Preliminary evaluation of human immunodeficiency virus type 1 (HIV-1) immunogen in children with HIV-1 infection.

The safety and preliminary activity of human immunodeficiency virus type 1 (HIV-1) immunogen were evaluated in 10 HIV-1-infected children with disease stage N1,2 or A1,2. Multiple inoculations of 2. 5 or 10 units (U) of HIV-1 immunogen were safe and well tolerated without an acceleration of disease progression. When antiretroviral agents were coadministered, the 10 U dose appeared to be associated with more sustained reduction in plasma HIV-1 RNA than the 2.5 U dose (median log10 HIV-1 RNA at month 18, 3.07 vs. 4.01 copies/mL in 10 U [n=4] vs. 2.5 U [n=3], respectively; P=.034). Levels of regulated-on-activation, normal T cell-expressed and -secreted chemokine produced from HIV-1 immunogen-stimulated lymphocytes in vitro were increased in the children who had HIV-1 immunogen-specific antibody responses (P<.02) and appeared to be inversely correlated with levels of plasma HIV-1 RNA (P<.01). These preliminary data warrant larger studies to determine the effectiveness of adjunctive therapy with HIV-1 immunogen in children with HIV-1 infection.

Safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) in neutropenic patients.

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.

Pharmacokinetics of the protease inhibitor KNI-272 in plasma and cerebrospinal fluid in nonhuman primates after intravenous dosing and in human immunodeficiency virus-infected children after intravenous and oral dosing.

KNI-272 is a human immunodeficiency virus (HIV) protease inhibitor with potent activity in vitro. We studied the pharmacokinetics of KNI-272 in the plasma and cerebrospinal fluid (CSF) of a nonhuman primate model and after intravenous and oral administration to children with HIV infection. Plasma and CSF were sampled over 24 h after the administration of an intravenous dose of 50 mg of KNI-272 per kg of body weight (approximately 1,000 mg/m2) to three nonhuman primates. The pharmacokinetics of KNI-272 were also studied in 18 children (9 males and 9 females; median age, 9.4 years) enrolled in a phase I trial of four dose levels of KNI-272 (100, 200, 330, and 500 mg/m2 per dose given four times daily). The plasma concentration-time profile of KNI-272 in the nonhuman primate model was characterized by considerable interanimal variability and rapid elimination (clearance, 2.5 liters/h/kg; terminal half-life, 0.54 h). The level of drug exposure achieved in CSF, as measured by the area under the KNI-272 concentration-time curve, was only 1% of that achieved in plasma. The pharmacokinetics of KNI-272 in children were characterized by rapid elimination (clearance, 276 ml/min/m2; terminal half-life, 0.44 h), limited (12%) and apparently saturable bioavailability, and limited distribution (volume of distribution at steady state, 0.11 liter/kg). The concentrations in plasma were maintained above a concentration that is active in vitro for less than half of the 6-h dosing interval. There was no significant increase in CD4 cell counts or decrease in p24 antigen or HIV RNA levels. The pharmacokinetic profile of KNI-272 may limit the drug's efficacy in vivo. It appears that KNI-272 will play a limited role in the treatment of HIV-infected children.

A phase I/II study of the protease inhibitor indinavir in children with HIV infection.

BACKGROUND: Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose. METHODS: Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m2, 350 mg/m2, and 500 mg/m2 per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and >/=12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks. RESULTS: Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm3, and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy. CONCLUSIONS: Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine.

A phase I/II study of the protease inhibitor ritonavir in children with human immunodeficiency virus infection.

BACKGROUND: Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects. METHODS: HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/m given every 12 hours) were evaluated in two age groups (2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks. RESULTS: A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/mm3 after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 log10 copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m for the 24-week period. CONCLUSIONS: The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine.

Safety, tolerance, and pharmacokinetics of amphotericin B lipid complex in children with hepatosplenic candidiasis.

The safety, tolerance, and pharmacokinetics of amphotericin B lipid complex (ABLC) were studied in a cohort of pediatric cancer patients. Six children with hepatosplenic candidiasis (HSC) received 2.5 mg of ABLC/kg of body weight/day for 6 weeks for a total dosage of 105 mg/kg. Mean serum creatinine (0.85 +/- 0.12 mg/dl at baseline) was stable at the end of therapy at 0.85 +/- 0.18 mg/dl and at 1-month follow-up at 0.72 +/- 0.12 mg/dl. There was no increase in hepatic transaminases. Mean plasma concentrations over the dosing interval (C(ave)) and area under the curve from 0 to 24 h (AUC(0-24h)) increased between the first and seventh doses but were similar between doses 7 and 42, suggesting that steady state was achieved by day 7 of therapy. Following the final (42nd) dose of ABLC, mean AUC(0-24h) was 11.9 +/- 2.6 microg h/ml, C(ave) was 0.50 +/- 0.11 microg/ml, maximum concentration of the drug in whole blood was 1.69 +/- 0.75 microg/ml, and clearance was 3.64 +/- 0.78 ml/min/kg. Response of hepatic and splenic lesions was monitored by serial computerized tomographic and magnetic resonance imaging scans. The five evaluable patients responded to ABLC with complete or partial resolution of physical findings and of lesions of HSC. During the course of ABLC infusions and follow-up, there was no progression of HSC, breakthrough fungemia, or posttherapy recurrence. Hepatic lesions continued to resolve after the completion of administration of ABLC. Thus, ABLC administered in multiple doses to children was safe, was characterized by a steady state attainable within 1 week of therapy, and was effective in treatment of HSC.

Ifosfamide and etoposide plus vincristine, doxorubicin, and cyclophosphamide for newly diagnosed Ewing's sarcoma family of tumors.

BACKGROUND: This study was conducted to determine the feasibility of, and improve outcome by, incorporating ifosfamide and etoposide (IE) into the therapy of newly diagnosed patients with Ewing's sarcoma family of tumors of bone and soft tissue. METHODS: Fifty-four newly diagnosed patients received 7 cycles of vincristine, doxorubicin, and cyclophosphamide (VAdriaC) and 11 cycles of IE. Radiation therapy after the fifth chemotherapy cycle was the primary approach to local control. RESULTS: Actuarial 5-year event-free survival (EFS) and overall survival rates were 42% and 45%, respectively, with a median duration of potential follow-up of 6.8 years. EFS was significantly better for patients with localized tumors than for those with metastatic lesions (64% v. 13%, P < 0.0001). Actuarial local progression-free survival at 5 years was 74%, and did not correlate with primary tumor size or site, histologic subtype, or the presence of metastases. Febrile neutropenia developed after 49% of cycles, and clinical or sub-clinical cardiac dysfunction was common (7% and 40% respectively). There were four toxic deaths and one case of secondary myelodysplastic syndrome. CONCLUSIONS: Despite substantial toxicity, the integration of IE into the front-line, VAdriaC-based therapy of patients with Ewing's sarcoma family of tumors is feasible and appeared to significantly improve the outcome for patients with high risk localized tumors, but had no impact on the poor prognosis of patients with metastatic tumors. Local control can be achieved in the vast majority of patients using radiotherapy exclusively, even among patients with bulky, central axis tumors. Longer follow-up is needed to evaluate the late effects of this intensive therapy.

Randomized trial of recombinant human granulocyte-macrophage colony-stimulating factor in pediatric patients receiving intensive myelosuppressive chemotherapy.

PURPOSE: To evaluate whether recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the hematologic toxicities and supportive care requirements of an intensive combination chemoradiotherapy regimen in pediatric and young adult sarcoma patients. PATIENTS AND METHODS: Thirty-seven newly diagnosed patients age 1 to 25 years were randomized to receive 18 cycles of chemotherapy alone or with GM-CSF beginning in cycle 3. GM-CSF (5 to 15 micrograms/kg/d subcutaneously) was begun 24 hours after the completion of chemotherapy and continued through day 19 of each cycle or until the absolute granulocyte count (AGC) was > or = 500/microliter on 2 consecutive days. RESULTS: GM-CSF reduced the median duration of grade 4 granulocytopenia from 9.0 days (range, 2 to 24) to 7.0 days (range, 1 to 21) (P < .0001), but did not significantly affect the grade of granulocyte nadir. No differences were seen in the incidence or types of infectious complications, incidence or duration of hospitalization and antimicrobial therapy, response to chemotherapy, or event-free or overall survival. GM-CSF was associated with more severe and protracted thrombocytopenia (median platelet nadir, 29,500/microliter [range, 3,000 to 288,000] v 59,000/microliter [range, 3,000 to 309,000], P < .0001; median time to recovery > 75,000/microliter, 16.0 days [range, 0 to 61] v 14.0 days [range, 0 to 38], P < .0001). CONCLUSION: GM-CSF does not produce clinically meaningful reductions in the degree or duration of severe granulocytopenia following intensive multiagent chemotherapy, but is associated with worsened thrombocytopenia. GM-CSF also does not reduce the need for hospitalization or the incidence of febrile neutropenia and infectious complications. We conclude that the costs and increased toxicities associated with the use of this agent are not justified by its minimal clinical benefit for regimens of this level of intensity.

Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin.

PURPOSE: We conducted an open-label, randomized trial to determine whether ICRF-187 would reduce doxorubicin-induced cardiotoxicity in pediatric sarcoma patients. METHODS: Thirty-eight patients were randomized to receive doxorubicin-containing chemotherapy (given as an intravenous bolus) with or without ICRF-187. Resting left ventricular ejection fraction (LVEF) was monitored serially with multigated radionuclide angiography (MUGA) scan. The two groups were compared for incidence and degree of cardiotoxicity, response rates to four cycles of chemotherapy, event-free and overall survival, and incidence and severity of noncardiac toxicities. RESULTS: Eighteen ICRF-187-treated and 15 control patients were assessable for cardiac toxicity. ICRF-187-treated patients were less likely to develop subclinical cardiotoxicity (22% v 67%, P < .01), had a smaller decline in LVEF per 100 mg/m2 of doxorubicin (1.0 v 2.7 percentage points, P = .02), and received a higher median cumulative dose of doxorubicin (410 v 310 mg/m2, P < .05) than did control patients. Objective response rates were identical in the two groups, with no significant differences seen in event-free or overall survival. ICRF-187-treated patients had a significantly higher incidence of transient grade 1 serum transaminase elevations and a trend toward increased hematologic toxicity. CONCLUSION: ICRF-187 reduces the risk of developing short-term subclinical cardiotoxicity in pediatric sarcoma patients who receive up to 410 mg/m2 of doxorubicin. Response rates to chemotherapy, event-free and overall survival, and noncardiac toxicities appear to be unaffected by the use of ICRF-187. Additional clinical trials with larger numbers of patients are needed to determine if the short-term cardioprotection afforded by ICRF-187 will reduce the incidence of late cardiac complications in long-term survivors of childhood cancer.

A prospective evaluation of ifosfamide-related nephrotoxicity in children and young adults.

BACKGROUND: Ifosfamide has been associated with proximal renal tubular dysfunction resembling Fanconi-like syndrome and leading to rickets in young children. The characteristic manifestations of this nephrotoxicity include phosphaturia and hypophosphatemia, glycosuria, aminoaciduria, renal tubular acidosis, and urinary loss of low molecular weight serum proteins. However, the relationship between acute ifosfamide nephrotoxicity, which is frequently subclinical, and long term renal damage is unclear. In this prospective study, the laboratory features of ifosfamide-induced acute nephrotoxicity were characterized further and correlated with the development of chronic nephropathy. METHODS: The renal function of newly diagnosed children and young adults with high risk sarcomas was followed during therapy with a high dose ifosfamide-containing regimen. Serum and urine were collected regularly immediately before and after 5-day cycles of ifosfamide throughout treatment for determination of the fractional excretion of electrolytes (sodium, potassium, phosphate, magnesium, calcium) and glucose and urinary excretion of amino acids and beta 2-microglobulin. RESULTS: Significant changes in the renal threshold of phosphate excretion, the fractional excretion of calcium and glucose, and the urinary excretion of beta 2-microglobulin were observed when comparing pretreatment values with those at the end of a 5-day treatment cycle. The median renal threshold of phosphate excretion decreased from 1.22 to 0.82 mmol/L (P < 0.0001). The median fractional excretions of calcium and glucose increased from 1.05% to 1.68% (P < 0.0001) and 0.05% to 0.08% (P = 0.0006), respectively. Beta 2-microglobulin excretion increased by 70-fold from 0.02 to 1.42 mg/mmol (P < 0.0001). Except for glucose and beta 2-microglobulin excretion, renal parameters returned to baseline before the next ifosfamide treatment cycle. Acute aminoaciduria was observed in 21 of 23 patients. Chronic nephrotoxicity, as defined by the development of a Fanconi-like syndrome or chronic tubular electrolyte loss requiring oral supplementation, developed in the three patients with the highest urinary excretion of beta 2-microglobulin after ifosfamide therapy. CONCLUSIONS: Prospectively, high dose ifosfamide was associated with a 4% incidence of Fanconi-like syndrome; however, evidence of acute reversible subclinical nephrotoxicity was observed for all patients. Severe beta 2-microglobulinuria appeared to be a prognostic laboratory indicator for the development of chronic nephrotoxicity.

Monotherapy for fever and neutropenia in cancer patients: a randomized comparison of ceftazidime versus imipenem.

PURPOSE: To compare the efficacy of ceftazidime and imipenem monotherapy for fever and neutropenia, and to determine whether fewer antimicrobial modifications (additions or changes) are required by the broader-spectrum agent, imipenem. PATIENTS AND METHODS: Adult and pediatric patients undergoing chemotherapy for solid tumors, leukemias, or lymphomas were randomized to receive open-label ceftazidime or imipenem on presentation with fever and neutropenia. Success with or without modifications of the initial antibiotic was defined as survival through neutropenia; failure was death due to infection. Comparisons were based on numbers of modifications made to each monotherapy during the course of neutropenia, in patients stratified as having unexplained fever or a documented infection. RESULTS: Among 204 ceftazidime and 195 imipenem recipients, the overall success rate with or without modification was more than 98%, regardless of initial antibiotic regimen. Modifications occurred in half of all episodes, primarily in patients with documented infections on either monotherapy. Antianaerobic agents were more frequently added to ceftazidime (P < .001), but addition of other antibiotics, including vancomycin and aminoglycosides, was similar between the two monotherapy groups. Imipenem therapy was associated with significantly greater toxicity, manifested by Clostridium difficile-associated diarrhea and by nausea and vomiting, which required discontinuation of imipenem in 10% of recipients. CONCLUSION: Ceftazidime and imipenem are both effective in the management of fever and chemotherapy-related neutropenia, provided that modifications are made in response to clinical and microbiologic data that emerge during the course of neutropenia. Imipenem, despite its broader antimicrobial spectrum, does not significantly decrease the overall need for antibiotic modifications and is more often complicated by gastrointestinal toxicity.

Clinical and pharmacokinetic evaluation of long-term therapy with didanosine in children with HIV infection.

BACKGROUND: Didanosine has demonstrated promising antiviral activity and a tolerable toxicity profile in short term studies. We describe a cohort of HIV-infected children who were treated for a prolonged period of time with didanosine. METHODS: Children (6 months to 18 years of age) with symptomatic HIV infection or an absolute CD4 count < 0.5 x 10(9) cells/L, received oral didanosine at doses between 20 mg/m2 to 180 mg/m2 every 8 hours. Clinical, immunological, and virological parameters were assessed at least every 2 months. The pharmacokinetics of didanosine were evaluated in 85 patients. RESULTS: Previously untreated children (n = 51) and children who had received prior antiretroviral therapy (n = 52) were enrolled in the study (median time on study 22.6 months; range 2 to 48). The long-term administration of didanosine was well tolerated and no new toxicities were observed. The absolute CD4 count increased by > or = .05 x 10(9) cells/L in 28 of 87 (32%) of patients after 6 months of therapy. Responses were also sustained in 41% of these children after 3 years of therapy. Children entering the study with a CD4 count > 0.1 x 10(9) cells/L (n = 51) had a marked survival advantage (P = .00002) with an estimated survival probability after 3 years of 80% compared to 39% for children with lower CD4 counts. Although the area under the curve of didanosine increased proportionally with the dose, there was considerable interpatient variability at each dose level. There was no apparent relationship between surrogate markers of clinical outcome and plasma drug concentration. CONCLUSIONS: Didanosine was well tolerated with chronic administration, and toxicities were uncommon and usually reversible. In 41% of patients, the CD4 count increased and was maintained at the higher level even after years of treatment.

Phase I study of continuous-infusion soluble CD4 as a single agent and in combination with oral dideoxyinosine therapy in children with symptomatic human immunodeficiency virus infection.

To determine the safety and pharmacokinetics of recombinant soluble CD4 (sCD4) administered by continuous intravenous infusion to children with symptomatic human immunodeficiency virus type 1 infection, we conducted a phase I study at the National Cancer Institute. Three dose levels of sCD4 were evaluated: 100, 300, and 1000 micrograms/kg per day. After an initial 12 weeks of treatment with sCD4 alone, dideoxyinosine at a dose of 90 mg/m2 every 8 hours was added and subjects were observed for an additional 12 weeks. Combination therapy was continued in patients in whom it was well tolerated. In addition to toxicity and pharmacokinetic monitoring, surrogate markers of antiviral activity were evaluated. Eleven children were enrolled in the study. During the 12 weeks of treatment with sCD4 alone, and during subsequent sCD4 plus dideoxyinosine combination therapy, no significant toxic reaction attributable to sCD4 or dideoxyinosine was encountered. Low-level anti-CD4 antibodies developed in two patients. Steady-state sCD4 levels increased proportionately at higher doses. The CD4 cell counts and serum p24 antigen levels did not provide evidence of antiviral activity. We conclude that sCD4 was well tolerated at doses up to 1000 micrograms/kg per day when administered by continuous intravenous infusion; however, evidence of in vivo antiviral activity was not observed in this study.

Treatment of aggressive cytomegalovirus retinitis with ganciclovir in combination with foscarnet in a child infected with human immunodeficiency virus.

Ganciclovir and foscarnet are both effective for cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome, but the benefits of either agent given alone are limited. A child infected with human immunodeficiency virus who had cytomegalovirus retinitis that progressed despite treatment with either agent alone received the combination of ganciclovir and foscarnet. This treatment resulted in a sustained clinical response.

Clinical pharmacology of 2',3'-dideoxyinosine in human immunodeficiency virus-infected children.

The pharmacokinetics of intravenous and oral 2',3'-dideoxyinosine (ddI) and the relationships between pharmacokinetic parameters and measures of response were studied in 48 human immunodeficiency virus-infected children. Disappearance of ddI from plasma after the intravenous dose was rapid and biexponential, with half-lives of 12 min and 1.0 h and a total clearance of 510 +/- 180 ml/min/m2. After oral administration, ddI absorption was limited and variable (mean bioavailability, 19% +/- 17%). A plasma ddI concentration-response relationship was observed for both decline in viral p24 antigen levels and improvement in intelligence quotient score. A limited sampling model was developed that accurately predicts the area under the ddI plasma concentration-time curve from one to three plasma samples. Although this pharmacokinetic study was done in children, the results also have relevance to adults and suggest that individualization of dose and schedule through therapeutic drug monitoring may be necessary to achieve optimal response.

Stability of zidovudine in 5% dextrose injection and 0.9% sodium chloride injection.

The stability of zidovudine at a concentration of 4 mg/mL in 5% dextrose injection and 0.9% sodium chloride injection in polyvinyl chloride infusion bags stored at room and refrigerated temperatures for up to eight days was studied. Zidovudine was diluted in 5% dextrose injection and in 0.9% sodium chloride injection to a concentration of 4 mg/mL. Six admixtures were prepared with each diluent; three were stored at room temperature (25 +/- 1 degree C) and three were refrigerated (4 +/- 1 degree C). At 0, 3, 6, 24, 48, 72, and 192 hours, 2-mL aliquots were removed. One milliliter of each aliquot was diluted to a zidovudine concentration of approximately 40 micrograms/mL and assayed in duplicate by a stability-indicating high-performance liquid chromatographic method. Visual inspection was performed at each sampling time for precipitation, turbidity, color change, and gas formation. Sample pH was recorded at 0 and 192 hours. In all admixtures, more than 97% of the initial zidovudine concentration remained throughout the study period. No visual or pH changes were observed. Zidovudine 4 mg/mL in admixtures with 5% dextrose injection or 0.9% sodium chloride injection stored in polyvinyl chloride infusion bags was stable for up to 192 hours (eight days) at room temperature and under refrigeration.

Dideoxyinosine in children with symptomatic human immunodeficiency virus infection.

BACKGROUND: 2',3'-Dideoxyinosine (ddl) is a dideoxynucleoside with potent activity in vitro against the human immunodeficiency virus (HIV). In initial clinical trials in adults, ddl showed evidence of antiretroviral activity with little hematologic toxicity. METHODS: We conducted a phase I-II study in 43 children with symptomatic (CDC class P-2) HIV infection. Of these children, 16 (median age, 10 years) had previously received zidovudine, and 27 (median age, 2.6 years) had not. ddl was administered orally in three divided doses totalling 60, 120, 180, 360, or 540 mg per square meter of body-surface area per day for 24 weeks. Eight of the 43 patients did not complete 24 weeks of ddl: 6 died, 1 was withdrawn because of progressive disease, and the other because of toxicity. RESULTS: After oral administration, ddl was rapidly absorbed, although its bioavailability varied greatly among patients. Pancreatitis developed in two children, one receiving ddl at each of the two highest doses. The median CD4 cell count in 38 patients with paired counts increased from 0.218 x 10(9) per liter (218 per cubic millimeter) at base line to 0.327 x 10(9) per liter (327 per cubic millimeter) after 20 to 24 weeks (P = 0.001). Those with CD4 cell counts above 0.1 x 10(9) per liter (100 per cubic millimeter) at base line were significantly more likely to improve in this respect. The median levels of p24 antigen (in 27 patients with detectable levels at entry) declined from 272 pg per milliliter at base line to 77 pg per milliliter at 20 to 24 weeks (P = 0.005). The plasma concentration of ddl correlated significantly with both the degree of decline in the p24 antigen and the degree of improvement in IQ score. Improvement in clinical and immunologic measures occurred in both the previously untreated patients and in those who had been treated with zidovudine. CONCLUSIONS: Dideoxyinosine was well tolerated and showed promising antiretroviral activity in HIV-infected children. The correlation between the clinical response and the plasma concentration of ddl indicates that bioavailability is an important consideration in the use of ddl to treat HIV infection and that individualized pharmacokinetic monitoring and dose adjustment may be important for optimal activity.

Dideoxycytidine alone and in an alternating schedule with zidovudine in children with symptomatic human immunodeficiency virus infection.

OBJECTIVE: To determine whether a short course of 2',3'-dideoxycytidine (ddC) could provide safe antiretroviral activity in children with symptomatic human immunodeficiency virus infection and whether it could be used with azidothymidine (AZT, zidovudine). The goal was to maintain uninterrupted antiretroviral therapy while sparing AZT-related myelosuppression and ddC-related neuropathy. METHODS: In a pilot study, we evaluated four dosage levels of ddC--0.015, 0.02, 0.03, and 0.04 mg/kg, given orally every 6 hours--in 15 children between 6 months and 13 years of age with Centers for Disease Control P2 (i.e., symptomatic) human immunodeficiency virus infection. Thirteen patients had not had any prior antiretroviral therapy; two patients had received and benefited from AZT, but dose-limiting neutropenia had developed. At each dosage level, ddC was given for 8 consecutive weeks and then stopped. After a 30-day rest, a schedule of ddC for 1 week was followed by 3 weeks of AZT therapy (180 mg/m2 every 6 hours); this alternating schedule was repeated for as long as tolerated. Age-appropriate psychometric testing was performed before the start of ddC therapy and after 8 weeks. RESULTS: During the 8 weeks of therapy with ddC alone, no neutropenia or anemia was observed; 6 of 9 patients had decreases in p24 antigen levels, and 8 of 15 had an increased CD4 cell count. At the 0.04 mg/kg level, a rash developed in three patients; mild mouth sores developed in 9 of 15 patients. On the alternating ddC/AZT schedule, no neuropathy was observed. CONCLUSIONS: 2',3'-Dideoxycytidine has antiretroviral activity in some children and appears to be safe for short intervals. Longer courses of ddC at lower dosage levels, and schedules integrating ddC into combination regimens, deserve to be explored.