DRUG STUDY AND INFORMATION FORM Generic Name: Hydroxyurea Trade Name: Hydrea, Droxia Drug Class: Hydroxyurea

Structure/Chemistry:

Pharmacodynamics

Mechanism of Action: Inhibits ribonucleoside diphosphate reductase, which catalyzes the reductive conversion of ribonucleotides to deoxyribonucleotides, a rate-limiting step in the synthesis of DNA. It also binds the iron molecules that are essential for activation of a tyrosyl radical in the catalytic subunit (hRRM2) of RNR (ribonucleotide reductase). It also increases the synthesis of fetal hemoglobin in adults which promotes solubility of hemoglobin and prevents sickling. Dowregulates expression of JAK2.

Pharmacologic Effects: Hydroxyurea is specific for the S phase of the cell cycle. It causes cells to arrest at or near the G1-S interface through borth p53-dependent and independent mechanisms. It also helps control sickle cell disease by inducing fetal hemoglobin synthesis (which, among other possible mechanisms, may arise to compensate for the suppression of erythroid precursor proliferation by hydroxyurea).

Drug Resistance or Tolerance: Increased synthesis of the catalytic subunit hRRM2 of ribonucleoside diphosphate reductase, thus restoring enzyme activity.

Pharmacokinetics

Absorption: Can be given either IV or orally. Bioavailability is excellent (80-100%). Peak plasma concentrations reached at 1-1.5 hours after oral doses of 15-80 mg/kg. Two oral dosage options for cancer treatment: intermittent therapy (80 mg/kg as a single dose every third day) or continuous therapy (20-30 mg/kg as a single daily dose). For thrombocythemia and sickle cell: a daily oral dose of 15 mg/kg, adjusting that dose upward or downward according to blood counts. Distribution: Crosses blood-brain barrier and appears in human breast milk

Elimination: t1/2 of 3.5-4.5 hours. Excreted in urine.

Metabolism: May occur but the extent has not been established.

Adverse Side Effects/Toxicity: Myelosuppression (leukopenia, anemia, and occasionally thrombocytopenia) is the major toxicity; recovery of bone marrow takes only a few days. Others include desquamative interstitial pneumonitis, GI disturbances, and mild dermatological reactions; more rarely, stomatitis, alopecia, and neurological manifestations. Drug Interactions: Hydroxyurea and irradiation have synergistic effects because cells are highly sensitive at the G1-S boundary. It also is synergistic with DNA-damaging agents such as cisplatin, alkylating agents, or topoisomerase II inhibitors and facilitates the incorporation of antimetabolites (such as Ara-C and fludarabine) because of its depletion of physiological deoxynucleotides. Therapeutic uses: As a myelosuppressive agent against myeloproliferative syndromes, particularly CML (chronic myelogenouse leukemia, has largely been replaced imatinib), polycythemia vera, myeloid metaplasia, and essential thrombocytosis, for controlling high platelet and white cell counts. Treatment is for six weeks to determine effectiveness. Potent radiosensitizer.

Miscellaneous: