A Pharmacometric Framework for Axitinib Exposure, Efficacy, and Safety in Metastatic Renal Cell Carcinoma Patients.

The relationships between exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble VEGF receptors (sVEGFR)-1, -2, -3, and soluble stem cell factor receptor (sKIT)), tumor sum of longest diameters (SLD), diastolic blood pressure (dBP), and overall survival (OS) were investigated in a modeling framework. The dataset included 64 metastatic renal cell carcinoma patients (mRCC) treated with oral axitinib. Biomarker timecourses were described by indirect response (IDR) models where axitinib inhibits sVEGFR-1, -2, and -3 production, and VEGF degradation. No effect was identified on sKIT. A tumor model using sVEGFR-3 dynamics as driver predicted SLD data well. An IDR model, with axitinib exposure stimulating the response, characterized dBP increase. In a time-to-event model the SLD timecourse predicted OS better than exposure, biomarker- or dBP-related metrics. This type of framework can be used to relate pharmacokinetics, efficacy, and safety to long-term clinical outcome in mRCC patients treated with VEGFR inhibitors. (ClinicalTrial.gov identifier NCT00569946.).

PK-PD modeling of individual lesion FDG-PET response to predict overall survival in patients with sunitinib-treated gastrointestinal stromal tumor.

Pharmacometric models were developed to characterize the relationships between lesion-level tumor metabolic activity, as assessed by the maximum standardized uptake value (SUVmax) obtained on [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), tumor size, and overall survival (OS) in 66 patients with gastrointestinal stromal tumor (GIST) treated with intermittent sunitinib. An indirect response model in which sunitinib stimulates tumor loss best described the typically rapid decrease in SUVmax during on-treatment periods and the recovery during off-treatment periods. Substantial interindividual and interlesion variability were identified in SUVmax baseline and drug sensitivity. A parametric time-to-event model identified the relative change in SUVmax at one week for the lesion with the most pronounced response as a better predictor of OS than tumor size. Based on the proposed modeling framework, early changes in FDG-PET response may serve as predictor for long-term outcome in sunitinib-treated GIST.

Clinical Trial Simulations From a Model-Based Meta-Analysis of Studies in Patients With Advanced Hepatocellular Carcinoma Receiving Antiangiogenic Therapy.

A mixed effect model describing median overall survival (mOS) in patients with advanced hepatocellular carcinoma (aHCC) treated with antiangiogenic therapy (AAT) was developed from literature data. Data were extracted from 59 studies, representing 4,813 patients. The final model included estimates of mOS after AAT (8.5 months) or placebo (7.1 months) administration. The mOS increased 21% when the AAT was sorafenib (SOR) or 42% when locoregional therapy was coadministered. The mOS decreased when patients received prior systemic therapy (↓7%) or concomitant chemotherapy (↓4%) or the percentage of patients with hepatitis B increased (↓∼0.4%/%). Clinical trial simulations of a phase II comparative trial predicted an mOS ratio (placebo:AAT) of 0.687 or 0.831, with a 65% or 22% probability of demonstrating superiority, for SOR or other AATs, respectively. Additionally, the 95% confidence interval (CI) of the simulated median mOS ratio for non-SOR AATs was similar to the 95% CI of the hazard ratio (HR) observed in the trial.

PKPD Modeling of Predictors for Adverse Effects and Overall Survival in Sunitinib-Treated Patients With GIST.

A modeling framework relating exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor (sVEGFR)-2, -3, soluble stem cell factor receptor (sKIT)), and tumor growth to overall survival (OS) was extended to include adverse effects (myelosuppression, hypertension, fatigue, and hand-foot syndrome (HFS)). Longitudinal pharmacokinetic-pharmacodynamic models of sunitinib were developed based on data from 303 patients with gastrointestinal stromal tumor. Myelosuppression was characterized by a semiphysiological model and hypertension with an indirect response model. Proportional odds models with a first-order Markov model described the incidence and severity of fatigue and HFS. Relative change in sVEGFR-3 was the most effective predictor of the occurrence and severity of myelosuppression, fatigue, and HFS. Hypertension was correlated best with sunitinib exposure. Baseline tumor size, time courses of neutropenia, and relative increase of diastolic blood pressure were identified as predictors of OS. The framework has potential to be used for early monitoring of adverse effects and clinical response, thereby facilitating dose individualization to maximize OS.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e85; doi:10.1038/psp.2013.62; advance online publication 4 December 2013.

PKPD Modeling of VEGF, sVEGFR-2, sVEGFR-3, and sKIT as Predictors of Tumor Dynamics and Overall Survival Following Sunitinib Treatment in GIST.

The predictive value of longitudinal biomarker data (vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, and soluble stem cell factor receptor (sKIT)) for tumor response and survival was assessed based on data from 303 patients with imatinib-resistant gastrointestinal stromal tumors (GIST) receiving sunitinib and/or placebo treatment. The longitudinal tumor size data were well characterized by a tumor growth inhibition model, which included, as significant descriptors of tumor size change, the model-predicted relative changes from baseline over time for sKIT (most significant) and sVEGFR-3, in addition to sunitinib exposure. Survival time was best described by a parametric time-to-event model with baseline tumor size and relative change in sVEGFR-3 over time as predictive factors. Based on the proposed modeling framework to link longitudinal biomarker data with overall survival using pharmacokinetic-pharmacodynamic models, sVEGFR-3 demonstrated the greatest predictive potential for overall survival following sunitinib treatment in GIST.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e84; doi:10.1038/psp.2013.61; advance online publication 20 November 2013.

Ritonavir 100 mg does not cause QTc prolongation in healthy subjects: a possible role as CYP3A inhibitor in thorough QTc studies.

To assess the QTc prolongation by ritonavir (RTV) 100 mg and explore its potential use as CYP3A inhibitor in thorough QTc (TQT) studies. Randomized, crossover study of single-dose RTV 100 mg, placebo, and moxifloxacin (MFLX) 400 mg in 65 healthy subjects with serial triplicate electrocardiograms obtained for 12 h post-dose. Largest mean placebo-adjusted QTcF increase from baseline (90% confidence interval (CI)) for RTV 100 mg was noninferior to placebo (0.16 ms (-1.38, 1.69)). Study sensitivity was validated by detecting the largest mean placebo-adjusted QTcF increase from baseline (90% CI) for MFLX of 8.31 ms (6.44, 10.18). A single dose of RTV 100 mg does not cause QTc prolongation in healthy subjects. Based on the potent CYP3A4 inhibition, lack of QTc effect and better safety profile, RTV 100 mg could replace ketoconazole as the CYP3A4 inhibitor in TQT studies.

The population pharmacokinetics of amphotericin B colloidal dispersion in patients receiving bone marrow transplants.

The purpose of this study was to identify the pharmacokinetics of Amphotericin B Colloidal Dispersion in patients undergoing bone marrow transplantations with systemic fungal infections and to assess the influence of ABCD on renal function. Seventy-five patients (42 females, 33 males) with a median age of 34.5 years and median weight of 70.0 kg were enrolled in the study. The plasma concentration data was available in 51/75 patients and was best described by a two-compartment model; both plasma clearance and volume of distribution increased with escalating doses; the overall average terminal elimination half-life was 29 h. Serum creatinine values over the duration of therapy were available in 59/75 patients. Overall, there was no net change in renal function over the duration of therapy.

Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) in tumor-bearing mice.

PURPOSE: The pharmacokinetics (PK), biodistribution and therapeutic efficacy of cisplatin encapsulated in long-circulating pegylated (Stealth) liposomes (SPI-077) were compared with those of nonliposomal cisplatin in two murine (C26 colon carcinoma and Lewis lung) tumor models. METHODS: In therapeutic effectiveness studies, mice bearing murine C26 or Lewis lung tumors received multiple intravenous doses of SPI-077 or cisplatin in a variety of treatment schedules and cumulative doses. In the PK and biodistribution study, mice received a single intravenous bolus injection of 3 mg/kg of either SPI-077 or cisplatin 14 days after inoculation with 10(6) C26 tumor cells. Plasma and tissues were analyzed for total platinum (Pt) content by graphite furnace (flameless) atomic absorption spectrophotometery (GF-AAS). RESULTS: Efficacy studies showed that SPI-077 had superior antitumor activity compared to the same cumulative dose of cisplatin. When lower doses of SPI-077 were compared to cisplatin at its maximally tolerated dose in Lewis lung tumors, equivalent SPI-077 antitumor activity was seen at only half the cisplatin dose. Higher cumulative doses of SPI-077 were well tolerated and had increased antitumor effect. SPI-077 PK were characterized by a one-compartment model with nonlinear (saturable) elimination, whereas cisplatin PK were described by a two-compartment model with linear elimination. SPI-077 had a 55-fold lower [corrected] volume of distribution, 3-fold higher peak plasma levels, and a 60-fold larger plasma AUC compared with cisplatin. In addition, SPI-077-treated animals displayed a 4-fold reduction in Pt delivered to the kidneys (primary target organ of toxicity) relative to cisplatin, but a 28-fold higher tumor AUC than cisplatin. CONCLUSIONS: Based on the results of our studies, encapsulation of cisplatin in long-circulating pegylated liposomes has overcome limitations experienced with other liposomal cisplatin formulations. SPI-077 has a prolonged circulation time and increased tumor Pt disposition, and its antitumor effect is significantly improved compared to cisplatin in murine colon and lung cancer models.

Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma.

OBJECTIVE: To characterize the population pharmacokinetics of pegylated-liposomal doxorubicin in patients with acquired immunodeficiency disease (AIDS)-related Kaposi's sarcoma and to explore the relationship between response of the cutaneous Kaposi's sarcoma lesions to treatment and measures of drug exposure. METHODS: Forty-three male patients (median age, 40 years; age range, 28 to 50 years), body surface area, 1.89 m2; range, 1.5 to 2.3 m2) with AIDS and at least five biopsy-proven cutaneous Kaposi's sarcoma lesions were randomized to receive either a 10 or 20 mg/m2 dose of study drug for their first cycle and the alternate dose 3 weeks later. Patients continued to receive the study drug at a dose of 20 mg/m2 every 3 weeks. Serial blood samples were obtained after the first two doses and analyzed by HPLC for determination of total plasma doxorubicin concentration. Kaposi's sarcoma lesion response was categorized as either progressive disease, stable disease, partial response, or complete response. Classification and regression tree (CART) analysis was used to determine the relationship between drug exposure and categorical lesion response. Iterative two-stage analysis was used to characterize both the pharmacokinetics of pegylated-liposomal doxorubicin and to model the probabilities of achieving a specific lesion response. RESULTS: The pharmacokinetics of pegylated-liposomal doxorubicin were best described by a two-compartment linear structural model. Lesion response was significantly related to both the average daily maximum doxorubicin concentration (Cmax,avg) and dose intensity. CONCLUSIONS: The pharmacokinetics of pegylated-liposomal doxorubicin are strikingly different from conventional doxorubicin. Identification of both Cmax,avg and dose intensity as predictors of lesion response will provide guidelines for future dosing regimen designs.

Pharmacokinetics and pharmacodynamics of oral grepafloxacin in patients with acute bacterial exacerbations of chronic bronchitis.

This analysis was designed to characterize the population pharmacokinetics and pharmacodynamics of oral grepafloxacin (OPC-17,116) in patients with acute bacterial exacerbations of chronic bronchitis (ABECB). The study group included 76 patients (43 male, 33 female) between 23 and 81 years of age, who were part of a multicentre, randomized, double-blind, dose-response study. Patients were randomly assigned to receive oral regimens of grepafloxacin, 200, 400 or 600 mg, each administered once daily for 14 days. Plasma samples for drug assay (typically eight per subject; four samples on either day 3, 4 or 5, plus troughs on other clinic visit days), were obtained during treatment. Population pharmacokinetic analysis was accomplished using iterative two-stage analysis. Cultures and quantitative Gram stains from serial 24 h collections of sputum were used to determine the time (in days) taken to eradicate each bacterial strain. Population pharmacodynamic analysis was performed for three measures of antibacterial response: probability of bacteriological cure, probability of clinical cure, and time to eradication. Grepafloxacin plasma concentration profiles were best fitted by a pharmacokinetic model with first-order absorption following a lag time between administration of the dose and onset of systemic absorption. All three measures of response were strongly related to the 24 h AUIC (AUC/MIC). At an AUIC of <75, the percent probability of clinical cure was 71%; at an AUIC of 75-175, it was 80% (P < 0.05) and at an AUIC of >175, it was 98% (P < 0.01). In conclusion, antibacterial response for grepafloxacin in ABECB patients was highly related to AUIC; values of <75 appear inadequate and values of >175 were optimal.

Modified oral ondansetron regimen for cyclophosphamide-induced emesis in lupus nephritis.

OBJECTIVE: To evaluate the antiemetic efficacy of a modified regimen of oral ondansetron and dexamethasone in patients with lupus nephritis undergoing treatment with cyclophosphamide whose conventional antiemetic regimen had failed. DESIGN: A before-after prospective observational pilot project. SETTING: A federal research hospital. PATIENTS: Fourteen outpatients with lupus nephritis receiving intravenous cyclophosphamide 0.75-1.0 g/m2 had previously experienced chemotherapy-induced emetic events (vomiting or retching) while receiving a standard combination intravenous antiemetic regimen. The regimen consisted of four doses of thiethylperazine 10 mg and diphenhydramine 25 mg every 6 hours, and two doses of lorazepam 0.5 mg every 6 hours starting at 1 hour prior to cyclophosphamide. A subset of 8 patients previously completed a blinded study in which they received the intravenous formulation of ondansetron (4 doses of 4-16 mg q4h) administered orally beginning 30 minutes prior to the cyclophosphamide infusion. MAIN OUTCOME MEASURES: The number of emetic events and cost of drug administration were assessed for the modified ondansetron intervention and compared with those of the standard antiemetic regimen. The incidence of emetic events and visual analog nausea scores for the subset of eight patients were also evaluated. INTERVENTIONS: To account for the delayed onset of emesis associated with cyclophosphamide, patients received both ondansetron 8 mg orally every 4 hours (3 doses) and dexamethasone 10 mg orally (1 dose) beginning 4 hours after the cyclophosphamide infusion. This is different from the manufacturer's recommended dose schedule, in which ondansetron is administered prior to chemotherapy. RESULTS: No emetic events were observed following the administration of oral ondansetron/dexamethasone. The 95% confidence interval for the true rate of emesis was 0% to 19.3%. There was a significant difference in efficacy between ondansetron/dexamethasone and the triple antiemetic regimen (p < 0.0002). None of the patients experienced adverse effects while receiving the ondansetron/dexamethasone regimen. Cost comparisons (including admixture and nursing administration times) for standard combination therapy and oral ondansetron/dexamethasone were $109.09 and $70.24, respectively. No difference in emetic events or nausea ratings was observed between oral ondansetron/dexamethasone tablets and oral administration of ondansetron using the intravenous formula. CONCLUSIONS: This study suggests that a modified oral ondansetron/dexamethasone regimen is safe and efficacious, and costs less than alternative regimens to prevent cyclophosphamide-induced emesis in patients with lupus nephritis.

Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi's sarcoma.

A study of the plasma pharmacokinetics, tumor localization, and safety of a single dose of doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol (PEG-liposomal doxorubicin) was conducted in patients with Kaposi's sarcoma (KS) as a manifestation of acquired immune deficiency syndrome (AIDS). Eighteen patients with AIDS-KS diagnosed by examination of biopsy specimens were randomly assigned to receive either standard doxorubicin or PEG-liposomal doxorubicin. Consecutive participants were entered at three dose levels (10, 20, and 40 mg/m2) in ascending fashion. Clearance of PEG-liposomal doxorubicin was 0.034 L/h/m2 to 0.108 L/h/m2, volume of distribution (Vd) was 2.2 L/m2 to 4.4 L/m2, and half-lives (t1/2) of the initial decline in the plasma concentration-time curve and of the terminal decline were 3.77 hours and 41.3 hours, respectively. Seventy-two hours after administration, doxorubicin levels observed in lesions of patients receiving PEG-liposomal doxorubicin were 5.2 to 11.4 times greater than those found in patients given comparable doses of standard doxorubicin. PEG-liposomal doxorubicin and standard doxorubicin were roughly equipotent in producing toxicity. Encapsulation in liposomes containing surface-bound PEG significantly limits the distribution and elimination of doxorubicin, results in greater accumulation of the drug in KS lesions 72 hours after dosing than does standard doxorubicin, and may improve drug efficacy and therapeutic index in the treatment of AIDS-KS.

Population pharmacokinetics and renal function-sparing effects of amphotericin B colloidal dispersion in patients receiving bone marrow transplants.

The purpose of this study was to evaluate the pharmacokinetics of amphotericin B colloidal dispersion and its effect on creatinine clearance in bone marrow transplant patients with systemic fungal infections. Seventy-five patients (42 females and 33 males) with a median age of 34.5 years and a median weight of 70.0 kg were enrolled in the study. Patients received 1 of 15 dose levels (range, 0.5 to 8.0 mg/kg of body weight) daily for a mean duration of 28 days and a mean cumulative dose amount of 8 g. Plasma samples for amphotericin B determination (median number, 4; range, 2 to 30) and daily serum creatinine values were obtained for each patient. Iterative two-stage analysis, one of several approaches to population pharmacokinetic and pharmacodynamic modelling, was employed for the pharmacokinetic analysis. The plasma data were available for 51 of 75 patients and were best described by a two-compartment model. Both plasma clearance and volume of distribution increased with escalating doses; the overall average terminal elimination half-life was 29 h. Of the covariates studied, only body weight and dose size were significant. Serum creatinine values over the duration of therapy were available for 59 of 75 patients. Overall, there was no net change in renal function over the duration of therapy; 12 patients had > 30% increases in creatinine clearance, whereas 13 had > 30% decreases. No measure of amphotericin B colloidal dispersion exposure, demographic values, or concomitant treatment with other medications was related to changes in the creatinine clearance.

Pharmacokinetics and safety of weekly dapsone and dapsone plus pyrimethamine for prevention of pneumocystis pneumonia.

The safety and pharmacokinetics of weekly dapsone and weekly dapsone plus pyrimethamine were examined in adult patients with human immunodeficiency virus infection who were at risk for pneumocystis pneumonia because of a prior episode or a CD4+ T-cell count less than 250 cells per mm3. Groups of patients received 100, 200, and 300 mg of dapsone as a single weekly dose. The maximum tolerated dose of weekly dapsone was established as 200 mg per week in patients receiving at least 500 mg of zidovudine concomitantly. This dose of dapsone was then found to be well tolerated when combined with pyrimethamine at 25 mg. Further patients were randomized to dapsone at 200 mg or dapsone at 200 mg plus pyrimethamine at 25 mg once weekly. Twenty-six patients each were followed for a median of 33 weeks on dapsone alone and 45 weeks on the combination. Seven patients in each group withdrew because of toxicity. Five patients receiving dapsone developed documented pneumocystis pneumonia, while four and two patients receiving dapsone plus pyrimethamine developed documented and presumptive pneumocystis pneumonia, respectively. To evaluate the tolerability of a higher dose of pyrimethamine, 11 patients had their regimen changed to dapsone at 200 mg plus pyrimethamine at 75 mg, which was well tolerated by 10 of the patients for a median period of 11 weeks. The pharmacokinetics of dapsone and pyrimethamine were examined by using a population pharmacokinetic model. Decreases in the apparent volume of the peripheral compartment were observed when multiple-dose regimens of dapsone were compared with single-dose dapsone and when multiple-dose regimens of dapsone with pyrimethamine were compared with multiple-dose dapsone alone. When administered weekly, dapsone at 200 mg and dapsone at 200 mg with pyrimethamine at 25 mg are both well-tolerated regimens. This preliminary study suggests that the efficacy of these regimens in preventing pneumocystis pneumonia, however, may be less than that of trimethoprim-sulfamethoxazole.

Pharmacokinetics and safety of a unilamellar liposomal formulation of amphotericin B (AmBisome) in rabbits.

A unilamellar liposomal formulation of amphotericin B (LAmB) known as AmBisome was safely administered intravenously to 20 rabbits at 0.5, 1.0, 2.5, 5, or 10 mg/kg of body weight, whereas of 12 rabbits given desoxycholate amphotericin B (DAmB) intravenously at 0.5, 1.0, or 1.5 mg/kg, 2 died of acute cardiac toxicity when DAmB was administered at the highest dose. Single-dose LAmB (1 mg/kg) achieved a maximum concentration in serum (Cmax) of 26 +/- 2.4 micrograms/ml and an area under the curve to infinity (AUC0-infinity) of 60 +/- 16 micrograms.h/ml, while single-dose DAmB (1.0 mg/kg), by comparison, achieved a lower Cmax (4.7 +/- 0.2 micrograms/ml; P = 0.001) and a lower AUC0-infinity (30.6 +/- 2.2 micrograms.h/ml; P = 0.07). Following administration of a single dose of LAmB (10 mg/kg), a disproportionately higher Cmax (287 +/- 14 micrograms/ml) and AUC0-infinity (2,223 +/- 246 micrograms.h/ml) occurred, indicating saturable elimination. After chronic dosing (n = 4) with LAmB at 5.0 mg/kg/day for 28 days or DAmB at 1.0 mg/kg/day for 28 days, LAmB achieved daily peak levels of 122.8 +/- 5.8 micrograms/ml and trough levels of 34.9 +/- 1.8 micrograms/ml, while DAmB reached a peak of only 1.76 +/- 0.11 microgram/ml and a trough of 0.46 +/- 0.04 microgram/ml (P < or = 0.001). Significant accumulations of amphotericin B into reticuloendothelial organs were observed, with 239 +/- 39 micrograms/g found in the liver after chronic LAmB dosing (5 mg/kg/day), which was seven times higher than the 33 +/- 6 micrograms/g after DAmB dosing (1 mg/kg/day) (P = 0.002). Accumulation in kidneys, however, remained 14-fold lower (P =0.04) following LAmB dosing (0.87 +/- 0.61 microgram/g) than after DAmB dosing (12.7 +/- 4.6 microgram/g). Nephrotoxicity occurred in only one of four LAmB treated animals, while it occurred in all four chronically DAmB-treated animals: mild hepatozicity with transaminase elevations was seen in one LAmB-treated rabbit. We conclude that LAmB safely achieved higher Cmax(s) and AUC0-infinity(s) and demonstrated saturable, nonlinear elimination from plasma via reticuloendothelial organ uptake. Take reduced nephrotoxicity of LAmB correlated with diminished levels of amphotericin B in the kidneys.

Catechol-O-methyltransferase inhibitor tolcapone prolongs levodopa/carbidopa action in parkinsonian patients.

The wearing-off phenomenon frequently complicates levodopa therapy of Parkinson's disease (PD). These response fluctuations appear when intrasynaptic dopamine concentrations begin to reflect the swings in levodopa availability that attend standard dosing regimens. Drugs that prolong the biologic half-life of levodopa and dopamine should thus prove beneficial. We administered levodopa/carbidopa in combination with single oral doses of tolcapone (Ro 40-7592), an inhibitor of catechol-O-methyltransferase, under controlled conditions to 10 PD patients with the wearing-off phenomenon. Tolcapone prolonged the antiparkinson response to levodopa/carbidopa by about 67% at several doses ranging from 50 to 400 mg (p < 0.05). There was no significant change in the peak levodopa effect on parkinsonian signs or in the severity of dyskinesias. No dose-limiting adverse effects occurred. Multiple daily dosing with tolcapone would thus be expected to safely reduce the wearing-off phenomenon associated with levodopa/carbidopa therapy.

Comparative safety, tolerance, and pharmacokinetics of amphotericin B lipid complex and amphotericin B desoxycholate in healthy male volunteers.

Amphotericin B lipid complex (ABLC), a lipid complex formulation of amphotericin B, and amphotericin B desoxycholate (AB) were compared for safety, tolerance, and pharmacokinetics in two groups of eight healthy male volunteers. After a 1-mg test dose, study drug was infused at 0.1, 0.25, and 0.5 mg/kg; the 0.5-mg/kg dose was not given to subjects receiving AB. ABLC caused few acute adverse effects except for mild somnolence (drowsiness) in six volunteers. In addition, three of eight ABLC recipient had asymptomatic, transient serum transaminase elevations that resolved spontaneously. The AB recipients experienced more acute side effects, but only one had a mild shaking chill: three of eight also experienced sleepiness. No significant changes in vital signs, electrocardiogram, oximetry, pulmonary function, or clinical status were observed in either group. Due to its increased estimate volume of distribution and estimated clearance. ABLC yielded decreased amphotericin B levels and area under the serum concentration versus time curve relative to AB.

Pharmacokinetics of oral and intravenous omeprazole in patients with the Zollinger-Ellison syndrome.

The pharmacokinetics and pharmacodynamics of oral and IV omeprazole after a single dose were studied in 9 patients with the Zollinger-Ellison syndrome to determine whether the increased dose required to control gastric acid hypersecretion could be explained on the basis of altered pharmacokinetics. Each patient was studied both after receiving a single IV bolus of omeprazole (40 mg) and after receiving a single oral dose of omeprazole (80 mg). Intravenous and oral omeprazole doses were administered 1 week apart. Gastric acid secretion and plasma concentrations of omeprazole after drug administration were determined in each patient. The area under the plasma concentration curve, clearance, and volume of distribution after IV omeprazole administration and the area under the plasma concentration curve, peak plasma concentration, and time required to reach the peak after oral omeprazole administration were not different from those reported previously for normal subjects and patients with peptic ulcer disease. Mean (+/- SEM) bioavailability of oral omeprazole for all patients was 68% +/- 16%, which was similar to the bioavailability reported previously for normal subjects. Three patients had a significantly lower bioavailability reported previously for normal subjects. Three patients had a significantly lower bioavailability (20% +/- 8%) than the others, and their basal acid outputs were significantly higher than those of the other 7 patients. For all patients there was an inverse correlation between bioavailability and basal acid output (r = 0.76; P less than 0.02). The mean (+/- SEM) elimination half-lives of IV and oral omeprazole were not different (2.3 +/- 0.4 vs. 2.4 +/- 0.5 hours) but were significantly longer than those reported previously for normal subjects (P less than 0.02). The duration of action correlated with the elimination half-life of the drug (r = 0.87; P less than 0.003) and area under the plasma concentration curve (r = 0.72; P less than 0.03). The mean durations of action of IV and oral omeprazole were not significantly different (34 +/- 7.2 vs. 35 +/- 6.2 hours). It was concluded that altered pharmacokinetics do not account for the increased drug requirement of omeprazole in patients with the Zollinger-Ellison syndrome. In contrast to a previous study, the oral and IV omeprazole had the same duration of action, suggesting that intermittent bolus administration of parenteral omeprazole will obviate the need for continuous infusion of histamine H2-receptor antagonists in patients requiring parenteral antisecretory drugs. Furthermore, an IV dose every 12 hours controlled acid secretion in all patients, suggesting this as the recommended dose interval in patients requiring parenteral drug therapy.

Standardization of a fluconazole bioassay and correlation of results with those obtained by high-pressure liquid chromatography.

An improved bioassay for fluconazole was developed. This assay is sensitive in the clinically relevant range (2 to 40 micrograms/ml) and analyzes plasma, serum, and cerebrospinal fluid specimens; bioassay results correlate with results obtained by high-pressure liquid chromatography (HPLC). Bioassay and HPLC analyses of spiked plasma, serum, and cerebrospinal fluid samples (run as unknowns) gave good agreement with expected values. Analysis of specimens from patients gave equivalent results by both HPLC and bioassay. HPLC had a lower within-run coefficient of variation (less than 2.5% for HPLC versus less than 11% for bioassay) and a lower between-run coefficient of variation (less than 5% versus less than 12% for bioassay) and was more sensitive (lower limit of detection, 0.1 micrograms/ml [versus 2 micrograms/ml for bioassay]). The bioassay is, however, sufficiently accurate and sensitive for clinical specimens, and its relative simplicity, low sample volume requirement, and low equipment cost should make it the technique of choice for analysis of routine clinical specimens.