Alternative Oseltamivir Dosing Strategies

Pandemic influenza infection has the potential for causing significant morbidity and mortality in the United States and elsewhere. Oseltamivir (Tamiflu[R]) is a selective inhibitor of influenza virus neuraminidase and is U.S. FDA approved for both treatment and prophylaxis against influenza A and B viruses. However, at a time of national emergency, the supply of oseltamivir may be limited and alternative dosing strategies may be needed in order to provide as wide protection as possible from influenza or to treat as many infected patients as possible. Agents such as Probenecid that may extend the half-life of oseltamivir while maintaining effective oseltamivir plasma levels may potentially be useful in this regard. In this multi-center, three-arm, open-label, 48 patient trial, we propose to explore the relative safety and pharmacokinetics of oseltamivir plus Probenecid for 14 days in normal volunteers above and below the age of 65, according to the following dosing strategies: 16 subjects will be assigned to Group I Control Arm (Tamiflu[R] 75 mg given orally once daily), 16 subjects will be assigned to Group II Treatment Arm (Tamiflu [R] 75 mg orally once every other day plus Probenecid 500 mg orally four times daily), and 16 subjects will be assigned to Group III Treatment Arm (Tamiflu[R] 75 mg orally every other day and Probenecid 500 mg orally twice daily).

• INCLUSION CRITERIA:

Subjects will include males and non-pregnant females 18 years or older.

Subjects who can understand the study and potential safety concerns and can sign the informed consent form prior to admission to this study.

Subjects that are willing to complete all the required assessments, tests and evaluations and able to make all study visits.

• Hemoglobin greater than or equal to 10.0 g/dL for males and greater than 9.0 g/dL for females;
• Platelet count of greater than or equal to 75,000 /micro L;
• Absolute neutrophil count greater than or equal to 1000 /micro L;
• SGOT and SGPT less than 2.5 times normal upper limit;
• Serum uric acid WNL;
• Creatinine less than 1.5 times normal upper limit (normal UL 1.5 mg/dL) for the less than 65 years of age group and must be within normal limits for the greater than or equal to 65 years of age group;
• creatinine clearance greater than or equal to 50 mL/min.

Exclusion criteria

Subjects with a creatinine clearance of less than 50 mL/min (as measured by the Cockcroft-Gault method)

Subjects who are pregnant or breast feeding females

Subjects who are not employing adequate contraception

Subjects who are drug or alcohol abusers and in the opinion of the investigator would interfere with subject compliance and safety

Subjects who are currently participating in any other clinical research study

Any acute serious infection requiring prescription therapy within 14 days prior to Day 0 of the study

Subjects with G6PD deficiency

Subjects who may have been recently exposed to influenza

Subjects with gout, blood dyscrasias, or history of hypersensitivity to sulfonamide drugs

Subjects with contraindications to the study medications

History of allergic reaction to probenecid

Have kidney disease, kidney stones, or poorly functioning kidneys

Have active peptic ulcer disease

On high dose aspirin or any dose non-aspirin salicylate therapy

Receiving any of the following medications (relative contraindication for probenecid):

Acyclovir, allopurinol, penicillamine, clofibrate, rifampin, methotrexate, zidovudine, theophylline, dapsone, penicillins or cephalosporins, nonsteroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen (Motrin, Advil, Nuprin, others), ketoprofen (Orudis, Oruvail, Orudis KT), diclofenac (Cataflam, Voltaren), etodolac (Lodine), fenoprofen (Nalfon), flurbiprofen (Ansaid), indomethacin (Indocin), ketorolac (Toradol), nabumetone (Relafen), oxaprozin (Daypro), piroxicam (Feldene), sulindac (Clinoril), tolmetin (Tolectin), and naproxen (Aleve, Anaprox, Naprosyn); a sulfa-based medication such as sulfamethoxazole (Bactrim, Septra, Gantanol), sulfasalazine (Azulfidine), sulfinpyrazone (Anturane), sulfisoxazole (Gantrisin), and others; an oral diabetes medicine such as glipizide (Glucotrol), glyburide (Micronase, Diabeta, Glynase), tolbutamide (Orinase), or tolazamide (Tolinase); a barbiturate such as phenobarbital (Luminal, Solfoton), amobarbital (Amytal), secobarbital (Seconal), and others; or a benzodiazepine (used to treat anxiety and panic disorders and to induce sleep) such as alprazolam (Xanax), diazepam (Valium), lorazepam (Ativan), temazepam (Restoril), chlordiazepoxide (Librium), clonazepam (Klonopin), clorazepate (Tranxene), oxazepam (Serax), estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), or triazolam (Halcion).