New Orleans,
Louisiana
70112
Purpose:
Primary objective: To study the pharmacokinetic interaction between zidovudine (AZT) and
valproic acid in asymptomatic HIV-infected patients, characterizing AZT's oral
bioavailability, plasma elimination half-time, plasma levels, and urinary excretion of AZT,
5'-O-glucuronide (GAZT), and 3'-amino-3'-deoxythymidine (AMT). Secondary objective: To
establish the safety of short-term administration of AZT and valproic acid in combination
with regard to hematologic parameters and liver function in asymptomatic HIV-infected
patients.
Preliminary studies using human liver tissue have shown that valproic acid inhibits the
metabolic inactivation of zidovudine (AZT), which may prolong the plasma half-life of AZT
and thus prolong the duration of the drug's effects in the body.
Study summary:
Preliminary studies using human liver tissue have shown that valproic acid inhibits the
metabolic inactivation of zidovudine (AZT), which may prolong the plasma half-life of AZT
and thus prolong the duration of the drug's effects in the body.
Six asymptomatic HIV-infected patients are treated with AZT orally every 8 hours on days 1
through 4, then with a single dose on day 5 (after 8 hours of fasting), followed by
pharmacokinetic sampling. On days 6 through 9, patients receive AZT orally every 8 hours in
combination with valproic acid (lowest dose in the first 5 patients and a higher dose in
patients 6 and 7) orally every 8 hours. On day 10, AZT and 1 of the 2 doses of valproic acid
are given orally as single doses, followed by pharmacokinetic sampling. AZT is continued
alone orally every 8 hours on days 11 through 14, then resumed at the patient's usual dose
beginning on day 15. Per 03/09/92 amendment, dosing schedule may be modified slightly to
accommodate patients with scheduling conflicts.
Criteria:
Inclusion Criteria
Concurrent Medication:
Allowed:
Vitamins if already being taken prior to start of therapy.
Patients must have:
- Asymptomatic HIV infection.
- CD4 count between 300 and 650.
Prior Medication:
Required:
- AZT at doses between 500 and 1200 mg/day for at least 6 weeks prior to enrollment.
Allowed:
- Aspirin, Tylenol, or ibuprofen up to 48 hours prior to start of therapy.
Exclusion Criteria
Co-existing Condition:
Patients with the following symptoms or conditions are excluded:
- Positive Hepatitis B surface antigen or clinical evidence of chronic active hepatitis
of any type.
- Signs or symptoms of HIV infection including oral candidiasis, history of
multidermatomal zoster, unexplained weight loss in excess of 10 percent body weight
in the past 6 months, chronic diarrhea, or history of AIDS-defining opportunistic
infections.
Concurrent Medication:
Excluded:
- Concomitant medications (other than AZT) for the 14 days prior to start of therapy.
Patients with the following prior conditions are excluded:
- History of AZT intolerance including hematologic, hepatic, and/or neurologic
toxicity.
- History of seizures.
- History of any antiepileptics within the past 10 years.
- History of abnormal bleeding or intrinsic or extrinsic coagulopathy.
- Signs or symptoms of HIV infection including oral candidiasis, history of
multidermatomal zoster, unexplained weight loss in excess of 10 percent body weight
in the past 6 months, chronic diarrhea, or history of AIDS-defining opportunistic
infections.
Prior Medication:
Excluded:
- Antiepileptics within the past 10 years.
- Prior valproic acid.
- Concomitant medications (other than AZT) within 14 days of enrollment.