Trimetrexate (NeuTrexin) Approved for Pneumocystis

Trimetrexate (brand name, NeuTrexin) has been approved for
treatment of moderate to severe pneumocystis pneumonia (PCP),
when the preferred treatment, trimethoprim-sulfamethoxazole
(also called co-trimoxazole, Bactrim, Septra, etc.), cannot
be used. US Bioscience, Inc., the developer, announced the
approval on December 17.

A clinical trial by the AIDS Clinical Trials Group (ACTG) of
the U.S. National Institute of Allergy and Infectious
Diseases found that trimetrexate was more likely to be
discontinued for lack of efficacy, whereas trimethoprim-
sulfamethoxazole was more likely to cause side effects
requiring discontinuation of the drug. The best strategy,
then, is to use the standard therapy first (unless it is
contraindicated for some reason), and keep trimetrexate in
reserve to use if necessary.

Trimetrexate must be used with leucovorin, to protect human
cells from toxic effects of the drug. The pneumocystis
organism cannot absorb the leucovorin.

Trimetrexate is expensive (comparable to pentamidine),
costing over $2000 to the wholesaler for the standard 21-day
course of treatment. There are discounts for Medicaid
patients and certain hospitals. For information about
reimbursement and patient-assistance programs, patients and
physicians can call 800/8-USBIOS, an information line run by
U.S. Bioscience.

Also, leucovorin is expensive; but its price varies greatly,
as much as several fold, with the intravenous preparation
costing less, and oral versions costing most, especially in
pharmacies. (Hospitals often pay much less; outpatients may
be changed much less at their hospital's pharmacy than at
other pharmacies.) Patient-assistance programs are available.
Also, the drug is off patent, and we hear that the oral
formulation is less expensive in Canada and elsewhere than in
the U.S.

Trimetrexate is only available in intravenous form at this
time, but an oral formulation is being developed.

Comment

The standard treatment, trimethoprim-sulfamethoxazole, is
highly effective because of its two-enzyme blockade; the drug
inhibits two different enzymes of the target organisms.
Trimetrexate is much more powerful than trimethoprim in
blocking one of those enzymes, but does not affect the other.
A trial to combine trimetrexate and dapsone, to block both
enzymes, is scheduled to start in early 1994.

A successful trial of trimetrexate to treat pneumocystis was
published in the New England Journal of Medicine in 1987. But
the drug has not been available until recently, apparently
because the company which owned it at that time, Warner-
Lambert, was not interested in developing it for AIDS-related
infections. U.S. Bioscience made trimetrexate available last
year, before approval, through the "treatment IND" procedure
of the FDA.