Supportive care during aldesleukin therapy for patients infected with human immunodeficiency virus.
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Acetaminophen↗
Biomedical subjects
S C Piscitelli
Publications and source records attributed to S C Piscitelli.
Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons.
The safety and efficacy were assessed of 5-day cycles of subcutaneous (sc) interleukin-2 (IL-2) every 8 weeks in human immunodeficiency virus type 1-infected outpatients with >200 CD4 cells/mm3. Immunologic, virologic, and toxicity parameters were measured in 18 patients receiving standard antiretrovirals plus 5-day courses of sc IL-2 (3-18 MIU/day) every 2 months. Systemic toxicities established the maximally tolerated dose (MTD) of IL-2 as 15 MIU/day. CD4 cell responses appeared to correlate directly with baseline CD4 cell counts, with several patients experiencing a dramatic rise after 3 cycles. Virus load increased only transiently in the peri-injection period. It was concluded that serial cycles of outpatient sc IL-2 can be administered safely, with an MTD of 15 MIU/day. Patients with higher baseline counts appear to have a greater CD4 cell response to sc IL-2 therapy.
Acquired Immunodeficiency Syndrome↗
Single-dose pharmacokinetics of thalidomide in human immunodeficiency virus-infected patients.
The pharmacokinetics of thalidomide in nine human immunodeficiency virus-infected patients were studied. Single doses of thalidomide were well absorbed, with mean peak concentrations (+/- standard deviations) of 1.17 +/- 0.21 and 3.47 +/- 1.14 microg/ml in the 100- and 300-mg dosing groups, respectively, and the mean elimination half-life was approximately 6 h. Adverse effects were mild, with drowsiness being reported for seven of nine patients.
Adult↗
Clarithromycin lowers plasma zidovudine levels in persons with human immunodeficiency virus infection.
The use of antiretroviral agents and drugs for the treatment and prophylaxis of opportunistic infections has lengthened the survival of persons with AIDS. In the era of multidrug therapy, drug interactions are important considerations in designing effective and tolerable regimens. Clarithromycin has had a significant impact on the treatment of disseminated Mycobacterium avium complex infection, and zidovudine is the best-studied and one of the most widely used antiretroviral agents in this population. We conducted a study to determine the maximally tolerated dose of clarithromycin and the pharmacokinetics of clarithromycin and zidovudine individually and in combination. Mixing studies were conducted to simulate potential interaction in the gastric environment. The simultaneous administration of zidovudine and clarithromycin had little impact on the pharmacokinetics of clarithromycin or of its major metabolite. However, coadministration of zidovudine and clarithromycin at three doses (500 mg orally [p.o.] twice daily [b.i.d.], 1,000 mg p.o. b.i.d., and 2,000 mg p.o. b.i.d.) reduced the maximum concentration of zidovudine by 41% (P < 0.005) and the area under the concentration-time curve from 0 to 4 h for zidovudine by 25% (P < 0.05) and increased the time to maximum concentration of zidovudine by 84% (P < 0.05), compared with zidovudine administered alone. Mixing studies did not detect the formation of insoluble complexes due to chelation, suggesting that the decrease in zidovudine concentrations results from some other mechanism. Simultaneous administration of zidovudine and clarithromycin appears to decrease the levels of zidovudine in serum, and it may be advisable that these drugs not be given at the same time. Drug interactions should be carefully evaluated in persons with advanced human immunodeficiency virus infection who are receiving multiple pharmacologic agents.
Adult↗
Pharmacokinetic studies with recombinant cytokines. Scientific issues and practical considerations.
Advances in molecular biology and recombinant DNA technology have led to the development of cytokines as therapeutic agents for a variety of disease states. The pharmacokinetic analysis of cytokines involves the understanding of analytical methods capable of detecting these agents in biological fluids and recognition of several factors which may have an impact on the cytokine concentration-time curves. Enzyme-linked immunosorbent assays (ELISA) have become the most common method of detection and commercial kits are available for a wide variety of cytokines. Monoclonal antibody products are sensitive, have minimal cross-reactivity and are relatively inexpensive when compared with high performance liquid chromatography (HPLC). However, the primary limitation of these assays is their inability to measure biologically active protein. Conversely, bioassays do measure a biological event (i.e. proliferation or cytotoxicity) but are generally not used for cytokine analysis because of their high cost, long assay completion time, lack of specificity, poor sensitivity and influence of environmental conditions on the outcome. The pharmacokinetic profile of recombinant cytokines is influenced by a number of variables: endogenous production, circulating soluble receptors and cell-associated receptors, immunocompetence and antibody production against the cytokine all may influence the disposition of the agent. Thus, pharmacokinetic modelling of cytokines may involve complex models capable of characterising these nonlinear processes and resulting effects. The route of administration is an important variable since cytokines administered by subcutaneous injection may be partially metabolised by proteases present in the subcutaneous tissue. Other methods to simplify cytokine delivery are being actively investigated and include formulations for inhalation, topical and oral administration. A variety of cytokines (including interferon-alpha, interleukin-6 and tumour necrosis factor) are capable of inhibiting cytochrome P450 hepatic enzymes and, therefore, possess the potential to cause drug-cytokine interactions. Inhibition has been demonstrated in several in vitro systems and animal models, although clinical data are currently limited. An increased understanding of the many factors which can alter the analysis and pharmacokinetics of cytokines is essential to the design of optimal dosage regimens.
Animals↗
Thalidomide in diseases associated with human immunodeficiency virus infection.
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HIV Infections↗
Drug interactions in patients infected with human immunodeficiency virus.
Patients with AIDS who are receiving optimal medical care, including combination therapy with antiretroviral agents and more effective prophylaxis and therapy for opportunistic infections and neoplasms, are surviving longer. However, the potential for drug interactions in these patients is increased because many of the currently used antibiotics and antiviral agents have profound effects on the hepatic cytochrome P-450 enzyme system, on renal tubular function, and on bone marrow function. In this AIDS Commentary, Dr. Piscitelli and colleagues have succinctly reviewed the current state of our knowledge regarding the potential for additive or synergistic drug interactions that can result in enhanced toxicity or, alternatively, augmented therapeutic benefit. Information on these interactions will become more important as more intensive and effective therapy becomes available for persons with far-advanced infection due to human immunodeficiency virus type 1.
Absorption↗
Combination therapy with didanosine and interferon-alpha in human immunodeficiency virus-infected patients: results of a phase I/II trial.
A nonrandomized trial was undertaken to evaluate the combination of didanosine and interferon-alpha (INF-alpha) in human immunodeficiency virus (HIV)-infected patients. Thirty-six volunteers with >200 x 10(6) CD4 cells/L received didanosine (one 100-, 250-, or 375-mg sachet twice daily) for at least 6 weeks, following which IFN-alpha (1, 5, 10, or 15 MU/day) was begun. Didanosine (one 375-mg sachet twice daily) was substituted for zidovudine in 14 additional patients who had received IFN-alpha and zidovudine for 7-45 months. Thirty-five patients completed the 34-week study. Clinical or chemical pancreatitis was the most common (6 patients) dose-limiting toxicity. CD4 cell counts increased with didanosine but declined following the addition of IFN-alpha; CD4 cell percents tended to increase and remain elevated. Thus, combination therapy with didanosine and IFN-alpha can be safely administered to patients with HIV infection. The clinical benefit of this combination therapy will require further evaluation.
Antiviral Agents↗
Inhibition of immunoreactive tumor necrosis factor-alpha by a chimeric antibody in patients infected with human immunodeficiency virus type 1.
Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine known to stimulate human immunodeficiency virus type 1 (HIV-1) replication, has been implicated in the pathogenesis of HIV-1 infection. Inhibition of TNF-alpha by a chimeric humanized monoclonal antibody, cA2, was investigated in 6 HIV-1-infected patients with CD4 cell counts < 200/mm3. Two consecutive infusions of 10 mg/kg 14 days apart were well tolerated, and a prolonged serum half-life for cA2 (mean, 257 +/- 70 h) was demonstrated. Serum immunoreactive TNF-alpha concentrations fell from a mean prestudy value of 6.4 pg/mL (range, 4.2-7.9) to 1.1 pg/mL (range, 0.5-2.2) 24 h after the first infusion and returned to baseline within 7-14 days. A similar response was seen after the second infusion. No consistent changes in CD4 cell counts or plasma HIV RNA levels were observed over 42 days. Future studies evaluating the therapeutic utility of long-term TNF-alpha suppression using anti-TNF-alpha antibodies are feasible and warranted.
Acquired Immunodeficiency Syndrome↗
Effects of cytokines on antiviral pharmacokinetics: an alternative approach to assessment of drug interactions using bioequivalence guidelines.
The effects of cytokines on the pharmacokinetics of nucleoside analogs were evaluated in two separate studies using zidovudine in combination with interleukin-2 and didanosine in combination with alpha interferon. In each study, drug interactions were evaluated by using both a standard method (Student's t test) and bioequivalence testing. Serial blood samples were collected from human immunodeficiency virus-infected patients prior to and during cytokine therapy for determination of nucleoside analog concentrations. Concentrations were fit separately to a two-compartment model by using the iterative two-stage approach to population analysis. No alterations in area under the curve or oral clearance were observed for either drug during combination therapy. In general, there was good agreement between statistical methods for determining if antiviral pharmacokinetic parameters were altered by concomitant cytokine therapy. However, large individual changes in the maximum concentration of zidovudine in serum were detected by bioequivalence testing but no difference was found by Student's t test. For didanosine, significant but clinically irrelevant decreases determined by standard hypothesis testing were seen for both the volume of the central compartment (1.91 to 1.86 liters) and the absorption rate constant (0.79 to 0.73 h-1) in the presence of alpha interferon. No interaction was noted for these parameters by using bioequivalence guidelines. Bioequivalence testing may provide an alternative approach to assessment of drug interactions. Interleukin-2 and alpha interferon do not alter the pharmacokinetics of zidovudine and didanosine, respectively.
Adult↗
Immune-based therapies for treatment of HIV infection.
OBJECTIVE: To review the in vitro, animal, and clinical data on immune-based therapies for treatment of HIV infection. DATA SOURCES: An extensive MEDLINE search was performed for interleukins, interferons, immunotoxins, tumor necrosis factor (TNF)-directed agents, vaccines, and gene therapy. STUDY SELECTION: In vitro experiments with immune-based agents in cell lines infected with HIV were included. In addition, all human studies and case reports that used these agents in patients infected with HIV were selected. Additional literature included abstracts from international meetings on HIV and AIDS. DATA EXTRACTION: Data regarding activity, efficacy, and toxicity were extracted from in vitro and in vivo studies. When conflicting data were observed, both viewpoints were stated to give an unbiased analysis. Because HIV research involves multiple social, ethical, and scientific issues, perspectives on these problems were addressed, where appropriate. DATA SYNTHESIS: Current antiretroviral therapy is limited to short-term responses and has minimal effect on overall survival. Because the human immune response to HIV infection is effective at keeping the virus suppressed for a number of years, a focus of HIV research has been to examine immune-based therapies for treatment of HIV infection that attempt to augment enhance, or boost the patient's immune system. Interleukins, interferons, immunotoxins, TNF-directed therapies, vaccines, and gene therapy have been studied in patients infected with HIV. Properties shared among these therapeutic modalities include adverse effect profiles, response rates dependent on baseline immunocompetence, the potential to activate viral replication, the need for supportive care, and sensitive laboratory tests required for monitoring. CONCLUSIONS: Immune-based agents represent a new approach to the treatment of HIV infection. Whereas antiretrovirals only inhibit viral replication, these agents are designed to enhance the immune system of the patient. Future attempts to manage HIV infection may combine standard nucleoside analogs with immune-based therapies.
AIDS Vaccines↗
Compatibility and activity of aldesleukin (recombinant interleukin-2) in presence of selected drugs during simulated Y-site administration: evaluation of three methods.
The compatibility and biological activity of aldesleukin (a form of recombinant interleukin-2) in the presence of selected i.v. drugs during simulated Y-site administration was studied. Five milliliters of aldesleukin 33,800 IU/mL in 5% dextrose injection was mixed in glass test tubes with 5 mL of each of 19 i.v. drugs prepared at concentrations used in routine clinical practice. The compatibility of the combinations was assessed by visual examination and spectrophotometry at 0, 0.5, 1, and 2 hours after preparation, and bioassays were conducted to determine the activity of aldesleukin in the combinations. Lorazepam was the only drug visually incompatible with aldesleukin. All the secondary drugs were spectrophotometrically compatible with aldesleukin. However, the bioassays showed that the following drugs reduced the activity of aldesleukin: ganciclovir sodium, lorazepam, pentamidine isethionate, prochlorperazine edisylate, and promethazine hydrochloride. Thus, aldesleukin became less biologically active when combined with four drugs for which visual examination suggested compatibility and when combined with five drugs for which spectrophotometry indicated compatibility. Aldesleukin 33,800 IU/mL in 5% dextrose injection lost significant biological activity in the presence of prochlorperazine edisylate, promethazine hydrochloride, lorazepam, ganciclovir sodium, and pentamidine isethionate during simulated Y-site administration. Visual assessment and spectrophotometry may not be valid methods for assessing possible changes in the biological activity of aldesleukin when combined with other agents.
Anti-Infective Agents↗
Role of interleukin-2 in managing infection with the human immunodeficiency virus.
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CD4 Lymphocyte Count↗
Disposition of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine.
Phenylacetate, an inducer of tumor cytostasis and differentiation, shows promise as a relatively nontoxic antineoplastic agent. Phenylacetate, however, has an unpleasant odor that might limit patient acceptability. Phenylbutyrate, an odorless compound that also has activity in tumor models, is known to undergo rapid conversion to phenylacetate by beta-oxidation in vivo. This phase I study examined the pharmacokinetics of phenylbutyrate and characterized the disposition of the two metabolites, phenylacetate and phenylacetylglutamine. Fourteen patients with cancer (aged 51.8 +/- 13.8 years) received a 30-minute infusion of phenylbutyrate at 3 dose levels (600, 1200, and 2000 mg/m2). Serial blood samples and 24-hour urine collections were obtained. Samples were assayed by high-performance liquid chromatography. A model to simultaneously describe the pharmacokinetics of all three compounds was developed using ADAPT II. Data were modeled as molar equivalents. The model fit the data well as shown by mean (+/- SD) coefficients of determination (r2) for phenylbutyrate, phenylacetate, and phenylacetylglutamine, which were 0.96 +/- 0.07, 0.88 +/- 0.10, and 0.92 +/- 0.06, respectively. The intrapatient coefficient of variation percentage (CV%) around the parameter estimates were small (range 7.2-33.5%). Phenylbutyrate achieved peak concentrations in the range of in vitro tumor activity (500-2000 mumol/L) and exhibited saturable elimination (Km = 34.1 +/- 18.1 micrograms/mL and Vmax = 18.1 +/- 18 mg/h/kg). Metabolism was rapid; the times to maximum concentration for phenylacetate and phenylacetylglutamine were 1 and 2 hours, respectively. The conversion of phenylbutyrate to phenylacetate was extensive (80 +/- 12.6%), but serum concentrations of phenylacetate were low owing to rapid, subsequent conversion to phenylacetylglutamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Pharmacokinetics of orally administered carboxyamido-triazole, an inhibitor of calcium-mediated signal transduction.
Carboxyamido-triazole (CAI), inhibits proliferation, invasion, and metastatic potential of a number of cancer cell lines at concentrations greater than 0.4 microgram/ml. The objective of this study was to characterize the pharmacokinetic profile from the first Phase I clinical trial of CAI for the single test dose and multiple daily dosing schedule. Two different p.o. formulations (liquid and gelcap) of CAI were administered. Thirty-nine patients with cancer were enrolled. The dose escalation schema was 100, 125, and 150 mg/m2/day and 200 and 330 mg/m2 every other day of the liquid formulation, plus 100 and 125 mg/m2/day and 200 mg/m2 every other day of the gelcap. The CAI pharmacokinetics are best described by a two-compartment open linear model. The gelcap was more rapidly absorbed than the liquid [time to maximum plasma concentration (Tmax) = 2.06 +/- 1.02 versus 5.31 +/- 3.59 h, P2 = 0.0012] which resulted in higher peak plasma concentrations. There was no evidence of saturable elimination as the dose was increased. The mean steady-state peak concentration was 5.1 +/- 1.0 microgram/ml for the 150 mg/m2/day multiple daily dosing regimen. The terminal half-life of CAI was relatively prolonged, 111 h, and the total body p.o. clearance was low (1.87 liters/h). The peak concentration for all dose levels explored was greater than the targeted concentration suggested by in vitro data for activity. Thus, these data suggest that an effective cytostatic exposure of CAI may be obtained with daily or every other day dosing without severe toxicity.
Administration, Oral↗
The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer.
BACKGROUND: The authors compared the pharmacokinetics of doxorubicin when administered with and without concomitant high dose cyclosporine for multidrug resistant (MDR) tumor modulation in small cell lung cancer. METHODS: Eight patients with small cell lung cancer served as their own controls and were studied first during an initial course of doxorubicin without cyclosporine, and then subsequently during a cyclosporine-modulated doxorubicin course. All patients received cyclophosphamide and vincristine in each course. Doxorubicin was administered as a 1-hour infusion after a 2-hour cyclosporine loading infusion, and cyclosporine was infused continuously for the next 48 hours. Serum concentrations of doxorubicin, doxorubicinol, and cyclosporine all were assayed by high-pressure liquid chromatography. Pharmacokinetic analysis of doxorubicin included area under the curve (AUC), clearance, apparent volume of distribution at steady state (Vss), and elimination half-life (T1/2). The percent of change and surviving fraction of leukocyte count and platelets were determined as pharmacodynamic indices. RESULTS: Cyclosporine modulation increased the AUC0-36 of doxorubicin by 48% (P = 0.042) and the AUC0-36 of doxorubicinol by 443% (P = 0.0001), whereas the doxorubicin clearance declined by 37% (P = 0.0495). No difference was found in the Vss or T1/2 for doxorubicin when cyclosporine was added to the regimen. The ratio of the doxorubicinol AUC0-36 to the doxorubicin AUC0-36 increased significantly with cyclosporine modulation (8.88 vs. 2.19; P = 0.001). Drug-related toxicity was also greater with the cyclosporine-modulated course of doxorubicin. A 91% reduction in the leukocyte count followed the modified course, compared with an 84% reduction following the initial course (P = 0.0074). A more prolonged and greater degree of myelosuppression was observed and a significant relationship was found between the systemic exposure to doxorubicin (defined by AUC) and the surviving fraction of the leukocyte count (r = -0.69; P = 0.006). Similarly, the reduction in the platelet count was significantly greater after the cyclosporine-modulated course (72.8%) than after the initial course (36.4%) (P = 0.0016). A significant correlation was found between the AUC of doxorubicinol and the surviving fraction of platelets (r = -0.71; P = 0.004). In addition, patients showed decreased performance status associated with significant weight loss and severe myalgias. CONCLUSIONS: The addition of high dose cyclosporine for MDR modulation resulted in the significant alteration of doxorubicin disposition and remarkable toxicity in all patients. The mechanisms responsible for the decreased doxorubicin clearance may include cyclosporine's ability both to interfere with P-glycoprotein in normal tissues and to selectively inhibit the cytochrome P-450 enzyme system. Further study of this potentially significant drug-drug interaction is warranted.
Antineoplastic Combined Chemotherapy Protocols↗
Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma.
Itraconazole and amphotericin B were compared by using a newly developed model of invasive pulmonary aspergillosis in rabbits immunosuppressed with methylprednisolone and cyclosporin A (CsA). Both itraconazole at 40 mg/kg (given orally) and amphotericin B at 1 mg/kg (given intravenously) had in vivo antifungal activity in comparison with controls. At these dosages, amphotericin B was more effective than itraconazole in reducing the tissue burden (log10 CFU per gram) of Aspergillus fumigatus (P < 0.05) and the number of pulmonary lesions (P < 0.01). However, there was considerable variation in the near-peak concentrations of itraconazole in plasma (median, 4.15 micrograms/ml; range, < 0.5 to 16.8 micrograms/ml) and a strong inverse correlation between concentrations of itraconazole in plasma and the tissue burden of A. fumigatus. An inhibitory sigmoid maximum-effect model predicted a significant pharmacodynamic relationship (r = 0.87, P < 0.001) between itraconazole concentrations in plasma and antifungal activity as a function of the tissue burden of A. fumigatus. This model demonstrated that levels in plasma of greater than 6 micrograms/ml were associated with a significantly greater antifungal effect. Levels in plasma of less than 6 micrograms/ml were associated with a rapid decline in the antifungal effect. Itraconazole, in comparison with amphotericin B, caused a twofold elevation of CsA levels (P < 0.01) but was less nephrotoxic (P < 0.01). This study of experimental pulmonary aspergillosis demonstrated that amphotericin B at 1 mg/kg/day was more active but more nephrotoxic than itraconazole at 40 mg/kg/day, that itraconazole increased concentrations of CsA in plasma, and that the antifungal activity of itraconazole strongly correlated with concentrations in plasma in an inhibitory sigmoid maximum-effect model. These findings further indicate the importance of monitoring concentrations of itraconazole in plasma as a guide to increasing dosage, improving bioavailability, and optimizing antifungal efficacy in the treatment of invasive pulmonary aspergillosis.
Amphotericin B↗
In vitro activities of metronidazole and its hydroxy metabolite against Bacteroides spp.
Metronidazole is metabolized to two major oxidative products: an acid metabolite and a hydroxy metabolite. While the activity of the acid metabolite is negligible, the activity of the hydroxy metabolite is approximately 65% of the activity of the parent drug. Pharmacokinetic studies of metronidazole and its hydroxy metabolite have shown that the MICs of both compounds remain above the MICs for most anaerobic organisms over an 8-h dosing interval. By a checkerboard assay, the combined activities of metronidazole and the hydroxy metabolite were examined against 4 quality control strains of Bacteroides species. Macrobroth tube dilutions were set up with Wilkins-Chalgren broth. Serial twofold dilutions of each agent were performed to achieve final concentrations ranging from 0.06 to 4.0 micrograms/ml. The MICs for Bacteroides fragilis and B. distasonis were 1.0 microgram/ml for both parent drug and metabolite. For B. thetaiotamicron and B. ovatus, the MICs of metronidazole and the hydroxy metabolite were 1.0 and 2.0 micrograms/ml, respectively. Synergy was determined by calculating the fractional inhibitory concentration (FIC) index. The interpretative criteria for the FIC index were as follows: synergy, FIC < or = 0.5; partial synergy, 0.51 to 0.75; indifference, FIC 0.76 to 4.0; and antagonism, FIC > 4.0. Partial synergy was observed for the four anaerobes tested, with FIC indices ranging from 0.63 to 0.75. On the basis of this data, in vitro susceptibilities to agents such as metronidazole may ultimately require reevaluation to account for active metabolites.
Bacteroides↗