Trabectedin

Trabectedin binds to the minor groove of deoxyribonucleic acid (DNA), bending the helix to the major groove. This binding to DNA triggers a cascade of events affecting several transcription factors, DNA binding proteins, and DNA repair pathways, resulting in perturbation of the cell cycle.

Pharmacodynamic effects

Trabectedin has been shown to exert antiproliferative in vitro and in vivo activity against a range of human tumour cell lines and experimental tumours, including malignancies such as sarcoma, breast, non-small cell lung, ovarian and melanoma.

Electrocardiogram (ECG) investigations

In a placebo-controlled QT/QTc study, trabectedin did not prolong the QTc interval in patients with advanced solid malignancies.

Distribution

Systemic exposure after intravenous administration as a constant rate infusion is dose proportional at doses up to and including 1.8 mg/m². Trabectedin pharmacokinetic profile is consistent with a multiple-compartment disposition model.

Following intravenous administration, trabectedin demonstrates a high apparent volume of distribution, consistent with extensive tissue and plasma protein binding (94 to 98% of trabectedin in plasma is protein bound). The distribution volume at steady state of trabectedin in human subjects exceeds 5,000 l.

Biotransformation

Cytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for the oxidative metabolism of trabectedin at clinically relevant concentrations. Other P450 enzymes may contribute to metabolism. Trabectedin does not induce or inhibit major cytochrome P450 enzymes.

Elimination

Renal elimination of unchanged trabectedin in humans is low (less than 1%). The terminal half-life is long (population value of the terminal elimination phase: 180-hr). After a dose of radiolabelled trabectedin administered to cancer patients, faecal mean (SD) recovery of total radioactivity is 58% (17%), and urinary mean (SD) recovery is 5.8% (1.73%). Based on the population estimate for plasma clearance of trabectedin (30.9 l/h) and blood/plasma ratio (0.89), the clearance of trabectedin in whole blood is approximately 35 l/h. This value is approximately one-half the rate of human hepatic blood flow. Thus the trabectedin extraction ratio can be considered moderate. The inter-patient variability of the population estimate for plasma clearance of trabectedin was 49% and intra-patient variability was 28%.

A population pharmacokinetic analysis showed that when administered in combination with PLD, the plasma clearance of trabectedin was decreased by 31%; the plasma pharmacokinetics of PLD were not influenced by the concomitant administration of trabectedin.

Special populations

A population pharmacokinetic analysis indicated that the plasma clearance of trabectedin is not influenced by age (range 19-83 years), gender, total body weight (range: 36 to 148 kg) or body surface area (range: 0.9 to 2.8 m²). A population pharmacokinetic analysis showed that plasma trabectedin concentrations observed in the Japanese population at dose level 1.2 mg/m² were equivalent to those obtained in the non-Japanese western population at 1.5 mg/m².

Renal impairment

There is no relevant influence of renal function measured by creatinine clearance on trabectedin pharmacokinetics within the range of values (≥30.3 ml/min) present in the patients included in the clinical studies. No data are available in patients with a creatinine clearance of less than 30.3 ml/min. The low recovery (<9% in all studied patients) of total radioactivity in the urine after a single dose of ¹⁴C-labelled trabectedin indicates that renal impairment has little influence on the elimination of trabectedin or its metabolites.

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of trabectedin was assessed in 15 cancer patients at doses ranging from 0.58 to 1.3 mg/m² administered as 3-hour infusion. The geometric mean dose normalized trabectedin exposure (AUC) increased by 97% (90% CI: 20%, 222%) in 6 patients with moderate hepatic impairment (increased serum bilirubin levels from 1.5 to 3 x ULN and increase of aminotransferases (AST or ALT) <8 x ULN) following administration of a single trabectedin dose of 0.58 mg/m² (n=3) or 0.9 mg/m² (n=3) compared to 9 patients with normal liver function following administration of a single trabectedin dose of 1.3 mg/m².

Preclinical data indicate that trabectedin has limited effect on the cardiovascular, respiratory and central nervous system at exposures below the therapeutic clinical range, in terms of AUC.

The effects of trabectedin on cardiovascular and respiratory function have been investigated in vivo (anesthetised Cynomolgus monkeys). A 1 hour infusion schedule was selected to attain maximum plasma levels (C_max values) in the range of those observed in the clinic. The plasma trabectedin levels attained were 10.6 ± 5.4 (C_max), higher than those reached in patients after infusion of 1,500 μg/m² for 24 (C_max of 1.8 ± 1.1 ng/ml) and similar to those reached after administration of the same dose by 3 hour infusion (C_max of 10.8 ± 3.7 ng/ml).

Myelosupression and hepatoxicity were identified as the primary toxicity for trabectedin. Findings observed included haematopoietic toxicity (severe leukopenia, anaemia, and lymphoid and bone marrow depletion) as well as increases in liver function tests, hepatocellular degeneration, intestinal epithelial necrosis, and severe local reactions at the injection site. Renal toxicological findings were detected in multi-cycle toxicity studies conducted in monkeys. These findings were secondary to severe local reaction at the administration site, and therefore uncertainly attributable to trabectedin; however, caution must be guaranteed in the interpretation of these renal findings, and treatment-related toxicity cannot be excluded.

Trabectedin is genotoxic both in vitro and in vivo. Long-term carcinogenicity studies have not been performed.

Fertility studies with trabectedin were not performed but limited histopathological changes were observed in the gonads in the repeat dose toxicity studies. Considering the nature of the compound (cytotoxic and mutagenic), it is likely to affect the reproductive capacity.

Placental transfer of trabectedin and fetal exposure to trabectedin were observed in a study in pregnant rats that received a single i.v. ¹⁴C-trabectedin dose at 0.061 mg/kg. Maximum fetal tissue radioactivity concentration was similar to that in maternal plasma or blood.