Trimetrexate for Pneumocystis Carinii Pneumonia in Patients with Aids

Abstract

OBJECTIVE: The primary objective of this article is to introduce readers to the use of a new agent, trimetrexate (TMTX), in the treatment of Pneumocystis carinii pneumonia (PCP). The article also gives the readers an overview of PCP and discusses some of the controversies surrounding it. Pharmacokinetic data and clinical trials are reviewed, as well as adverse effects, drug interactions, and dosage guidelines. DATA SOURCES: A MEDLINE search was used to identify pertinent literature, including reviews. STUDY SELECTION: As both pharmacokinetic and clinical trials were few in number, all available trials were reviewed. DATA EXTRACTION: Pharmacokinetic data from trials involving patients with AIDS was sparse; therefore, those involving oncology patients, including a pediatric population, were included. Although more trials need to be done in AIDS patients, the results from the oncologic trials give us a baseline from which to extrapolate. All clinical trials available at the time of publication were reviewed as were all of the preliminary results from three ongoing trials, which were made available through a personal communication. DATA SYNTHESIS: TMTX has been found to be 1500 times more potent than trimethoprim as a dihydrofolate reductase inhibitor, and has the potential to provide an effective therapeutic option for PCP. TMTX is a lipid-soluble analog of methotrexate and is thus capable of greater penetration into Pneumocystis cells, which lack the folate membrane transport system necessary to take up classic folate structures like leucovorin and methotrexate, thereby negating any clinical effectiveness of methotrexate and allowing leucovorin to be used for host cell rescue. TMTX's pharmacokinetic parameters best fit a multicompartmental model with a terminal half-life of up to 12 hours. It is cleared both hepatically and renally with up to 41 percent excreted unchanged in the urine. Although TMTX's pharmacokinetic parameters are variable, the need for plasma concentration monitoring at present is unclear, as no dose-response relationship has been established. Efficacy trials involving TMTX have been conducted mostly in patients with moderate to severe PCP who were either intolerant and/or refractory to standard therapies. Response rates to TMTX therapy have ranged from 6 to 90 percent, thereby demonstrating that TMTX may be useful in the treatment of certain patients with PCP. CONCLUSIONS: Although more well-designed clinical trials comparing TMTX with standard therapies are necessary, initial results indicate that TMTX is a promising alternative for moderate to severe episodes of PCP. Also, additional studies of TMTX's use as a prophylactic agent in PCP, and when it should be initiated in relation to a patient's CD4 count are needed. Furthermore, difficulty may arise in using TMTX on a regular basis because of the potential cost of therapy with concomitant leucovorin.