Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy.

PURPOSE: This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance. PATIENTS AND METHODS: Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors. RESULTS: ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts. CONCLUSION: Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

Phase I dose-escalation study of plitidepsin in combination with sorafenib or gemcitabine in patients with refractory solid tumors or lymphomas.

This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients. The study included two treatment arms: a sorafenib/plitidepsin (S/P) and a gemcitabine/plitidepsin (G/P) arm. In the S/P arm, patients were treated orally with sorafenib continuous dosing at two dose levels (DL1: 200 mg twice daily and DL2: 400 mg twice daily) combined with plitidepsin (1.8 mg/m, day 1, day 8, day 15, and, q4wk, intravenously). In the G/P arm, patients with solid tumors or lymphoma were treated at four different DLs with a combination of gemcitabine (DL1: 750 mg/m, DL2-DL4: 1000 mg/m) and plitidepsin (DL1-DL2: 1.8 mg/m; DL3: 2.4 mg/m; DL4: 3 mg/m). Both agents were administered intravenously on day 1, day 8, day 15, and, q4wk. Forty-four patients were evaluable for safety and toxicity. The safety of the combination of plitidepsin with sorafenib or gemcitabine was manageable. Most adverse events (AEs) were mild; no grade 4 treatment-related AEs were reported in any of the groups (except for one grade 4 thrombocytopenia in the gemcitabine arm). The most frequently reported study drug-related (or of unknown relationship) AEs were palmar-plantar erythrodysesthesia, erythema, nausea, vomiting, and fatigue in the S/P arm and nausea, fatigue, and vomiting in the G/P arm. In the S/P arm, one dose-limiting toxicity occurred in two out of six patients treated at the maximum dose tested (DL2): palmar-plantar erythrodysesthesia and grade 2 aspartate aminotransferase/alanine aminotransferase increase that resulted in omission of days 8 and 15 plitidepsin infusions. In the G/P arm, one dose-limiting toxicity occurred in two out of six patients at DL4: grade 2 alanine aminotransferase increase resulted in omission of days 8 and 15 plitidepsin infusions and grade 4 thrombocytopenia. The recommended dose for the combination of plitidepsin with sorafenib was not defined because of a sponsor decision (no expansion cohort to confirm) and for plitidepsin with gemcitabine, it was 2.4 mg/m plitidepsin with 1000 mg/m gemcitabine. In the S/P group, objective disease responses were not observed; however, disease stabilization (≥3months) was observed in four patients. In the gemcitabine group, two lymphoma patients showed an objective response (partial response and complete response) and nine patients showed disease stabilization (≥3months). Combining plitidepsin with gemcitabine and sorafenib is feasible for advanced cancer patients; some objective responses were observed in heavily pretreated lymphoma patients.

Population pharmacokinetics of kahalalide F in advanced cancer patients.

PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Experience with trabectedin in an advanced sarcoma patient on peritoneal dialysis for end-stage renal failure.

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.

Population pharmacokinetic-pharmacodynamic analysis of neutropenia in cancer patients receiving PM00104 (Zalypsis(®)).

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 ß]) 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 ß 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.

A comprehensive safety analysis confirms rhabdomyolysis as an uncommon adverse reaction in patients treated with trabectedin.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Population pharmacokinetics of PM00104 (Zalypsis(®)) in cancer patients.

OBJECTIVE: The aim of this study was to characterize the population pharmacokinetics of PM00104 (Zalypsis(®)) in cancer patients. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Phase I and pharmacokinetic study of trabectedin 3-hour infusion every three weeks in patients with advanced cancer and alteration of hepatic function.

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.

Pharmacokinetics of trabectedin on hemodialysis: an application for the management of cancer patients with end-stage renal disease.

PURPOSE: The pharmacokinetics of trabectedin has never been reported in patients with impaired renal function or in patients on hemodialysis. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Plitidepsin has a safe cardiac profile: a comprehensive analysis.

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.

Trabectedin has a low cardiac risk profile: a comprehensive cardiac safety analysis.

PURPOSE: This analysis provides a cross-study evaluation of the cardiac safety of trabectedin. METHODS: 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). RESULTS: 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. CONCLUSIONS: Trabectedin has a low incidence of CAEs, consisting mainly of arrhythmias. This extensive data review indicates a low cardiac risk profile for trabectedin.

Phase I study of weekly plitidepsin as 1-hour infusion combined with carboplatin in patients with advanced solid tumors or lymphomas.

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.

Phase I and pharmacokinetic study of sequential paclitaxel and trabectedin every 2 weeks in patients with advanced solid tumors.

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

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

OBJECTIVE: To characterize the population pharmacokinetics of plitidepsin (Aplidin) in cancer patients. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment.

PURPOSE: Reversible transient elevations in transaminases have been observed after trabectedin administration. A semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed to evaluate the time course of alanine aminotransferase (ALT) elevation, tolerance development, and the hepatoprotective effect of dexamethasone on trabectedin-induced transient transaminitis following different dosing schedules in cancer patients. PATIENTS AND METHODS: Trabectedin was administered to 711 patients as monotherapy (dose range: 0.024-1.8 mg/m(2)) as 1-, 3-, or 24-h infusions every 21 days; 1- or 3-h infusions on days 1, 8, and 15 every 28 days; or 1-h infusions daily for five consecutive days every 21 days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711 pt), ECOG performance status scores (89.7% pts or=3 toxicity by 13 and 39% following two and four cycles of therapy, respectively. CONCLUSIONS: A PKPD model quantifying the hepatoprotective effect of dexamethasone on transient and reversible transaminitis following trabectedin treatment has been developed. The model predicts that co-administration of dexamethasone and the suggested dose reduction strategy based on the serum concentration of liver enzymes will enhance the safe use of trabectedin in the clinic.

Population pharmacokinetic meta-analysis of trabectedin (ET-743, Yondelis) in cancer patients.

OBJECTIVE: To characterise the population pharmacokinetics of trabectedin (ET-743, Yondelis(R)) in cancer patients. METHODS: A total of 603 patients (945 cycles) receiving intravenous trabectedin as monotherapy at doses ranging from 0.024 to 1.8 mg/m(2) and given as a 1-, 3- or 24-hour infusion every 21 days; a 1- or 3-hour infusion on days 1, 8 and 15 of a 28-day cycle; or a 1-hour infusion daily for 5 consecutive days every 21 days were included in the analysis. An open four-compartment pharmacokinetic model with linear elimination, linear and nonlinear distribution to the deep and shallow peripheral compartments, respectively, and a catenary compartment off the shallow compartment was developed to best describe the index dataset using NONMEM V software. The effect of selected patient covariates on trabectedin pharmacokinetics was investigated. Model evaluation was performed using goodness-of-fit plots and relative error measurements for the test dataset. Simulations were undertaken to evaluate covariate effects on trabectedin pharmacokinetics. RESULTS: The mean (SD) trabectedin elimination half-life was approximately 180 (61.4) hours. Plasma accumulation was limited when trabectedin was given every 3 weeks. Systemic clearance (31.5 L/h, coefficient of variation 51%) was 19.2% higher in patients receiving concomitant dexamethasone. The typical values of the volume of distribution at steady state for male and female patients were 6070L and 5240L, respectively. Within the range studied, age, body size variables, AST, ALT, alkaline phosphatase, lactate dehydrogenase, total bilirubin, creatinine clearance, albumin, total protein, Eastern Cooperative Oncology Group performance status and presence of liver metastases were not statistically related to trabectedin pharmacokinetic parameters. The pharmacokinetic parameters of trabectedin were consistent across the infusion durations and dose regimens evaluated. CONCLUSIONS: The integration of trabectedin pharmacokinetic data demonstrated linear elimination, dose-proportionality up to 1.8 mg/m(2) and time-independent pharmacokinetics. The pharmacokinetic impact of dexamethasone and sex covariates is probably limited given the moderate to large interindividual pharmacokinetic variability of trabectedin. The antiemetic and hepatoprotective effects are still a valid rationale to recommend dexamethasone as a supportive treatment for trabectedin.