Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment
- 373 Downloads
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/m2) 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 ≤ 1), and body weight (36–122 kg)] on PD parameters, followed by model validation. Simulations assessed the influence of dosing regimen and selected patient factors on the time course of ALT and the effectiveness of the dose reduction strategy.
A precursor-dependent PKPD model described the temporal relationship between ALT elevation and trabectedin concentrations, where the transfer process of ALT from hepatocytes to plasma is stimulated by trabectedin plasma concentrations. Overall, 66% of patients had transaminitis. Mean predicted (%SEM) baseline ALT (ALTo) and t 1/2 in plasma were 31.5 (5.1) IU/L and 1.5 days, respectively. The magnitude of the trabectedin stimulation of the ALT transfer rate from hepatocytes to plasma was 11.4% per 100 pg/mL of trabectedin plasma concentration. Dexamethasone decreased the rate of trabectedin-induced ALT release from hepatocyte by 63% (P < 0.001). Model evaluation showed that the model predicted incidence of grade 3/4 transaminase elevation was similar to the observed values. Simulations showed that severity of ALT elevation was dose- and schedule-dependent. The dose reduction strategy decreased the incidence of grade ≥3 toxicity by 13 and 39% following two and four cycles of therapy, respectively.
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.
KeywordsDexamethasone Dose reduction Liver toxicity NONMEM Population Pharmacokinetics/pharmacodynamics Trabectedin Transaminitis Tolerance
The authors would like to thank the hundreds of patients, investigators, and their medical, nursing, and laboratory staff who participated in the clinical studies included in the present study. We also thank Andrew Chow and Jill Fiedler-Kelly for the comments and suggestions provided during this analysis.
- 1.Alexandre J, Bleuzen P, Bonneterre J, Sutherland W, Misset JL, Guastalla J, Viens P, Faivre S, Chahine A, Spielman M, Bensmaine A, Marty M, Mahjoubi M, Cvitkovic E (2000) Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients. J Clin Oncol 18:562–573PubMedGoogle Scholar
- 2.Beal SL, Sheiner LB (1992) (eds) NONMEM Users guides. Hanover, MD: GloboMax, LLCGoogle Scholar
- 5.Common Toxicity Criteria (CTC) (1998) Cancer therapy evaluation program, Version 2.0, DCTD, NCI, NIH, DHHS. Common Toxicity Criteria, March 1998Google Scholar
- 7.Donald S, Verschoyle RD, Greaves P, Gant TW, Colombo T, Zaffaroni M, Frapolli R, Zucchetti M, D’incalci M, Meco D, Riccardi R, Lopez-Lazaro L, Jimeno J, Gescher AJ (2003) Complete protection by high-dose dexamethasone against the hepatotoxicity of the novel antitumor drug yondelis (ET-743) in the rat. Cancer Res 63:5902PubMedGoogle Scholar
- 12.Garcia-Carbonero R, Supko JG, Manola J, Seiden MV, Harmon D, Ryan DP, Quigley MT, Merriam P, Canniff J, Goss G, Matulonis U, Maki RG, Lopez T, Puchalski TA, Sancho MA, Gomez J, Guzman C, Jimeno J, Demetri GD (2004) Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol 22:1480PubMedCrossRefGoogle Scholar
- 14.Gomez J, Lopez-Lazaro L, Guzman C (2000) Identification of biochemical parameters that predict the onset of severe toxicities in patients treated with ET-743. Proc Am Soc Clin Oncol 19(96a):727Google Scholar
- 17.Hartung G, Stehle G, Sinn H, Wunder A, Schrenk HH, Heeger S, Kranzle M, Edler L, Frei E, Fiebig HH, Heene DL, Maier-Borst W, Queisser W (1999) Phase I trial of methotrexate-albumin in a weekly intravenous bolus regimen in cancer patients. Phase I Study Group of the Association for Medical Oncology of the German Cancer Society. Clin Cancer Res 5:753PubMedGoogle Scholar
- 20.Jimeno JM, Faircloth G, Cameron L (1996) Progress in the acquisition of new marine-derived anticancer compounds: development of Ecteinascidin-743 (ET-743). Drugs Future 21:1155Google Scholar
- 23.Lau L, Supko JG, Blaney S, Hershon L, Seibel N, Krailo M, Qu W, Malkin D, Jimeno J, Bernstein M, Baruchel S (2005) A phase I and pharmacokinetic study of ecteinascidin-743 (Yondelis) in children with refractory solid tumors. A Children’s Oncology Group study. Clin Cancer Res 11:672PubMedGoogle Scholar
- 24.Laverdiere C, Kolb EA, Supko JG, Gorlick R, Meyers PA, Maki RG, Wexler L, Demetri GD, Healey JH, Huvos AG, Goorin AM, Bagatell R, Ruiz-Casado A, Guzman C, Jimeno J, Harmon D (2003) Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer 98:832PubMedCrossRefGoogle Scholar
- 25.Le Cesne A, Blay JY, Judson I, Van Oosterom A, Verweij J, Radford J, Lorigan P, Rodenhuis S, Ray-Coquard I, Bonvalot S, Collin F, Jimeno J, Di Paola E, Van Glabbeke M, Nielsen OS (2005) Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol 23:576PubMedCrossRefGoogle Scholar
- 29.Morgan JA, Le Cesne A, Chawla S, von Mehren M, Schuetze S, Casali PG, Nieto A, Elsayed Y, Izquierdo MA, Demetri GD (2007) Randomized phase II study of trabectedin in patients with liposarcoma and leiomyosarcoma (l-sarcomas) after failure of prior anthracylines (A) and ifosfamide (I). In: ASCO Annual Meeting Proceedings Part I. J Clin Oncol 25(No. 18S): 10060 (June 20 Supplement)Google Scholar
- 32.Perez-Ruizo JJ, Zannikos P, Hirankarn S, Stuyckens K, Ludwig EA, Soto-Matos A, Lopez-Lazaro L, Owen JS (2007) Population pharmacokinetics meta-analysis of trabectedin (ET-743, Yondelis®) in cancer patients. Clin Pharmacokinet (In press)Google Scholar
- 33.Puchalski TA, Ryan DP, Garcia-Carbonero R, Demetri GD, Butkiewicz L, Harmon D, Seiden MV, Maki RG, Lopez-Lazaro L, Jimeno J, Guzman C, Supko JG (2002) Pharmacokinetics of ecteinascidin 743 administered as a 24-h continuous intravenous infusion to adult patients with soft tissue sarcomas: associations with clinical characteristics, pathophysiological variables and toxicity. Cancer Chemother Pharmacol 50:309PubMedCrossRefGoogle Scholar
- 39.Takebayashi Y, Pourquier P, Zimonjic DB, Nakayama K, Emmert S, Ueda T, Urasaki Y, Kanzaki A, Akiyama SI, Popescu N, Kraemer KH, Pommier Y (2001) Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 7:961PubMedCrossRefGoogle Scholar
- 40.Twelves C, Hoekman K, Bowman A, Vermorken JB, Anthoney A, Smyth J, van Kesteren C, Beijnen JH, Uiters J, Wanders J, Gomez J, Guzman C, Jimeno J, Hanauske A (2003) Phase I and pharmacokinetic study of Yondelis (Ecteinascidin-743; ET-743) administered as an infusion over 1 h or 3 h every 21 days in patients with solid tumours. Eur J Cancer 39:1842PubMedCrossRefGoogle Scholar
- 41.van Kesteren C, Cvitkovic E, Taamma A, Lopez-Lazaro L, Jimeno JM, Guzman C, Mathot RA, Schellens JH, Misset JL, Brain E, Hillebrand MJ, Rosing H, Beijnen JH (2000) Pharmacokinetics and pharmacodynamics of the novel marine-derived anticancer agent ecteinascidin 743 in a phase I dose-finding study. Clin Cancer Res 6:4725PubMedGoogle Scholar
- 42.van Kesteren C, Twelves C, Bowman A, Hoekman K, Lopez-Lazaro L, Jimeno J, Guzman C, Mathot RA, Simpson A, Vermorken JB, Smyth J, Schellens JH, Hillebrand MJ, Rosing H, Beijnen JH (2002) Clinical pharmacology of the novel marine-derived anticancer agent Ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study. Anticancer Drugs 13:381PubMedCrossRefGoogle Scholar
- 43.Villalona-Calero MA, Eckhardt SG, Weiss G, Hidalgo M, Beijnen JH, van Kesteren C, Rosing H, Campbell E, Kraynak M, Lopez-Lazaro L, Guzman C, Von Hoff DD, Jimeno J, Rowinsky EK (2002) A phase I and pharmacokinetic study of ecteinascidin-743 on a daily x 5 schedule in patients with solid malignancies. Clin Cancer Res 8:75PubMedGoogle Scholar
- 47.Yver A, Cohen R, Williams D, Vossen J, VonMehren M (2006) Assessment of trabectedin (T) induced liver toxicity with correlation to liver morphology in a phase I study of T + pegylated liposomal doxorubicin (PLD). Proc Am Soc Clin Oncol 24(18S)Google Scholar