Phase I Safety and Pharmacokinetics Study of Microparticulate Atovaquone (m-Atovaquone; 566C80) in HIV-Infected and Perinatally Exposed Infants and Children

Phase I Safety and Pharmacokinetics Study of Microparticulate Atovaquone (m-Atovaquone; 566C80) in HIV-Infected and Perinatally Exposed Infants and Children

To determine the safety, tolerance, and pharmacokinetics of a new improved microparticulate suspension formulation of atovaquone administered at one of two dose levels (per 09/30/94 amendment, a third dose level was added) daily for 12 days in HIV-infected and perinatally exposed (per 8/9/95 amendment) infants and children who are at risk of developing Pneumocystis carinii pneumonia (PCP).

Atovaquone has shown prophylactic potential in adults in the treatment of PCP but is poorly absorbed in tablet form. To improve the bioavailability of atovaquone, a new formulation has been prepared as a microparticulate suspension. Since studies in adults have demonstrated substantial safety of this drug, evaluation in children is being pursued.

Atovaquone has shown prophylactic potential in adults in the treatment of PCP but is poorly absorbed in tablet form. To improve the bioavailability of atovaquone, a new formulation has been prepared as a microparticulate suspension. Since studies in adults have demonstrated substantial safety of this drug, evaluation in children is being pursued.

Three cohorts of four patients each (ages 2-12 years, 3 months to less than 2 years, and 1 month to less than 3 months) receive atovaquone daily for 12 days. The oldest age group is treated first. In the absence of unacceptable toxicity, the dose of atovaquone is escalated in subsequent 4-patient cohorts representing each of the age stratifications and (per 9/30/94 amendment) in a separate 4-patient cohort aged 3 months to less than 2 years. If two of four patients in a given cohort experience unacceptable toxicity at the initial dose, two additional patients in the same age range are entered. Blood samples are drawn for pharmacokinetic evaluation. Patients are followed to day 24. Per 9/30/94 amendment, patients aged 3 months to less than 2 years of age who received one of the lower doses may re-enroll in the higher dose cohort after a 1-month washout.

Inclusion Criteria

Concurrent Medication:

Allowed:

• Zidovudine (AZT).
• Dideoxycytidine (zalcitabine; ddC).
• Didanosine (ddI).
• Nonaminoglycoside, nonmacrolide, and nonsulfonamide antibiotics.
• Factor VIII.
• IVIG.

Patients must have:

• AIDS, documented HIV infection, perinatal exposure to HIV, or risk of developing PCP.
• Normal EKG and chest radiograph.
• No blood or protein on urinalysis.
• Consent of parent or guardian.

Prior Medication:

Allowed:

• Prophylactic TMP/SMX if given no less than 3 days prior to study entry.
• Prophylactic aerosolized pentamidine (or a single intravenous dose of 4.0 mg/kg pentamidine) if given no less than 7 days prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Anticipated organ system or laboratory abnormalities (other than immune system abnormalities) from the primary disease and its treatment during the study.
• Acute or chronic infections requiring treatment during the study. NOTE:
• Thrush and herpes labialis are allowed if these conditions do not require treatment.
• Diarrhea or vomiting.

Concurrent Medication:

Excluded:

• Trimethoprim/sulfamethoxazole.
• Sulfadoxine and pyrimethamine (Fansidar).
• Primaquine.
• Aspirin.
• Amphotericin B.
• Aminoglycoside antibiotics.
• Sulfonamides.
• Dapsone.
• Benzodiazepines.
• Rifampin.
• Erythromycin, clarithromycin, and azithromycin.
• Digitalis.
• Para-aminosalicylic acid (PAS).
• Isoniazid.
• Anticoagulants.
• Any other investigational therapies.

Patients with the following prior condition are excluded:

• History of G6PD deficiency.