FORMULARY FORUM
TRIMETREXATE FOR PNEUMOCYSTIS CARINII PNEUMONIA IN PATIENTS WITH AIDS Guy W. Amsden, Steven F. Kowalsky, and Gene D. Morse
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 swrounding it. Phannacokinetic data and clinical trials are reviewed, as well as adverse effects, drug interactions, and dosage guidelines. OBJECTIVE:
A MEDLINE search was used to identify pertinent literature, including reviews.
DATA SOURCES:
srunv SELECIlON: As both phannacokinetic and clinical trials were few in number, all available trials were reviewed. Phannacokinetic 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 EXTRACTION:
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 phannacokinetic parameters best fit a multicompartrnental 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 phannacokinetic parameters are variable, the need for plasma concentration monitoring at present is unclear, as no dose-response relationship has been established. DATA SYNTIIESIS:
GUY W. AMSDEN, Pharm.D.• is an Infectious Diseases/Pharmacokinetics Research Fellow , Clini cal Pharmacokinetics Laboratory. Millard Fillmore Hospital, 3 Gates Cir., Buffalo, NY 14209; STEVEN F. KOWALSKY, Pharm.D., is the Assistant Di· rector of Medical Research, Anti-Infective Research Group , Pharmaceutical Division, Miles, Inc., West Haven, Cl' ; and GENE D. MORSE, Pharm.D.• is an Associate Professor of Pharmacy, Center for Clin ical Pharmacy Research, State University of New York at Buffalo , a Coinvestigator, University of Rochester AIDS Clinical Trials Unit, and a Member, Department of Pharmaceutical Services, Erie County Medical Center, Buffalo, NY. Reprints: Guy W. Amsden, Pharm.D. Trimetrexateglucuonate, Parke-Davis.
This article is approved for continuing education credit.
218 •
The Annals ofPharmacotherapy
•
CHO
I I
HCOH HOCH
I
HCOH
I
HCOH
I
CQOH
Figure 1. Graphic formula of trirnetrexate glucuronate .
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 CD 4 count are needed. Furthermore, difficulty may arise in using TMfX on a regular basis because of the potential cost of therapy with concomitant leucovorin.
Ann Pharmacother 1992;26:218-26. WITH TIIE INCREASED USE OF CHRONIC IMMUNOSUPPRESSION
and the rise in the number of cases of AIDS, the incidence of opportunistic infections, especially among those who are human immunodeficiency virus (HIV)-positive with an immunocompromised status, has increased dramatically. The prevalence of Pneumocystis carinii pneumonia (PCP) far exceeds that of cryptococcosis, Mycobacterium avium complex, or bacterial pulmonary infections.' In AIDS patients the annual prevalence rate of PCP is greater than 30 percent. This is in contrast to that of renal transplant recipients and patients with leukemia or lymphoma, in whom the rate appears to be between 0.01 and I percent.' In fact, more than 80 percent of patients with AIDS will develop PCP; in 55 percent of these people, this disease will actually be pathognomonic of their underlying syndrome.' Suitable therapies for PCP are currently under investigation. Pentamidine isethionate and trimethoprim/ sulfamethoxazole (TMP/SMX) have been the traditional treatments for
1992 February, Volume 26
PCP, but the high incidence of adverse effects associated with both of these regimens-e" makes new and better-tolerated therapeutic options necessary. Trimetrexate (TMTX) glucuronate, a new, nonclassic folate antagonist (Figure 1), is presently under investigation in Phase II trials as a chemotherapeutic agent for breast, pancreatic, colorectal, lung, and head and neck cancer. 8- U Phase ill clinical trials with TMTX, under orphan drug status, are also currently underway in AIDS patients for the treatment of PCP. Thus far, these trials have yielded promising results. Although this report focuses primarily on TMTX, we also review PCP, including its clinical features, current standard therapeutic regimens, and some of the controversies surrounding genus identification, which we believe are necessary to put TMTX and its therapeutic role into proper perspective.
Microbiology ofPneumocystis carinii There have been numerous reviews describing the microbiology and pathophysiology of PCP.l,3,13-1S P. carinii is an opportunistic organism of uncertain taxonomy. Until recently the majority of investigators considered Pneumocystis to be a unicellular parasite. Current studies of the dihydrofolate reductase enzymes of all known parasites (large, bifunctional enzymes that mediate both dihydrofolate reductase and thymidylate synthetase activity) show these to be different from those of P. carinii, which have a lower molecular weight and are devoid of thymidylate synthetase activity. This lack of bifunctional activity makes them comparable to the enzymes of other eukaryotes such as those in the cells of fungi and mammals. In addition, Edman et al. isolated the 16S ribosomal RNA subunit from P. carinii and compared its nucleotide homology with those of numerous other organisms. They reported that this subunit is most closely related (>90 percent) to that of the fungal genus Saccharomyces, and that it is more closely related to the mammalian 16S RNA subunit than to those of unice1lular parasites. However, the structure and antimicrobial susceptibility patterns of P. carinii differ a great deal from those of other pathogenic fungi. Thus, whether this organism comprises a unique genus or family of fungi or is merely a unique pathogen within a known family or genus remains to be determined.Pe" P. carinii exists in the lungs of immunocompromised patients either as a small pleomorphic form (trophozoite) or a thick-walled cystic form (sporozoite). The latter carries up to eight daughter forms. P. carinii is thought to be transmitted via the air; however, because of the questions surrounding its classification, an environmental reservoir, such as soil, must also be considered as a potential route of transmission. Most children are exposed to P. carinii by the age of three or four. The organism propagates in the alveoli of certain types of patients and causes an acellular, eosinophilic, proteinaceous material containing cysts and trophozoites to accumulate, leading to subsequent damage to type I pneumocytes.
ClinicalFeatures and Diagnosisof Pneumocystis carinii Pneumonia The clinical features of PCP are diverse. Symptoms may be present between one and two weeks prior to diagnosis in
patients without AIDS and up to four weeks in those with AIDS. The most common signs and symptoms include dyspnea and tachypnea, fever, nonproductive cough, tachycardia, hypoxemia and cyanosis, a variable white blood cell count (depending on underlying disease), increased alveolar-arterial (A-a) oxygen gradient, respiratory alkalosis, decreased vital and diffusing capacities, and bilateral diffuse infiltrates beginning in the perihilar regions on chest Xray.3,13,14,18 These signs and symptoms are important criteria upon which patient selection and evaluation of new therapies are based. Other systemic findings such as lymphadenopathy, goiter, and hepatosplenomegaly, have been reported in patients with disseminated pneumocystosis.w" Diagnosis of PCP is usually made by observing the sporozoite form with a methenamine silver stain preparation. A representative sample may be retrieved by inducing sputum with hypertonic saline, but the effectiveness of this method is suboptimal. For the most part representative samples may be obtained by fiberoptic bronchoscopy with concomitant bronchoalveolar lavage and transbronchial biopsies. This will result in a greater than 90 percent yield in AIDS patients, but unfortunately only about a 40 percent yield in those without AIDS. If bronchoscopy is nondiagnostic or infection with other organisms is suspected, a lung biopsy may be performed. 13,14,21,22 Another method used to assist with diagnosis and to monitor the infectious process is the measurement of serum lactate dehydrogenase (LDH) concentrations. Although there is a greater increase in LDH in bronchoalveolar lavage fluid than in serum in patients with PCP, it is thought that there is selective back-diffusion of isoenzymes 1 and 2 into the serum. However, isoenzymes 3, 4, and 5 appear to be retained in the lung secretions. With serial determinations of LDH it is possible to monitor the patient's disease course and his response to therapy.P Although diagnostic methods have improved our ability to identify PCP, many patients with the signs and symptoms described above receive treatment on an empiric basis. Standard Therapies
TMP/SMX is the usual primary therapy for PCP. The pharmacologic rationale behind this combination is that SMX prevents formation of dihydrofolic acid by inhibiting dihydropteroate synthetase and TMP decreases the formation of the necessary tetrahydrofolic acid by inhibiting dihydrofolate reductase. Usual dosages are approximately 20 mg/kg/d (based on the TMP component) for 14 days in non-AIDS patients and 21 days in those with AIDS, although there is no evidence that a three-week course of therapy provides any specific advantages (such as a lower relapse rate) over a two-week course. l8,24 In addition to the length of therapy, there is controversy regarding the optimal route of administration. When initiating therapy, clinicians may be reluctant to administer TMP/SMX orally and may prefer to administer the drug intravenously, at least until the patient shows obvious evidence of improvement. However, oral TMP/SMX is well absorbed. For compliant patients without obvious gastrointestinal dysfunction who can be monitored carefully as in- or outpatients and who have mild pulmonary dysfunction, the initiation of oral drug therapy is an acceptable alternative. When TMP/SMX (20 and 100 mg/kg/d, respectively) is given in three or four di-
The AnnalsofPharmacotherapy • 1992 February, Volume 26 • 219
vided doses per day, the mean survival rate for a given episode of pcp in patients with AIDS is approximately 75 percent. Furthermore, for the first episode of pCP, especially in patients with mild disease (A-a oxygen gradient
TRIMETREXATE FOR PNEUMOCYSTIS CARINII PNEUMONIA IN PATIENTS WITH AIDS Guy W. Amsden, Steven F. Kowalsky, and Gene D. Morse
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 swrounding it. Phannacokinetic data and clinical trials are reviewed, as well as adverse effects, drug interactions, and dosage guidelines. OBJECTIVE:
A MEDLINE search was used to identify pertinent literature, including reviews.
DATA SOURCES:
srunv SELECIlON: As both phannacokinetic and clinical trials were few in number, all available trials were reviewed. Phannacokinetic 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 EXTRACTION:
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 phannacokinetic parameters best fit a multicompartrnental 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 phannacokinetic parameters are variable, the need for plasma concentration monitoring at present is unclear, as no dose-response relationship has been established. DATA SYNTIIESIS:
GUY W. AMSDEN, Pharm.D.• is an Infectious Diseases/Pharmacokinetics Research Fellow , Clini cal Pharmacokinetics Laboratory. Millard Fillmore Hospital, 3 Gates Cir., Buffalo, NY 14209; STEVEN F. KOWALSKY, Pharm.D., is the Assistant Di· rector of Medical Research, Anti-Infective Research Group , Pharmaceutical Division, Miles, Inc., West Haven, Cl' ; and GENE D. MORSE, Pharm.D.• is an Associate Professor of Pharmacy, Center for Clin ical Pharmacy Research, State University of New York at Buffalo , a Coinvestigator, University of Rochester AIDS Clinical Trials Unit, and a Member, Department of Pharmaceutical Services, Erie County Medical Center, Buffalo, NY. Reprints: Guy W. Amsden, Pharm.D. Trimetrexateglucuonate, Parke-Davis.
This article is approved for continuing education credit.
218 •
The Annals ofPharmacotherapy
•
CHO
I I
HCOH HOCH
I
HCOH
I
HCOH
I
CQOH
Figure 1. Graphic formula of trirnetrexate glucuronate .
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 CD 4 count are needed. Furthermore, difficulty may arise in using TMfX on a regular basis because of the potential cost of therapy with concomitant leucovorin.
Ann Pharmacother 1992;26:218-26. WITH TIIE INCREASED USE OF CHRONIC IMMUNOSUPPRESSION
and the rise in the number of cases of AIDS, the incidence of opportunistic infections, especially among those who are human immunodeficiency virus (HIV)-positive with an immunocompromised status, has increased dramatically. The prevalence of Pneumocystis carinii pneumonia (PCP) far exceeds that of cryptococcosis, Mycobacterium avium complex, or bacterial pulmonary infections.' In AIDS patients the annual prevalence rate of PCP is greater than 30 percent. This is in contrast to that of renal transplant recipients and patients with leukemia or lymphoma, in whom the rate appears to be between 0.01 and I percent.' In fact, more than 80 percent of patients with AIDS will develop PCP; in 55 percent of these people, this disease will actually be pathognomonic of their underlying syndrome.' Suitable therapies for PCP are currently under investigation. Pentamidine isethionate and trimethoprim/ sulfamethoxazole (TMP/SMX) have been the traditional treatments for
1992 February, Volume 26
PCP, but the high incidence of adverse effects associated with both of these regimens-e" makes new and better-tolerated therapeutic options necessary. Trimetrexate (TMTX) glucuronate, a new, nonclassic folate antagonist (Figure 1), is presently under investigation in Phase II trials as a chemotherapeutic agent for breast, pancreatic, colorectal, lung, and head and neck cancer. 8- U Phase ill clinical trials with TMTX, under orphan drug status, are also currently underway in AIDS patients for the treatment of PCP. Thus far, these trials have yielded promising results. Although this report focuses primarily on TMTX, we also review PCP, including its clinical features, current standard therapeutic regimens, and some of the controversies surrounding genus identification, which we believe are necessary to put TMTX and its therapeutic role into proper perspective.
Microbiology ofPneumocystis carinii There have been numerous reviews describing the microbiology and pathophysiology of PCP.l,3,13-1S P. carinii is an opportunistic organism of uncertain taxonomy. Until recently the majority of investigators considered Pneumocystis to be a unicellular parasite. Current studies of the dihydrofolate reductase enzymes of all known parasites (large, bifunctional enzymes that mediate both dihydrofolate reductase and thymidylate synthetase activity) show these to be different from those of P. carinii, which have a lower molecular weight and are devoid of thymidylate synthetase activity. This lack of bifunctional activity makes them comparable to the enzymes of other eukaryotes such as those in the cells of fungi and mammals. In addition, Edman et al. isolated the 16S ribosomal RNA subunit from P. carinii and compared its nucleotide homology with those of numerous other organisms. They reported that this subunit is most closely related (>90 percent) to that of the fungal genus Saccharomyces, and that it is more closely related to the mammalian 16S RNA subunit than to those of unice1lular parasites. However, the structure and antimicrobial susceptibility patterns of P. carinii differ a great deal from those of other pathogenic fungi. Thus, whether this organism comprises a unique genus or family of fungi or is merely a unique pathogen within a known family or genus remains to be determined.Pe" P. carinii exists in the lungs of immunocompromised patients either as a small pleomorphic form (trophozoite) or a thick-walled cystic form (sporozoite). The latter carries up to eight daughter forms. P. carinii is thought to be transmitted via the air; however, because of the questions surrounding its classification, an environmental reservoir, such as soil, must also be considered as a potential route of transmission. Most children are exposed to P. carinii by the age of three or four. The organism propagates in the alveoli of certain types of patients and causes an acellular, eosinophilic, proteinaceous material containing cysts and trophozoites to accumulate, leading to subsequent damage to type I pneumocytes.
ClinicalFeatures and Diagnosisof Pneumocystis carinii Pneumonia The clinical features of PCP are diverse. Symptoms may be present between one and two weeks prior to diagnosis in
patients without AIDS and up to four weeks in those with AIDS. The most common signs and symptoms include dyspnea and tachypnea, fever, nonproductive cough, tachycardia, hypoxemia and cyanosis, a variable white blood cell count (depending on underlying disease), increased alveolar-arterial (A-a) oxygen gradient, respiratory alkalosis, decreased vital and diffusing capacities, and bilateral diffuse infiltrates beginning in the perihilar regions on chest Xray.3,13,14,18 These signs and symptoms are important criteria upon which patient selection and evaluation of new therapies are based. Other systemic findings such as lymphadenopathy, goiter, and hepatosplenomegaly, have been reported in patients with disseminated pneumocystosis.w" Diagnosis of PCP is usually made by observing the sporozoite form with a methenamine silver stain preparation. A representative sample may be retrieved by inducing sputum with hypertonic saline, but the effectiveness of this method is suboptimal. For the most part representative samples may be obtained by fiberoptic bronchoscopy with concomitant bronchoalveolar lavage and transbronchial biopsies. This will result in a greater than 90 percent yield in AIDS patients, but unfortunately only about a 40 percent yield in those without AIDS. If bronchoscopy is nondiagnostic or infection with other organisms is suspected, a lung biopsy may be performed. 13,14,21,22 Another method used to assist with diagnosis and to monitor the infectious process is the measurement of serum lactate dehydrogenase (LDH) concentrations. Although there is a greater increase in LDH in bronchoalveolar lavage fluid than in serum in patients with PCP, it is thought that there is selective back-diffusion of isoenzymes 1 and 2 into the serum. However, isoenzymes 3, 4, and 5 appear to be retained in the lung secretions. With serial determinations of LDH it is possible to monitor the patient's disease course and his response to therapy.P Although diagnostic methods have improved our ability to identify PCP, many patients with the signs and symptoms described above receive treatment on an empiric basis. Standard Therapies
TMP/SMX is the usual primary therapy for PCP. The pharmacologic rationale behind this combination is that SMX prevents formation of dihydrofolic acid by inhibiting dihydropteroate synthetase and TMP decreases the formation of the necessary tetrahydrofolic acid by inhibiting dihydrofolate reductase. Usual dosages are approximately 20 mg/kg/d (based on the TMP component) for 14 days in non-AIDS patients and 21 days in those with AIDS, although there is no evidence that a three-week course of therapy provides any specific advantages (such as a lower relapse rate) over a two-week course. l8,24 In addition to the length of therapy, there is controversy regarding the optimal route of administration. When initiating therapy, clinicians may be reluctant to administer TMP/SMX orally and may prefer to administer the drug intravenously, at least until the patient shows obvious evidence of improvement. However, oral TMP/SMX is well absorbed. For compliant patients without obvious gastrointestinal dysfunction who can be monitored carefully as in- or outpatients and who have mild pulmonary dysfunction, the initiation of oral drug therapy is an acceptable alternative. When TMP/SMX (20 and 100 mg/kg/d, respectively) is given in three or four di-
The AnnalsofPharmacotherapy • 1992 February, Volume 26 • 219
vided doses per day, the mean survival rate for a given episode of pcp in patients with AIDS is approximately 75 percent. Furthermore, for the first episode of pCP, especially in patients with mild disease (A-a oxygen gradient
