Pentostatin

-1.1

-2.09

White crystals from methanol/water

White to off-white solid

Freely soluble in water, aqueous solubility > 100 mg/ml

1.07e+01 g/L

H2O >30 (mg/mL)

pH 9 borate buffer >50 (mg/mL)

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

220-225 °C

Mp: also reported as 204-209.5 °C with darkening at > 150 °C.

220 °C

Specific optical rotation: + 76.4 deg at 25 °C/D (concentration by volume = 1 g 100 ml water); specific optical rotation: + 73.0 deg at 23 °C/D (concentration by volume = 1 g in 100 ml water pH 7 buffer)

(c = 1, H2O) [a]25D = +76.4 ± 2°

Commercially available pentostatin powder for injection should be stored at 2-8 °C. ... When stored at 2-8 °C, the manufacturer states that currently available pentostatin powder for injection is stable for 18 mo after the date of manufacture when stored as directed. ... Pentostatin is compatible with 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's. When reconstituted with 0.9% sodium chloride injection to a final concentration of 2 mg/ml, pentostatin solutions are physically and chemically stable for at least 72 hr at room temperature (22-25 °C). When diluted to a final concentration of 20 ug/ml, the drug is chemically compatible at room temperature with 0.9% sodium chloride or lactated Ringer's injection for at least 48 hr and with 5% dextrose injection for at least 24 hr. Up to an 8-10% loss in potency has been reported to occur within 48 hr in such solutions diluted in 5% dextrose, However, because such reconstituted and/or diluted pentostatin solutions contain no preservatives, the manufacturer recommends that they be used within 8 hr when stored at room temperature in ambient light, and that unused portions be discarded.

Bulk: Bulk samples stored at 60 °C for 9 days showed no decomposition (TLC and UV). Bulk material should be stored at -20 °C for long term storage.

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.

Danger

H301 (97.6%): Toxic if swallowed [Danger Acute toxicity, oral]

P264, P270, P301+P316, P321, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 41 reports by companies from 2 notifications to the ECHA C&L Inventory.

Hazard Traits - Developmental Toxicity

Imidazo4,5-d1,3diazepin-8-ol, 3-(2-deoxy-.beta.-D-erythro-pentofuranosyl)-3,4,7,8-tetrahydro-, (8R)-: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl pentostatin, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act.

Limited data suggest that concomitant therapy with pentostatin (4 mg/sq m every 2 weeks) and fludarabine (principally 10 mg/sq m daily for 4 days at 28 day intervals), a synthetic purine nucleoside, may be associated with severe and/or fatal pulmonary toxicity (eg, pneumonitis). In one study, 4 of 6 patients receiving the drugs concomitantly for treatment of refractory chronic lymphocytic leukemia reportedly developed such toxicity.

Although therapy with either pentostatin or allopurinol alone has been associated with the development of skin rash, limited evidence suggests that concomitant use of the drugs, compared with pentostatin therapy alone, in patients with refractory hairy cell leukemia is not associated with an increased incidence of rash. However, other toxicities, including abnormalities in renal or hepatic function, have been observed in a few patients receiving concomitant pentostatin and allopurinol. ... One patient reportedly developed a fatal hypersensitivity vasculitis while receiving pentostatin and allopurinol concurrently; however, a causal relationship to the drugs has not been established.

Pentostatin inhibits the degradation of vidarabine and enhances its cytotoxicity in cell culture and in animals with experimentally induced leukemia. In addition, limited data in patients with acute leukemia suggest that combined therapy with the drugs may be associated with increased plasma vidarabine concentrations and/or half-life and greater toxicity compared with pentostatin therapy alone. Although improvement and/or remission has been reported in a few patients with acute T cell lymphoblastic leukemia who received vidarabine and pentostatin concomitantly.

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)

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl pentostatin, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Pentostatin is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia and hairy cell leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. 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).

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).

... Adenosine deaminase inhibitor

The precise mechanism(s) of action of pentostatin in hairy cell leukemia and other lymphoid malignancies has not been fully elucidated. Pentostatin is a potent transition state (tight binding) inhibitor of adenosine deaminase, an enzyme involved in purine metabolism. This enzyme appears to regulate intracellular adenosine concentrations via irreversible deamination of adenosine and deoxyadenosine. Although adenosine deaminase is widely distributed in mammalian tissues, highest levels are found in lymphoid tissue: levels in circulating T cells (particularly in T cell lymphoblastic leukemia) are higher than those in B cells. While the level of enzyme activity is low in healthy bone marrow, it is high in myeloid leukemic blast cells. ... Inhibition of adenosine deaminase by pentostatin results in intracellular accumulation of toxic levels of adenine deoxynucleotides (eg, deoxyadenosine triphosphate), which in the presence of deoxyadenosine can lead to cell death. Pentostatin alone, even in concentrations high enough to inhibit adenosine deaminase completely, is not cytotoxic to lymphoid cells cultured in the absence of cytotoxic nucleosides (eg, deoxyadenosine). Thus, unlike many other nucleoside-analog antineoplastic agents, the cytoxic effects of pentostatin do not appear to be attributable directly to the drug or its metabolites but instead appear to result indirectly from the effects of the substrates for adenosine deaminase (adenosine and deoxyadenosine) and/or their metabolites. Although elevated deoxyadenosine triphosphate concentrations in the cell can block DNA synthesis via inhibition of ribonucleotide reductase, the precise role of high deoxyadenosine triphosphate concentrations in pentostatin-induced cytotoxicity is controversial. Pentostatin also can inhibit RNA synthesis, cause DNA strand breaks, disrupt ATP-dependent cellular processes, and inhibit adenosylhomocysteinase (S-adenosylhomocysteine hydrolase), all of which also may contribute to the drug's lymphocytotoxic effects.

The degree to which pentostatin inhibits adenosine deaminase varies among cell types, possibly because of differences in enzyme inhibitor dissociation constants in different cells as well as differences in cellular accumulation of the drug. There generally has been no clear relation between adenosine deaminase inhibition and pentostatin induced cytotoxicity in clinical studies. However, the cytotoxic and growth inhibitory effects of adenosine deaminase inhibition appear to be greater in T cells than in B cells. Although conflicting data exist, some evidence suggests that T cells accumulate more deoxyadenosine triphosphate than B cells and thus may be more susceptible to the effects of adenosine deaminase inhibition; deoxyadenosine triphosphate concentrations in B cells may be lower because these cells possess higher membrane associated ecto-5'-nucleotidase activity, which promotes the hydrolysis of higher phosphate compounds to more freely diffusible nucleosides. Differences in the sensitivity of B and T cells to pentostatin's effects also may be artifactual as a result of testing procedure variables (eg, cell source, culture media conditions). The time course of adenosine deaminase inhibition appears to differ in erythrocytes and lymphocytes and depends on the intrinsic activity of the enzyme in the cell as well as cell specific pharmacodynamics (eg, protein synthesis, rate of cellular proliferation). In some cells, inhibition by a single dose of pentostatin may persist for 1 week or longer. It is not known whether recovery from adenosine deaminase inhibition occurs as a result of slow efflux of pentostatin from the cell or regeneration of adenosine deaminase; however, recovery of blood adenosine deaminase activity may result from replenishment of enzyme from newly formed erythrocytes in that such recovery in animals has been reported to coincide with the life span of erythrocytes in circulation (eg, 40-60 days). ... Response to pentostatin varies according to the type and sensitivity of the neoplasm being treated. Conditions associated with relatively low adenosine deaminase activity (eg, hairy cell and chronic lymphocytic leukemias) manifest prolonged and complete adenosine deaminase inhibition in response to relatively low dosages of pentostatin, whereas conditions associated with high adenosine deaminase activity (eg, acute leukemias) are less sensitive to the drug, requiring higher doses that produce relatively incomplete inhibition of adenosine deaminase activity.

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).

MEDICATION

For the treatment of hairy cell leukaemia refractory to alpha interferon.