ペントスタチン

5.2

pKa = 5.2 in water

Pentostatin differs from the physiologic nucleosides, adenosine and deoxyadenosine, by the interposition of a methylene group between N-1 and C-6 of the purine ring, resulting in a 7-membered (imidazobenzopin) rather than a 6-membered ring, and by the deletion of an amino group from, and the addition of a hydroxyl group to, the ring; the sugar moiety, deoxyribose, is common to both pentostatin and deoxyadenosine, while adenosine contains ribose. The resultant stereochemical and tautomeric differences in the compounds provide an increased binding affinity of pentostatin for the catalytic center of adenosine deaminase compared with the affinities of these physiologic substrates for the enzyme. Pentostatin is thought to resemble closely the transition-state intermediates of the adenosine deaminase reaction involving these nucleosides (ie, the intermediaries formed during the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively), The drug is a purine antagonist antimetabolite that acts as an adenosine deaminase inhibitor.

In clinical trials, serum enzymes elevations occurred in up to 25% of patients receiving pentostatin, but the abnormalities were generally mild and transient and rarely required dose modification. Clinically apparent liver injury from pentostatin is rare, but striking instances of severe liver injury leading rapidly to multiorgan failure and death have been described both in adults and children. The time to onset varied from a few days to six months. The possible role of shock, ischemia, opportunistic infections and sepsis in these cases has not always been well defined. Both hepatocellular and cholestatic patterns of enzyme elevations have been described. Immunoallergic features and autoantibodies were not typical.

Pentostatin is a potent transition state inhibitor of adenosine deaminase (ADA), the greatest activity of which is found in cells of the lymphoid system. T-cells have higher ADA activity than B-cells, and T-cell malignancies have higher activity than B-cell malignancies. The cytotoxicity that results from prevention of catabolism of adenosine or deoxyadenosine is thought to be due to elevated intracellular levels of dATP, which can block DNA synthesis through inhibition of ribonucleotide reductase. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Cytotoxicity is cell cycle phase-specific (S-phase).

The frequency and severity of pentostatin-induced myelosuppression appear to be related principally to the underlying disease type and tumor mass. In patients whose malignancy includes bone marrow involvement (eg; in hairy cell leukemia), myelosuppression associated with the drug generally is more frequent and more severe than in those without such involvement (eg; in mycosis fungoides); thus, even at low dosages, substantial myelosuppression can occur in certain patients. ... Leukopenia, anemia, thrombocytopenia, and hemorrhage have been reported in 60, 35, 32%, and 3-10%, respectively, of patients receiving pentostatin therapy for the treatment of hairy cell leukemia. Myelosuppression appears to be particularly likely during the first several courses of therapy with the drug. Assessing the myelosuppressive effect of pentostatin can be difficult because many patients with hairy cell leukemia have preexisting disease related myelosuppression. As response to pentostatin therapy occurs, a corresponding improvement in marrow status also may be observed, and each subsequent treatment course may be associated with a lesser degree of marrow suppression. ... Adverse hematologic effects reported in less than 3% of patients receiving pentostatin and for which a causal relationship has not been established include abnormal erythrocytes, hemolysis, eosinophilia, leukocytosis, pancytopenia, splenomegaly,thrombocythemia, lymphoma like reaction, and unspecified hematologic disorder.

Pentostatin appears to cause dosage schedule dependent nervous system toxicity, even in patients with normal renal function. Increasing lethargy with successive doses of pentostatin has been reported in some patients receiving the drug weekly, and most clinicians recommend that the drug generally not be administered more frequently than every 2 weeks. If weekly therapy is used, some clinicians recommend that no more than 3 successive weekly doses be given. It has been suggested that CNS effects may be related to intracerebral accumulation of deoxyadenosine and/or adenosine; such cumulative toxicity has not been reported with the currently recommended every other week dosage schedule for pentostatin. Pentostatin-induced nervous system toxicity (eg; seizures, coma) rarely can be fatal.

Fatigue, pain, headache, and unspecified CNS disorder have been reported in 29, 20, 13, and 11%, respectively, of patients receiving pentostatin therapy. Adverse nervous system effects reported in 3-10% of patients receiving the drug include abnormal thinking (eg; mental slowing), anxiety, confusion, depression, dizziness, insomnia, nervousness, paresthesia, and somnolence. Abnormal dreams, abnormal gait, agitation, amnesia, apathy, ataxia, CNS depression, coma, decreased libido, decreased reflexes, depersonalization, emotional lability, facial paralysis, hyperesthesia or hypoesthesia, hypertonia, incoordination, neuropathy, parosmia, postural dizziness, seizures, stupor, taste perversion, tremor, and vertigo have been reported in less than 3% of patients receiving pentostatin; however, a causal relationship to the drug has not been established. Multiple, small, nonhemorrhagic cerebral infarcts were found in one patient receiving the currently recommended dosage of pentostatin who developed a change in mental status and arm weakness; however, the CNS deficit subsequently improved, and the role of pentostatin in the development of these infarcts is unclear.

Adverse ocular and otic effects reported in 3-10% of patients receiving pentostatin include abnormal vision, keratoconjunctivitis, otic pain, and ocular pain. Blepharitis, cataract formation, deafness, diplopia, exophthalmos, lacrimation disorder, optic neuritis, otitis media, retinal detachment, and tinnitus have been reported in less than 3% of patients receiving pentostatin; however, a causal relationship to the drug has not been established. One patient receiving the drug for hairy cell leukemia reportedly developed unilateral uveitis with vision loss.

For more Human Toxicity Excerpts (Complete) data for PENTOSTATIN (17 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Pentostatin

vMost-DILI-concern

3

Box warning

DOI:10.1016/j.drudis.2016.02.015

There was no evidence of mutagenicity when pentostatin was tested in several strains of Salmonella typhimurium; however, when tested in strain TA-100 with or without metabolic activation, a reproducible mutagenic response was observed. The mutagenic response was approximately two fold higher than the standard at the maximum drug concentration tested (10 mg/plate). The commercially available formulation of pentostatin was clastogenic in vivo when tested in the mouse bone marrow micronucleus assay at concentrations of 20, 120, and 240 mg/kg. Pentostatin with or without metabolic activation was not mutagenic nor did it increase chromosomal aberrations in Chinese hamster lung cells exposed to the drug at concentrations of 1-3 mg/ml for 3 hrs.

Pentostatin produced both maternal and fetal (teratogenic) toxicity in animal studies at dosages approximating those currently recommended in humans.

Mild seminiferous tubular degeneration was observed in animals during an iv toxicity study of the drug at doses of 1 and 4 mg/kg.

No specific antidote for pentostatin overdosage is known. Administration of pentostatin in dosages higher than those currently recommended (20-50 mg/sq m over 5 days as compared with 4 mg/sq m every other week, respectively) has been associated with severe renal, hepatic, pulmonary, and CNS toxicity, which was unpredictable and occasionally fatal. In case of overdosage, management should include discontinuance of the drug and initiation of supportive measures appropriate to the type of toxicity observed.

Mouse(iv): LD50 122 mg/kg

LD50=128 mg/kg (mouse)

5.7 hours (with a range between 2.6 and 16 hrs)

Following iv administration of 4 mg/sq m of pentostatin as a single dose over 5 min in healthy individuals, the distribution half-life and terminal elimination half-life reportedly averaged 11 min and 5.7 hr, respectively. In a multiple dose study in a limited number of patients receiving 36 courses of pentostatin at a dosage of 4 mg/sq m iv, distribution half-life and terminal elimination half-life reportedly averaged 9.6 min (range: 3.1-48.5 min) and 4.9 hr, respectively. In other studies in a limited number of patients with advanced cancer, the distribution half-life averaged 17-85 min and the terminal elimination half-life averaged 2.6-15 hr following single iv doses of 0.1 or 0.25 mg/kg of pentostatin.

In patients with renal impairment (creatinine clearance less than 60 ml/min),the half-life of pentostatin averages approximately 18 hr.

Primarily hepatic, but only small amounts are metabolized.

Primarily hepatic, but only small amounts are metabolized. Route of Elimination: In man, following a single dose of 4 mg/m2 of pentostatin infused over 5 minutes, approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity. Half Life: 5.7 hours (with a range between 2.6 and 16 hrs)

395575MZO7

PENTOSTATIN

Mechanisms of Action [MoA] - Nucleic Acid Synthesis Inhibitors

Established Pharmacologic Class [EPC] - Nucleoside Metabolic Inhibitor

Pentostatin is a Nucleoside Metabolic Inhibitor. The mechanism of action of pentostatin is as a Nucleic Acid Synthesis Inhibitor.

PENTOSTATIN

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Drugs that inhibit ADENOSINE DEAMINASE activity.

Not absorbed orally, crosses blood brain barrier.

In man, following a single dose of 4 mg/m2 of pentostatin infused over 5 minutes, approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity.

68 mL/min/m2

Plasma concentrations of pentostatin following direct iv injection of 0.25 mg/kg daily for 4 or 5 days in a limited number of patients with advanced, refractory cancer ranged from approximately 3.2-9.7 ng/ml. Plasma concentrations appear to increase linearly with dose; in a study in patients with leukemia, plasma pentostatin concentrations determined 1 hour after administration of 0.25 or 1 mg/kg of the drug as a 30 min iv infusion averaged approximately 0.4 or 1.26 ug/ml, respectively.

No apparent correlation has been documented between mean or absolute plasma adenosine or deoxyadenosine concentrations and therapeutic or toxic responses to pentostatin; however, limited data suggest that there may be a correlation between response to the drug and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in lymphoblasts. In addition, increases in plasma deoxyadenosine reportedly parallel the accumulation of deoxyadenosine triphosphate in erythrocytes and lymphoblasts, and there appears to be a correlation between toxicity and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in erythrocytes.

Studies in animals indicate that pentostatin distributes rapidly to all body tissues, but the extent of drug accumulation in different tissues appears to vary among species. Following intraperitoneal injection in mice, the highest concentrations of the drug were found in the kidneys, liver, and spleen. In dogs, pentostatin tissue concentrations following iv administration were proportional to tissue adenosine deaminase activity, with the highest concentrations in the lungs, spleen, pancreas, heart, liver, and jejunum. Pentostatin reportedly enters erythrocytes via a facilitated transport system common to other nucleosides or by simple diffusion; efflux of the drug from cells has not been characterized, although the time course of pentostatin's effects (eg, adenosine deaminase inhibition) varies among different types of cells (eg, lymphocytes, erythrocytes).