A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq™ (nolatrexed dihydrochloride) given by 10-day oral administration

• Published in: British journal of cancer Vol. 79; no. 5-6; pp. 915 - 920
• Main Authors: JODRELL, D. I, BOWMAN, A, RYE, R, BYRNE, B, BODDY, A, RAFI, I, TAYLOR, G. A, JOHNSTON, A, CLENDENINN, N. J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-02-1999
• Subjects: Administration, Oral; Adult; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - pharmacokinetics; Antineoplastic agents; Biological and medical sciences; Biological Availability; Chemotherapy; Deoxyuridine - blood; Dose-Response Relationship, Drug; Drug Administration Schedule; Exanthema - chemically induced; Humans; Liver Function Tests; Medical sciences; Nausea - chemically induced; Neoplasms - drug therapy; Neutropenia - chemically induced; Pharmacology. Drug treatments; Quinazolines - administration & dosage; Quinazolines - adverse effects; Quinazolines - pharmacokinetics; Regular; Stomatitis - chemically induced; Thrombocytopenia - chemically induced; Thymidylate Synthase - antagonists & inhibitors; Vomiting - chemically induced; Antineoplastic agent; Human; Enzyme; Transferases; Oral administration; Enzyme inhibitor; Administration schedule; Malignant tumor; Thymidylate synthase; Lipophilic compound; Chemotherapy; Treatment; Methyltransferases; Nolatrexed; Phase I trial; Pharmacokinetics
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6690146

2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor of thymidylate synthase, was developed using protein structure-based drug design. Intravenously administered nolatrexed is active clinically. As oral bioavailability is high (70-100%), nolatrexed was administered orally, 6 hourly for 10 days, at 3-week intervals, and dose escalated from 80 to 572 mg m(-2) day(-1) in 23 patients. Common toxicity criteria (CTC) grade 3 toxicities included nausea, vomiting, stomatitis and liver function test (LFT) abnormalities. Thrombocytopenia (grade 1 or 2) occurred at doses > or = 318 mg m(-2) day(-1) and neutropenia (grade 2) at 429 and 572 mg m(-2) day(-1). An erythematous maculopapular rash occurred at dosages > or = 318 mg m(-2) day(-1) (7 out of 19 patients). LFT abnormalities occurred in two out of six patients (grade 3 or 4 bilirubin and grade 3 alanine transaminase) at 572 mg m(-2) day(-1). Nolatrexed plasma concentrations 1 h after dosing were 6-16 microg ml(-1), and trough 3-8 microg ml(-1), at 572 mg m(-2) day(-1). Inhibition of thymidylate synthase was demonstrated by elevation of plasma deoxyuridine. Six-hourly oral nolatrexed for 10 days was associated with antiproliferative effects, but nausea and vomiting was dose limiting at 572 mg m(-2) day(-1). Nine patients were treated at 429 mg m(-2) day(-1); three out of nine experienced grade 3 nausea, but 17 out of 22 treatment courses were completed (with the co-administration of prophylactic antiemetics) and this dose level could be considered for phase II testing.