Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor.

BACKGROUND: GSK1265744 is an HIV integrase strand transfer inhibitor selected for clinical development. OBJECTIVE: This first-time-in-human and phase IIa investigation assessed GSK1265744 antiviral activity, pharmacokinetics, safety, and tolerability in healthy and HIV-1-infected subjects. METHODS: This double-blind, placebo-controlled study consisted of a dose escalation of single (part A) and multiple (part B) oral doses in 48 healthy subjects and an oral dose (part C) in 11 HIV-1-infected subjects. In part A, 2 cohorts of 9 subjects received either 5 and 25 mg or 10 and 50 mg. In part B, 3 cohorts of 10 subjects received 5, 10, or 25 mg once daily for 14 days. In part C and the phase IIa study, subjects received 5 or 30 mg once daily for 10 days. RESULTS: Dose-proportional increases in drug exposure were observed in healthy and HIV-1-infected subjects. In healthy subjects, pharmacokinetic variability was low following single or repeat dosing (coefficient of variation, 13%-34% and 15%-23%, respectively). Mean plasma half-life was 31.5 hours. GSK1265744 monotherapy significantly reduced plasma HIV-1 RNA from baseline to day 11 in HIV-1-infected subjects receiving 5 or 30 mg versus placebo (P < .001); mean decrease was 2.2 to 2.3 log10 copies/mL, respectively. Study drug was generally well tolerated with no clinically relevant trends in laboratory values, vital signs, or electrocardiograms. CONCLUSIONS: GSK1265744 was well tolerated in healthy and HIV-1-infected subjects. Results demonstrate once-daily doses of 5 or 30 mg exceeded minimum target therapeutic concentrations and produced a significant reduction in plasma HIV-1 RNA viral load.

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.

Phase I study of a five-day dose schedule of 4-Ipomeanol in patients with non-small cell lung cancer.

The mammalian pulmonary toxin 4-ipomeanol (IPO) is activated by the cytochrome P450 system in bronchial Clara cells in animals. The resulting metabolites bind rapidly to macromolecules, producing localized cytotoxicity. IPO has in vitro and in vivo antitumor activity in non-small cell lung cancer (NSCLC) and thus was proposed as a lung cancer-specific antitumor agent. We have completed a directed Phase I trial in patients with NSCLC. Forty-four patients (34 men and 10 women) with NSCLC were treated with IPO. All but two patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. They received 91 courses of therapy with i.v. IPO; 82 courses were administered daily for five days, and 9 were single bolus doses. The dose-limiting toxicity of elevated serum transaminases was observed in three of seven patients at 922 mg/m2/day. The maximum tolerated dose was 693 mg/m2/day on 5 consecutive days every 3 weeks. One patient developed grade 4 pulmonary toxicity at 167 mg/m2/day. There was no significant hematological or renal toxicity. No objective antitumor responses were observed. Pharmacokinetic analysis of 39 patients from day 1 of IPO administration showed biexponential elimination with mean half-lives of 8.6 (alpha half-life) and 76 min (beta half-life). There was a linear relationship between the area under the plasma drug concentration-time curve and the dose of IPO. There was no significant difference between the pharmacokinetic parameters measured on day 1 and day 5. Using a 4-day in vitro cytotoxicity assay, two tumor cell lines established from patients treated at 693 mg/m2/day had IC50s of approximately 6 mM, a concentration more than 75-fold higher than the plasma levels measured in these patients. Thus, although the total amount of drug administered per cycle on a daily times five dose schedule is more than 2.5-fold higher than the recommended single daily dose, IPO is unlikely to be a useful drug for patients with lung cancer.

Insulin resistance is associated with impaired cardiac sympathetic innervation in patients with heart failure.

AIMS: Insulin resistance (IR) represents, at the same time, cause and consequence of heart failure (HF) and affects prognosis in HF patients, but pathophysiological mechanisms remain unclear. Hyperinsulinemia, which characterizes IR, enhances sympathetic drive, and it can be hypothesized that IR is associated with impaired cardiac sympathetic innervation in HF. Yet, this hypothesis has never been investigated. Aim of the present observational study was to assess the relationship between IR and cardiac sympathetic innervation in non-diabetic HF patients. METHODS AND RESULTS: One hundred and fifteen patients (87% males; 65 ± 11.3 years) with severe-to-moderate HF (ejection fraction 32.5 ± 9.1%) underwent iodine-123 meta-iodobenzylguanidine ((123)I-MIBG) myocardial scintigraphy to assess sympathetic innervation and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) evaluation to determine the presence of IR. From (123)I-MIBG imaging, early and late heart to mediastinum (H/M) ratios and washout rate were calculated. Seventy-two (63%) patients showed IR and 43 (37%) were non-IR. Early [1.68 (IQR 1.53-1.85) vs. 1.79 (IQR 1.66-1.95); P = 0.05] and late H/M ratio [1.50 (IQR 1.35-1.69) vs. 1.65 (IQR 1.40-1.85); P = 0.020] were significantly reduced in IR compared with non-IR patients. Early and late H/M ratio showed significant inverse correlation with fasting insulinemia and HOMA-IR. CONCLUSION: Cardiac sympathetic innervation is more impaired in patients with IR and HF compared with matched non-IR patients. These findings shed light on the relationship among IR, HF, and cardiac sympathetic nervous system. Additional studies are needed to clarify the pathogenetic relationship between IR and HF.

Lack of effect of St John's Wort on carbamazepine pharmacokinetics in healthy volunteers.

BACKGROUND: St John's Wort is a popular herbal product used by approximately 7% of patients with epilepsy. Previous reports have described reductions in concentrations of CYP3A4 substrates indinavir and cyclosporine (INN, ciclosporin) associated with St John's Wort. OBJECTIVE: Our objective was to determine the effect of St John's Wort on steady state carbamazepine and carbamazepine-10,11-epoxide pharmacokinetics. METHODS AND SUBJECTS: Eight healthy volunteers (5 men; age range, 24-43 years) participated in this unblinded study. Subjects received 100 mg of carbamazepine twice daily for 3 days, 200 mg twice daily for 3 days, and then 400 mg once daily for 14 days. Blood samples were collected before and 1, 2, 4, 6, 8, 10, 12, and 24 hours after the dose on day 21. The subjects then took 300 mg of St John's Wort (0.3% hypericin standardized tablet) 3 times daily with meals and with carbamazepine for 14 days. On day 35, blood sampling was repeated. Plasma samples were analyzed for carbamazepine and carbamazepine-10,11-epoxide with HPLC. We compared carbamazepine and carbamazepine-10,11-epoxide noncompartmental pharmacokinetic parameter values before and after St John's Wort with a paired Student t test. RESULTS: We found no significant differences before or after the administration of St John's Wort in carbamazepine peak concentration (7.2 +/- 1 mg/L before versus 7.6 +/- 1.3 mg/L after), trough concentration (4.8 +/- 0.5 mg/L before versus 4.3 +/- 0.8 mg/L after), area under the plasma concentration-time curve (142.4 +/- 12.9 mg x h/L before versus 143.8 +/- 27.2 mg x h/L after), or oral clearance (2.8 +/- 0.3 L/h before versus 2.9 +/- 0.6 L/h after). Similarly, no differences were found in peak concentration (2 +/- 0.5 mg/L before versus 2.1 +/- 0.4 mg/L after), trough concentration (1.3 +/- 0.3 mg/L before versus 1.4 +/- 0.3 mg/L after), and area under the plasma concentration-time curve (37.5 +/- 7.4 mg x h/L before versus 41.9 +/- 10.3 mg x h/L after) of carbamazepine-10,11-epoxide. CONCLUSIONS: The results suggest that treatment with St John's Wort for 14 days did not further induce the clearance of carbamazepine.

Pharmacokinetics and pharmacodynamics of doxorubicin in patients with small cell lung cancer.

The pharmacokinetics and pharmacodynamics of doxorubicin and its metabolite, doxorubicinol, were studied in 35 adult (mean age, 66 1/2 years) patients with small lung cell cancer after a 1-hour intravenous infusion at a dose ranging from 45 to 72 mg/m2. All patients also received concomitant therapy with cyclophosphamide and vincristine. Serum concentrations were sampled to 48 hours after dosing. Wide interpatient variability was observed for all pharmacokinetic parameters with coefficients of variation for apparent volume of distribution, clearance, and area under the curve (AUC) of 62%, 65%, and 65%, respectively. Four patients with impaired liver function showed a significant (p < 0.05) decrease in clearance (239 versus 666 ml/min/m2) and increases in AUC (4610 versus 1834 ng.hr/ml) and elimination half-life (49.3 versus 25.6 hours) compared with patients with normal hepatic function. A significant relationship was found between systemic exposure of doxorubicin (defined by AUC) and surviving factor of white blood cells (r = 0.57, p = 0.0025). No relationships were noted between doxorubicinol exposure and surviving factor of white blood cells or platelets. These findings show the important relationship between systemic exposure of doxorubicin and the degree of myelosuppression in patients with small cell lung cancer.

Pharmacokinetic modeling of recombinant interleukin-2 in patients with human immunodeficiency virus infection.

A novel model was developed to characterize the time-varying clearance of recombinant interleukin-2 (IL-2). Sixty-eight patients with human immunodeficiency virus infection received 83 cycles of IL-2 either by continuous infusion or by subcutaneous injection for 5 days. IL-2 concentrations after intravenous infusions peaked at 24 hours and then declined by 55% to 78% during the remainder of the infusion. Soluble IL-2 receptors increased greater than 10-fold before gradually returning to baseline. Subcutaneous administration showed a dose-dependent decrease in area under the concentration-time curve (AUC) between days 1 and 5. A model was developed in 9 patients who had IL-2 concentrations and soluble IL-2 receptors determined by ELISA. Concentrations were fitted by an indirect stimulatory pharmacodynamic model. An additional 59 patients with only IL-2 concentrations were fitted to a simplified empiric model. Both models provided an overall r2 of 0.99 for the plot of observed versus fitted concentrations. The time-dependent increase in IL-2 clearance, likely receptor-mediated, was well described with use of an indirect-effects pharmacokinetic-pharmacodynamic model.

Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives.

Metronidazole was first introduced for the treatment of trichomoniasis. Its therapeutic use has subsequently been expanded to include amoebiasis, giardiasis and, more recently, anaerobic infections. Most of the early pharmacokinetic studies employed nonspecific assays such as microbiological and chemical assays. These assays were not able to differentiate the parent drug from the metabolites or other interfering substances. Pharmacokinetic data obtained through the use of specific chromatographic techniques provide the basis for this review of recent pharmacokinetic findings concerning metronidazole and other nitroimidazole antibiotics. When given intravenously or orally at usual recommended doses, metronidazole attains concentrations well above the minimum inhibitory concentrations for most susceptible micro-organisms. The drug has an oral bioavailability approaching 100%. Rectal and vaginal administration results in a smaller amount of drug absorption and lower serum concentrations. Metronidazole has limited plasma protein binding but can attain very favourable tissue distribution, including into the central nervous system. The drug is extensively metabolised by the liver to form 2 primary oxidative metabolites: the hydroxy and acetic acid metabolites. The kidney is responsible for the elimination of only a small amount of the parent drug; however, normal excretion of the 2 metabolites is dependent on the integrity of kidney function. The metabolism of metronidazole was found to vary among patient groups. Preterm and term infants have lower total body clearance (CL) and prolonged elimination half-lives. However, children older than 4 years old were observed to have pharmacokinetic parameters similar to those in adults. Reduced CL was also observed in children who are malnourished. Elderly patients have reduced renal excretion of both the parent drug and hydroxy metabolite. Pharmacokinetic parameters in pregnant patients were not significantly different from those in nonpregnant women; however, the drug is distributed into breastmilk and the infant will be exposed to the drug through the nursing mother. Patients undergoing gastrointestinal surgery or having enteric diseases and those who are hospitalised or critically ill also have altered pharmacokinetics. Metabolism of the drug is reduced in patients with liver dysfunction, giving delayed production of metabolites. In contrast, renal failure has little effect on the elimination of the parent drug, but affects the excretion of the metabolites more significantly. Haemodialysis was found to remove a substantial amount of the metronidazole while the effect of peritoneal dialysis was more limited. Energy and protein deficient diets as well as occupational exposure to gasoline did not alter metronidazole pharmacokinetics. However, the effect of alcohol consumption on metronidazole CL requires further study.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response.

BACKGROUND: Plasma clozapine and haloperidol concentrations were studied in adolescents being treated for childhood-onset schizophrenia. METHOD: Eleven patients (9 boys, 2 girls; mean age = 14.1 +/- 2.1 years) received a 6-week blinded or open trial of clozapine. Five patients also received 6 weeks of blinded or open haloperidol. Doses were increased on an individual basis to a mean 6-week dose of 5.99 +/- 2.6 mg/kg/day for clozapine and 0.24 +/- 0.20 mg/kg/day for haloperidol. The Brief Psychiatric Rating Scale and Bunney Hamburg Rating Scale were completed weekly for each subject. Weekly blood samples were obtained during therapy and assayed by high performance liquid chromatography. RESULTS: The mean clozapine level at Week 6 was 378.3 ng/mL and ranged from 77.5 to 1050 ng/mL. The mean Week 6 haloperidol level was 23.0 ng/mL (range, 6.2-44.3 ng/mL). The clozapine desmethyl and N-oxide metabolites achieved mean concentrations of 77% and 18%, respectively, of those of the parent compound. The mean ratio of haloperidol/reduced haloperidol was 4.48 (range, 0.76-8.76). Clozapine concentrations versus clinical benefit exhibited a consistent linear relationship among patients (correlation range, 0.26-0.96). Conversely, poor and inconsistent correlations between haloperidol concentrations and clinical effects were observed. No relationships were noted between clozapine or haloperidol dose and clinical effects. CONCLUSION: Adolescents with schizophrenia produce a greater amount of desmethylclozapine than previously seen in adults. Plasma clozapine concentrations appear to be related in a linear fashion to clinical improvement.

A risk-benefit assessment of interleukin-2 as an adjunct to antiviral therapy in HIV infection.

Immunomodulation has become a major focus of HIV research in an effort to augment, boost or restore the patient's damaged immune system. Recombinant interleukin-2 is currently being studied in phase II/III trials in HIV-infected patients. Several clinical studies have demonstrated that intermittent regimens are associated with marked rises in CD4+ cell counts without an increase in viral load. Most of these studies employ 5 consecutive days of interleukin-2 therapy by continuous intravenous infusion or subcutaneous injection, repeated every 8 weeks. An alternative strategy is the daily administration of low doses of interleukin-2, but clinical experience with this regimen is limited. Interleukin-2 administration can adversely affect virtually every organ system, requiring aggressive supportive care. A variety of administration strategies and interventions are being evaluated to minimise toxicity. Currently, no clinical end-point data are available for interleukin-2 in HIV-infected patients. Until phase III studies are completed, interleukin-2 can be used in the research setting as an immunomodulator and adjunct to antiretroviral therapy. Its potential to activate latently infected cells and promote HIV eradication from reservoir sites is also an important area for further study. If clinical benefit can be demonstrated, interleukin-2 could be useful as an adjunct to antiretroviral therapy if adverse effects can be minimised and therapy can be given infrequently on an outpatient basis.

The disposition of doxorubicin on repeated dosing.

Twelve cancer patients (aged 49-74 years) receiving doxorubicin (66 +/- 8 mg/m2) as a 1-hour intravenous infusion had serial serum samples (0-48 hours) obtained after the first and second courses of therapy. Mean number of days between courses was 24.3, and all patients had normal liver function. Patients received the same concomitant antineoplastic agents and doses in both courses. Doxorubicin and doxorubicinol concentrations were assayed by high-performance liquid chromatography and fitted to a two- or three-compartment infusion model. White blood cell and platelet toxicity were evaluated as (initial--nadir/initial)* 100. Differences in pharmacokinetic parameters were determined by a paired t test. Wide intrapatient and interpatient variability was seen between therapeutic courses. A significant decrease in the apparent volume of distribution of the central compartment (Vc = 16.6 versus 10.4 L/m2; P < .05), and a nonsignificant decrease in clearance (CL = 748 versus 658 mL/min/m2) was observed on the second course of therapy. Doxorubicinol area under the curve and elimination half-life were similar between courses. Extensive chemotherapy-induced changes in white blood cell and platelet counts were observed but were similar in degree for courses 1 and 2. These data suggest that higher initial doxorubicin concentrations on the second course of therapy are secondary to an alteration in distribution volume (Vc). In this subset of patients, however, these changes were not associated with an increase in hematologic toxicity.

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)

Drug-cytokine interactions: mechanisms and clinical implications.

The potential for certain cytokines to alter cytochrome P450-mediated drug metabolism was first described over 20 years ago. Since that time, a number of in vitro studies in a variety of models have confirmed those observations and evaluated the possible mechanisms. Although the actual mechanism(s) remains unknown, several potential theories have been proposed, including the inhibition of mRNA transcription, increased haem oxygenase activity, increased xanthine oxidase activity and the induction of killer cells cytotoxic to liver cells containing cytochrome P450. Clinical data regarding drug-cytokine interactions are currently limited to the results of studies with small patient numbers and case reports. In addition, the results of different reports are often conflicting. Some clinical studies have reported associations between exogenous or endogenous cytokines and alterations in concomitantly administered drugs, whereas others have reported a lack of effect. Differences in cytokine dosages, route of administration, time course of therapy, sample collection times and patient variability are all likely to account for the varied results. In this rapidly expanding field, additional research will better define the mechanisms of these interactions and their clinical implications.

Candidal urinary tract infections: a comprehensive review of their diagnosis and management.

Despite its prevalence, the significance of candiduria remains uncertain. The pathogenesis of candidal urinary tract infections has been relatively well characterized and many risk factors have been identified. The disorders lack consistent diagnostic criteria, however, such as the presence of pyuria or a colony count above which is predicative of presence, location, or severity of infection. Treatment is unclear due to lack of data defining the natural progression of the disease. Although often recommended, it may not always be possible to remove risk factors. Amphotericin B, fluconazole, 5-flucytosine, and other antifungal agents are important agents for managing candidal urinary tract infections.

Antifungal pharmacodynamics: concentration-effect relationships in vitro and in vivo.

The pharmacodynamics of antifungal compounds involve relationships among drug concentrations, time, and antimicrobial effects in vitro and in vivo. Beyond better understanding of a drug's mode of action, characterization of these relationships has important implications for setting susceptibility breakpoints, establishing rational dosing regimens, and facilitating drug development. Important advances have been made in the experimental investigation of pharmacokinetics and pharmacodynamics of antifungal drugs; however, much remains to be learned about specific pathogens and specific sites of infection. Increased incorporation of pharmacokinetic and pharmacodynamic principles in experimental and clinical studies with antifungal agents is an important objective that will benefit the treatment and prophylaxis of life-threatening invasive fungal infections in immunocompromised patients.

Development of resistance during antimicrobial therapy: a review of antibiotic classes and patient characteristics in 173 studies.

The incidence of emergent resistance and clinical factors affecting its development were evaluated by retrospective review of 173 studies encompassing over 14,000 patients. Eight antibiotic classes and 225 individual treatment regimens were evaluated. Emergent resistance occurred among 4.0% of all organisms and 5.6% of all infections treated. It appeared to be significantly more frequent with penicillin and aminoglycoside monotherapy, with significantly lower rates associated with imipenem-cilastatin, aztreonam, and combination therapy. Clinical failure also appeared to be significantly more likely to occur after emergence of resistance among organisms treated with fluoroquinolones or aminoglycosides. Infections associated with higher resistance rates were cystic fibrosis, osteomyelitis, and lower respiratory tract infections. Resistance was most common in patients in intensive care units or receiving mechanical ventilation. It was also significantly frequent among studies performed in university or teaching hospitals. Organisms associated with high resistance rates were Pseudomonas aeruginosa, Serratia, Enterobacter, and Acinetobacter sp. Factors such as infection type, underlying diseases, type of institution, and specific pathogens warrant consideration when examining emergent resistance.

The effect of ritonavir on the pharmacokinetics of meperidine and normeperidine.

STUDY OBJECTIVE: To determine the effects of ritonavir on the pharmacokinetics of meperidine and normeperidine. DESIGN: Open-label, crossover, pharmacokinetic study. SETTING: United States government research hospital. SUBJECTS: Eight healthy volunteers who tested negative for the human immunodeficiency virus. INTERVENTION: Subjects received oral meperidine 50 mg and had serial blood samples collected for 48 hours. They then received ritonavir 500 mg twice/day for 10 days, followed by administration of a second 50-mg meperidine dose and collection of serial samples. MEASUREMENTS AND MAIN RESULTS: Plasma samples were assayed for meperidine, normeperidine, and ritonavir. Meperidine's area under the curve (AUC) decreased in all subjects by a mean of 67+/-4% in the presence of ritonavir (p<0.005). Mean +/- SD maximum concentration was decreased from 126+/-47 to 51+/-21 ng/ml. Normeperidine's mean AUC was increased 47%, suggesting induction of hepatic metabolism. CONCLUSION: Meperidine's AUC is significantly reduced, not increased, by concomitant ritonavir. Based on these findings, the risk of narcotic-related adverse effects from this combination appears to be minimal. However, increased concentrations of normeperidine suggest a potential for toxicity with increased dosages or long-term therapy.

Pharmacometric analysis of the effect of furosemide on suramin pharmacokinetics.

STUDY OBJECTIVE: To characterize the effects of furosemide on the pharmacokinetics of suramin, a renally eliminated investigational antineoplastic agent. DESIGN: Retrospective population pharmacokinetic analysis. SETTING: Government biomedical research facility. PATIENTS: Twenty-six men with hormone-refractory prostate cancer and one with adrenocortical carcinoma. INTERVENTIONS: Patients received suramin by continuous or intermittent infusion with and without concomitant furosemide. MEASUREMENTS AND MAIN RESULTS: Optimum suramin regimens were achieved by adaptive feedback control, and pharmacokinetic data were collected both in the presence and absence of furosemide. Suramin concentrations were determined by high-performance liquid chromatography (coefficient of variation < 8%). Suramin concentrations were fit to a three-compartment linear model with six coefficients and two rate inputs, which allowed furosemide to affect suramin pharmacokinetics. Individual and population parameter estimates were determined using the iterative two-stage approach. Concomitant furosemide was associated with a median decrease in total body clearance of suramin by 36% (range 0-63%, p < 0.0001). No other parameter was significantly altered, and there was no trend for change in any pharmacokinetic value with time. Suramin plasma concentrations were simulated with and without prolonged furosemide therapy in 26 patients for 12 weeks. The average suramin concentration increased by greater than 33% in 12 patients; 2 patients had a greater than 67% increase in this extreme case model. CONCLUSION: Coadministration of furosemide with suramin can cause an increase in suramin concentrations; however, due to suramin's long half-life, its rate of accumulation is very slow. Nonetheless, in individuals receiving suramin by nonadaptive control, appropriate precautions should be taken when prolonged furosemide therapy is begun.

Pharmacokinetics and pharmacodynamics of subcutaneous interleukin-2 in HIV-infected patients.

STUDY OBJECTIVES: To assess the pharmacokinetics and pharmacodynamics of subcutaneously administered interleukin-2 (IL-2) in patients infected with the human immunodeficiency virus (HIV). DESIGN: Open, dose-escalating phase I clinical trial. SETTING: Government research hospital. PATIENTS: Eighteen patients infected with HIV. INTERVENTIONS: Recombinant IL-2 at dosages of 12, 15, or 18 MIU/day was administered subcutaneously once or twice/day for 5 consecutive days every 2 months. A total of 28 cycles of therapy were included in the analysis. MEASUREMENTS AND MAIN RESULTS: Concentrations of IL-2 in serum were determined by a commercial enzyme-linked immunosorbent assay. Interleukin-2 was well absorbed, with peak concentrations from 21.9-112.9 IU/ml. Absorption was slow, with mean (+/- SD) time to maximum of 4.4 +/- 1.8 hours and a lag time of 26.9 +/- 13.7 minutes. Elimination half-life was 3.3 +/- 0.9 hours. The concentrations had wide variability both within and among patients. Levels of tumor necrosis factor-alpha were increased. Maximum body temperature and systemic side effects were associated with peak serum levels. CONCLUSION: Interleukin-2 is well absorbed after subcutaneous injection in HIV-infected patients, and that route of administration is an alternative to intravenous infusions.