Pentostatin Other names: Deoxycoformycin

Pentostatin is a potent transition state inhibitor of the enzyme adenosine deaminase. The greatest activity of ADA is found in cells of the lymphoid system with T-cells having higher activity than B-cells and T-cell malignancies higher ADA activity than B-cell malignancies. Pentostatin inhibition of ADA, as well as direct inhibition of RNA synthesis and increased DNA damage, may contribute to the overall cytotoxic effect of pentostatin. The precise mechanism of pentostatin’s antitumour effect, however, in hairy cell leukaemia is not known.

Pentostatin has been shown to have activity against a variety of lymphoid malignancies, but is most active against indolent cancers with lower ADA concentration, such as hairy cell leukaemia.

In man, pentostatin pharmacokinetics are linear with plasma concentrations increasing proportionately with dose. Following a single dose of 4 mg/m² of pentostatin infused over 5 minutes, the distribution half-life was 11 minutes and the mean terminal half-life was 5.7 hours, with a range of 2.6 to 10 hours; the mean plasma clearance was 68 ml/min/m², and approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity. The plasma protein binding of pentostatin is low, approximately 4%.

A positive correlation was observed between pentostatin clearance and creatinine clearance (CrCl) in patients with creatinine clearance values ranging from 60 ml/min to 130 ml/min. Pentostatin half-life in patients with renal impairment (CrCl <50 ml/min, n=2) was 18 hours, which was much longer than that observed in patients with normal renal function (CrCl >60 ml/min, n=14), about 6 hours.

Results from a published study in 13 patients with impaired renal function suggested dosage adjustment of pentostatin based on creatinine clearance (Clcr) values. Dosage was adjusted to 75% at a Clcr of 40-59 ml/min (3 mg/m²) and to 50% at a Clcr of 35-39 ml/min (2 mg/m²). There are insufficient data to recommend a starting or a subsequent dose for patients with creatinine clearance <35 ml/min.

A tissue distribution and whole-body autoradiography study in the rat revealed that radioactivity concentrations were highest in the kidneys with very little central nervous system penetration.

Pentostatin penetrates the blood-brain barrier leading to measurable concentrations in the cerebrospinal fluid (CSF).

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

Acute Toxicity

The combined-sex intravenous LD₁₀, LD₅₀ and LD₉₀ values in mice given formulated pentostatin were 129, 300 and 697 mg/kg (387, 900, and 2091 mg/m²), respectively.

Signs of acute toxicity in rodents and dogs were hypoactivity, dehydration, and emaciation. Lymphoid tissue was a principal target of pentostatin in rats and dogs; thymic atrophy and liver damage occurred in mice. There were no gonadal effects in rodents or dogs.

Multidose Toxicity

Five daily dose IV combined-sex LD₁₀, LD₅₀ and LD₉₀ values in mice administered bulk pentostatin were 4.9, 6.4, and 8.3 mg/kg (14.8, 19.1, and 24.8 mg/m²), respectively.

Regardless of route or duration of treatment, lymphoid tissue was the primary target of pentostatin in all species examined in toxicology studies. This is consistent with pentostatin’s antineoplastic activity in hairy cell leukaemia. Effects of lymphoid tissue may be related to adenosine deaminase inhibition, the major pharmacologic action of pentostatin. Increased serum hepatic enzymes and liver changes in rodents and dogs indicate that the liver is also a target organ at high doses. Testicular changes in rats and dogs may be indicative of potential effects on male fertility. Effects on lymphoid tissue, liver, and testes did not resolve completely during observation periods after drug withdrawal. Target organ effects occurring only in rats included alveolar duct metaplasia and/or goblet cell hyperplasia of the bronchioles, lymphoplasmacytic thyroiditis, and an increased incidence of spontaneous glomerulonephritis. Published studies, not conducted by the sponsor, indicate that pentostatin has immunosuppressive properties in mice and rats given multiple doses.

Mutagenesis

Pentostatin was not mutagenic in Salmonella typhimurium at concentrations up to 10000 µg/plate or in V79 Chinese hamster lung cells at concentrations up to 3000 µg/ml, in the presence or absence of metabolic activation. Pentostatin was not clastogenic in V79 Chinese hamster lung cells in vitro at concentrations up to 3000 µg/ml. However, pentostatin did increase the frequency of micronucleus formation in mice administered single intravenous injections of formulated pentostatin at 60, 360, and 720 mg/m². The relevance of the positive mouse micronucleus test for man is not known.

Carcinogenicity

The carcinogenic potential of pentostatin has not been evaluated. The possibility that pentostatin causes tumours cannot be ruled out.

Pentostatin has been shown to be teratogenic from studies perfomed in rats and mice. Following systemic administration in rats, foetal abnormalities were observed.