Journal of Antimicrobial Chemotherapy (2001) 47, 720-721
© 2001 The British Society for Antimicrobial Chemotherapy
Correspondence |
Termination of development of D0870
Department of Infectious Diseases and Tropical Medicine, Monsall Unit, North Manchester General Hospital, Delaunays Road, Manchester M8 6RB, UK
Sir,
We refer to the recent papers concerning D0870 and Chagas' disease by Molina and colleagues1,2 in the July 2000 and January 2001 issue of your journal. Your readers should be aware that Zeneca (now AstraZeneca) terminated the development of this azole antifungal in 1995 due to an adverse event in an HIV-positive patient receiving the drug for fluconazole-resistant oropharyngeal and oesophageal candidosis (OPC). She was enrolled in a dose- ascending trial of D0870 for patients with low CD4 counts and OPC unresponsive to azoles.
We had already shown that D0870 was well tolerated and effective at doses as low as 10 mg for fluconazole sensitive infections3 and also at intermediate doses for some patients with fluconazole-resistant OPC.4
Early toxicity work had shown a propensity to QT prolongation in beagle dogs so that plasma concentrations of D0870 above 3000 ng/mL increased QT, with changes proportional to serum concentrations. However, it was only at above 30 000 ng/mL and up to 70 000 ng/mL that three dogs died of sudden cardiac events.
Pharmacokinetic modelling was performed and doses were selected with the aim of ensuring that no patients achieved levels in excess of 3000 ng/mL, and that this level was approached gradually. Only patients with a normal ECG and QTc less than 450 ms were recruited. Concurrent agents known to interact with azoles or prolong the QT interval were excluded.
An ascending-dose study in a population of patients with few or no other therapeutic avenues (late-stage AIDS patients with azole-refractory oral and/or oesophageal candidosis) was initiated. Careful QT monitoring and contemporaneous serum D0870 concentrations were an integral part of the study. Two patients had QTc prolongation to >500 ms (though one was withdrawn because of hypokalaemia) before the 47th of the 48 planned potential enrollees. QTc interval rose from 406 to 535 ms and the drug was stopped. She received haloperidol, bromazepam, pentamidine and prednisolone, and 3 days later suffered dizziness associated with bradycardia, gross T wave changes and a short run of ventricular tachycardia, followed by a cardiac arrest from which she was resuscitated. It was determined retrospectively that her plasma D0870 concentration was 3241 ng/mL at the time of the event.
Subsequent to this more was learned about the pharmacokinetics of D0870 in man. Human liver microsomal work showed that D0870 is a potential inhibitor of CYP 2C9 and 2C10 (greater than licensed azoles). There was some inhibitor activity of CYP 3A4 but less than licensed oral azoles.
These in vitro results, together with the large data set of patient pharmacokinetic samples, indicated that the kinetics of D0870 were unpredictable. Given the QT prolongation at modest serum concentrations and the single cardiac adverse event, Zeneca stopped development of the drug, despite its impressive clinical activity.
Notes
* Corresponding author. Tel: +44-161-720-2734; Fax: +44-161-720-2732; E-mail: ddenning{at}man.ac.uk 
References
1
.
Molina, J., Brener, Z., Romanha, A. J. & Urbina, J. A. (2000). In vivo activity of the bis-triazole D0870 against drug-susceptible and drug-resistant strains of the protozoan parasite Trypanosoma cruzi. Journal of Antimicrobial Chemotherapy 46, 137–40.
2
.
Molina, J., Urbina, J., Gref, R., Brener, Z. & Rodriguez, J. (2001). Cure of experimental Chagas' disease by the bis-triazole D0870 incorporated into ‘stealth’ polyethyleneglycol–polylactide nanospheres. Journal of Antimicrobial Chemotherapy 47, 101–4.
3 . de Wit, S., Dupont, B., Cartledge, J. D., Hawkins, D. A., Gazzard, B. G., Clumeck, N. et al. (1997). A dose comparison study of a new triazole antifungal (D0870) in HIV positive patients with oral candidiasis. AIDS 11, 759–64.[Medline]
4 . Cartledge, J. D., Denning, D. W., Dupont, B., Clumeck, N., de Wit, S., Midgley, J. et al. (1998). Treatment of HIV related fluconazole-resistant oropharyngeal candidiasis with D0870, a new triazole antifungal. AIDS 12, 411–6.[Medline]
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