doxorubicin or pegylated liposomal doxorubicin (PLD) and in a phase III trial (with PLD). CAEs [grade 4 cardiac arrest with severe pancytopenia and sepsis (n = 1 patient), grade 4 atrial fibrillation (n = 2), and grade 1 tachycardia (n = 1)] occurred in 4/283 patients (1.4%) in 6 single-agent phase I trials. CAEs (grade 1 sinus tachycardia in a hypertensive patient and grade 1 ventricular dysfunction) occurred in 2/155 patients (1.3%) in 4 phase I combination trials. Results from 19 single-agent phase II trials showed CAEs in 20/1,132 patients (1.8%): arrhythmias (tachycardia/palpitations; n = 13; 1.1%) were the most common. A rather similar rate of symptomatic CAEs was observed in both arms of a phase III trial in recurrent ovarian cancer: 6/330 patients (1.8%; PLD) and 11/333 patients (3.3%; trabectedin/PLD). No clinically relevant LVEF changes occurred in phase I combination trials. In the phase III trial, LVEF decreases from baseline were similar: 9% of patients (PLD) and 7% (trabectedin/PLD), with no relevant symptoms. During postmarketing experience in soft tissue sarcoma (2,046 patients treated), 4 CAEs (2 cardiac arrest, 2 cardiac failure; ~0.2%) occurred in patients with preexisting conditions. Trabectedin has a low incidence of CAEs, consisting mainly of arrhythmias. This extensive data review indicates a low cardiac risk profile for trabectedin.
    Full-text · Article · Mar 2011 · Cancer Chemotherapy and Pharmacology

  • No preview · Article · Nov 2010 · EJC Supplements
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    ABSTRACT: This phase I study evaluated the feasibility, safety, pharmacokinetics (PK), and preliminary evidence of anticancer activity of the sequential administration of paclitaxel and trabectedin on an every-2-week schedule in patients with refractory solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) level on this schedule, as well as to recommend doses for disease-directed studies. Twenty-seven patients were treated with paclitaxel (80-120 mg/m(2); 1-hour i.v. infusion, day 1) and trabectedin (0.525-0.775 mg/m(2); 3-hour i.v. infusion, day 2) with doses increased in successive cohorts. Blood sampling for PK and drug-drug interaction studies was done. Neutropenia, which resulted in treatment delay exceeding 1 week, was the principal dose-limiting toxicity for this paclitaxel-trabectedin regimen and precluded dose escalation above 120 mg/m(2) paclitaxel and 0.650 mg/m(2) trabectedin. At the MTD (120 mg/m(2) paclitaxel and 0.650 mg/m(2) trabectedin), the safety profile was favorable in patients receiving cumulative treatment. Relevant drug-drug PK interactions between paclitaxel and trabectedin were not identified. A patient with soft tissue sarcoma had a complete response and several patients with various refractory solid malignancies showed protracted stable disease as their best response. The MTD level of sequential paclitaxel 1-hour infusion (day 1) and trabectedin 3-hour infusion (day 2) administered every 2 weeks is 120 and 0.650 mg/m(2), respectively. The manageable toxicities at the MTD, preliminary evidence of antitumor activity, and lack of notable PK drug-drug interactions warrant further disease-directed studies of this regimen in relevant tumor types and settings.
    Full-text · Article · May 2010 · Clinical Cancer Research
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    ABSTRACT: To characterize the population pharmacokinetics of plitidepsin (Aplidin) in cancer patients. A total of 283 patients (552 cycles) receiving intravenous plitidepsin as monotherapy at doses ranging from 0.13 to 8.0 mg/m(2) and given as 1- or 24-h infusions every week; 3- or 24-h infusion biweekly; or 1-h infusion daily for 5 consecutive days every 21 days were included in the analysis. An open three-compartment pharmacokinetic model and a nonlinear binding to red blood cells model were used to describe the plitidepsin pharmacokinetics in plasma and blood, respectively, using NONMEM V software. The effect of selected covariates on plitidepsin pharmacokinetics was investigated. Model evaluation was performed using goodness-of-fit plots, posterior predictive check and bootstrap. Plasma clearance and its between subject variability (%) was 13.6 l/h (71). Volume of distribution at steady-state was calculated to be 4791 l (59). The parameters B (max) and C (50) of the non-linear blood distribution were 471 microg/l (56) and 41.6 microg/l, respectively. Within the range of covariates studied, age, sex, body size variables, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, creatinine clearance, albumin, total protein, performance status, co-administration of inhibitors or inducers of CYP3A4 and presence of liver metastases were not statistically related to plitidepsin pharmacokinetic parameters. Bootstrap and posterior predictive check evidenced the model was deemed appropriate to describe the time course of plitidepsin blood and plasma concentrations in cancer patients. The integration of phase I/II pharmacokinetic data demonstrated plitidepsin linear elimination from plasma, dose-proportionality up to 8.0 mg/m(2), and time-independent pharmacokinetics. The distribution to red blood cells can be considered linear at doses lower than 5 mg/m(2) administered as 3-h or longer infusion. No clinically relevant covariates were identified as predictors of plitidepsin pharmacokinetics.
    No preview · Article · Nov 2008 · Cancer Chemotherapy and Pharmacology