Faculty Bibliography

Myelosuppression is associated with human immunodeficiency virus (HIV) infection and may also be produced by agents used for the treatment of the disease or the treatment of its complications. Didanosine (ddl; 2',3'-dideoxyinosine) is a newer purine nucleoside that has recently become available for therapy for HIV infection. The effects of didanosine on peripheral blood counts have been retrospectively evaluated in the first 170 patients treated with this new agent in four phase I trials. Patients treated with didanosine showed statistically significant improvements in hemoglobin levels, white cell counts, and granulocyte and platelet numbers as compared with baseline values. These changes were seen with or without prior therapy with zidovudine, were somewhat more pronounced at higher doses of didanosine, and persisted for up to 1 year. Reported adverse events included peripheral neuropathy, diarrhea, and most notably, pancreatitis. It is concluded that, while some toxic side effects occur, didanosine therapy in HIV infection is associated with an amelioration of HIV-induced myelosuppression

A comparison of the proliferative responses of lymphocytes to human immunodeficiency virus (HIV) antigens from long-term, seronegative heterosexual partners of HIV-infected subjects, from normal unexposed controls and from healthy seropositive heterosexual partners or seropositive, asymptomatic men, reveals that lymphocytes from healthy seropositive individuals with strong proliferative responses to recall, microbial antigens respond only minimally to HIV proteins or envelope peptides, and that even these low responses do not occur in all individuals. If the frequency of responses to several HIV antigens are analyzed, lymphocytes from both HIV-exposed seropositive and seronegative partners of infected individuals proliferate to HIV antigens to a greater degree than lymphocytes from unexposed, normal control individuals. Although lymphocytes from seropositive partners proliferate to a greater degree than those from seronegative partners, the latter are more similar to seropositive partners than they are to normal controls. This observation suggests that these seronegative partners may have become sensitized to HIV antigens through sexual exposure but without infection, and/or that the presence or development of these small immune responses in some individuals might be associated with a failure to become infected

OBJECTIVE: To describe the incidence, clinical characteristics and dose relationship of dideoxyinosine (ddI)-associated pancreatitis. DESIGN: Patients enrolled in a Phase I dose escalation trial of ddI [AIDS Clinical Trials Group (ACTG) 064] were evaluated for signs and symptoms of pancreatic dysfunction. SETTING: Two ACTG sites. PATIENTS: Forty-four patients with AIDS or AIDS-related complex (ARC) and a CD4 cell count less than or equal to 400 x 10(6)/l. MAIN OUTCOME MEASURES: Seven patients developed pancreatitis that lasted from 1 to 7 weeks and varied in severity from mild to life-threatening. Seven other patients had evidence of hyperamylasemia or hypertriglyceridemia. Six patients who developed pancreatitis were able to tolerate rechallenge with lower doses of ddI. RESULTS: Development of pancreatitis correlated with cumulative dose of ddI but not with stage of disease or concomitant medications. Cumulative dose was not significantly associated with development of hyperamylasemia or hypertriglyceridemia in patients without clinical pancreatitis. CONCLUSIONS: The development of pancreatitis in AIDS or ARC patients receiving ddI varies in severity and time course and is associated with cumulative dose. Patients who develop pancreatitis may be able to tolerate therapy with a lower dose after resolution of their symptoms. Patients receiving ddI require careful monitoring for the development of this complication

The objective of this study was to determine the population pharmacokinetic parameters and the extent of absorption of 2',3'-dideoxyinosine, a nucleoside analog with activity against human immunodeficiency virus in vitro and in vivo, after oral and intravenous administration through the use of NON-linear Mixed Effects Modeling. The data were drawn from the pharmacokinetics section of an open-label, multicenter phase I study. One center administered ddI on a once-daily schedule. The other centers administered the drug once every 12 h. Drug was administered intravenously, and the plasma concentration-time profile was determined. Patients were then given the drug orally at twice the dose used in the intravenous portion of the study, and the pharmacokinetic profile was again determined. A 40-fold range of doses was examined. Forty-six human immunodeficiency virus-infected patients were studied. Concentrations in plasma were determined by high-pressure liquid chromatography. Clearance of the drug from plasma was 47.7 liters/h/70 kg of body weight. The terminal half-life was 1.4 h. The volume of distribution in the central compartment was 18.8 liters/70 kg. Absorption was rapid, with an absorption half-life of 0.52 h. Bioavailability with once-daily administration was 27%. For twice-daily administration, bioavailability rose to 36%. This difference was significant (P much less than 0.01). For doses of less than or equal to 5.1 mg/kg given every 12 h (10.2 mg/kg/day), bioavailability was 41%. We conclude that once-daily administration results in lower mean bioavailability, probably because of a saturation of the absorption process similar to that seen with acyclovir.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE: To determine the relation between exposure to dideoxyinosine (ddl) and increased CD4 cell counts and suppression of serum p24 antigen in patients infected with the human immunodeficiency virus (HIV). DESIGN: Open-label, phase I study. SETTING: Two university hospitals. Patients were studied in both inpatient and outpatient settings. PATIENTS: Of 36 HIV-infected patients enrolled, 18 had adequate pharmacokinetic information for analysis. INTERVENTION: Dideoxyinosine was administered intravenously every 12 hours for 2 weeks. Patients were switched to oral administration at twice the intravenous dose. Pharmacokinetic profiles were obtained twice during each period. A 40-fold range of dose was examined. MEASUREMENTS: CD4-positive T-lymphocyte counts and serum p24 antigen levels were determined. Plasma area under the ddl concentration-time curve was determined for a single dose and at steady state. RESULTS: Increases in CD4-positive T-lymphocyte counts were independent of ddl exposure and were proportional to the starting CD4 count. Suppression of circulating p24 antigen was influenced by cumulative exposure to ddl and was statistically significant. CONCLUSIONS: The CD4-positive T-lymphocyte count increased at low ddl concentrations or exposures; the extent of this increase was directly proportional to the patient's CD4 count at the start of therapy. Suppression of p24 antigen was related to cumulative exposure to ddl. Therapeutic responses can probably be obtained with ddl, while minimizing long-term toxicity, using daily doses of 10 mg/kg body weight, or less

Plasma didanosine concentration data from 36 patients receiving once-a-day therapy and from 33 patients receiving twice-a-day therapy were subject to population pharmacokinetic analysis with the computer program NONMEM. Once- or twice-a-day regimens of didanosine were administered intravenously (i.v.) (dose: 0.8-33 mg/kg) during the first 2 weeks of therapy, and orally (dose: 1.6-66 mg/kg) for the remaining 4 weeks of therapy. Plasma pharmacokinetics were determined after the first and last (steady-state) i.v. and oral doses. Population pharmacokinetic parameters for the combined i.v. and oral steady-state data were (mean [%CV]): systemic clearance, CL, 0.70 (5.2) L/h/kg; central compartment volume, Vc, 0.18 (32) L/kg; steady-state distribution volume, Vdss, 0.84 (6.8) L/kg; first-order absorption rate constant, Ka, 1.3 (9.5) hr-1; and bioavailable fraction, F, 0.34 (8.5). Interindividual variability (omega) was (%CV) 22.3 and 71.0 for CL and Vc, respectively. Intraindividual (residual) variability (sigma) in plasma concentrations (%CV) was 50.2. Body weight, sex, and age did not account for the variability in either CL or Vc, and the use of alternate pharmacokinetic models did not reduce the value of intraindividual variability. Population parameters for the combined i.v. and oral first-dose data were generally similar to those for the steady-state data. The parameters can be used to design dosing regimens in patients using the Bayesian feedback approach

Neuropathic complaints were frequently observed in a Phase I study of dideoxyinosine (ddI) in 44 patients with AIDS and AIDS-related complex. Ten patients (23%) were thought to have a ddI-related peripheral neuropathy. The symptoms were primarily sensory, and there was limited motor involvement. The sensory symptoms improved in all patients with discontinuation of ddI. Some patients tolerated reintroduction of ddI at lower doses without significant recurrence of the neuropathic symptoms. Although the neuropathy was usually seen in patients taking higher doses of ddI than used in current treatment protocols, clinicians must be aware of this potential toxicity as more human immunodeficiency virus-infected patients are being treated with ddI

The pharmacokinetics of didanosine (2',3'-dideoxyinosine) after intravenous and oral administration were evaluated in an open, escalating-dose phase I study in patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex. Didanosine was administered twice a day for 2 weeks as an intravenous infusion of 60 minutes duration at doses ranging from 0.4 to 16.5 mg/kg, followed by 4 weeks of oral treatment at twice the intravenous dose. Serial blood and urine samples were obtained on the first and final day of intravenous administration and after the first oral dose, as well as at steady state. Didanosine demonstrated linear pharmacokinetic behavior over the dose ranges of 0.4 to 16.5 mg/kg intravenously and 0.8 to 10.2 mg/kg orally. There was no indication of significant changes in pharmacokinetic parameters with repeated administration. The apparent elimination half-life after oral administration was approximately 1.4 hour. Renal clearance values exceeded the glomerular filtration rate, indicating that active tubular secretion of didanosine occurs. Bioavailability of didanosine when administered as a solution with an antacid was approximately 43% for doses from 0.8 to 10.2 mg/kg in patients with AIDS and advanced AIDS-related complex. Bioavailability of didanosine from the citrate-phosphate-buffered solution, the formulation currently used in phase II and expanded access studies, was comparable to the formulation used in the phase I trials