Ampicillin and sulbactam pharmacokinetics and pharmacodynamics in continuous ambulatory peritoneal dialysis (CAPD)

The fixed combination antibiotic ampicillin/sulbactam may provide a new, safe, and effective method of treating dialysis-related bacterial peritonitis. The pharmacokinetics of this antibiotic combination were determined in patients receiving continuous ambulatory peritoneal dialysis (CAPD). The pharmacodynamic activity of this drug was also determined by use of mean bactericidal titers against selected bacterial strains. Six noninfected CAPD patients in a randomized two-way crossover study were given a fixed dose of ampicillin (2 gm) and sulbactam (1 gm) either intravenously or intraperitoneally. The mean peak ampicillin and sulbactam serum concentrations following intravenous dosing were 170.3 and 87.5 micrograms/mL, respectively. The mean peak serum concentrations of ampicillin and sulbactam following intraperitoneal dosing were 48.0 and 27.8 micrograms/mL, respectively. Absolute bioavailabilities of the intraperitoneal ampicillin and sulbactam doses were 60% and 68%. Both drugs exhibited similar distribution and elimination characteristics. Renal failure markedly reduced drug elimination. Intraperitoneal administration of ampicillin/sulbactam provided satisfactory inhibitory and bactericidal antibiotic titers for most organisms in dialysate at 6 h but not 24 h. Ampicillin/sulbactam (2 gm/1 gm) should be administered every 12 h to patients with peritoneal dialysis-related peritonitis.     

Phase I and pharmacokinetic evaluation of intravenous hyaluronic acid in combination with doxorubicin or 5-fluorouracil

BACKGROUND: Pre-clinically, hyaluronan (HA) has been demonstrated to systemically target chemotherapeutic drugs to tumours while ameliorating treatment toxicities. This study is a preliminary clinical investigation to determine if HA could be safely used in combination with 5-fluorouracil (5-FU) and doxorubicin (DOX). METHODS: Thirty patients with metastatic cancer were intravenously administered 500 mg/m2 HA in combination with escalating doses of DOX (30-60 mg/m2) or 5-FU (cumulative dose of 1,350-2,250 mg/m2 per cycle). The effect of pre-administration of 20 mg/m2 of folinic acid on HA/5-FU chemotherapy was also investigated. Patients were randomized to receive either HA/chemotherapy or chemotherapy alone in their first treatment cycle and vice versa for the second cycle. Patients received HA and chemotherapy in all subsequent cycles. RESULTS: Treatment was well tolerated, tumour responses were observed and the co-administration of HA did not alter the pharmacokinetics of clinically relevant doses of 5-FU or DOX. CONCLUSION: High doses of intravenous high-molecular-weight HA can be safely co-administered with clinical doses of chemotherapy without significantly altering the toxicity or pharmacokinetics of the drugs or HA.     

5-fluorouracil with cytosine arabinoside in metastatic gastrointestinal cancer.

A 2-drug combination chemotherapy regimen of 5-fluorouracil (FU) and cytosine arabinoside (ara-C) was used in 23 patients with gastrointestinal cancer. The drugs were administered as a mixture by daily continuous infusion for 5 days at 4-wk intervals. Dosages for each drug were: FU, 1.1 gm/m2/day and ara-C, 50 mg/m2/day. The incidence of leukopenia (WBC, less than 3,500/mm3) was 36% and of thrombocytopenia (platelets, less than 125,000/mm3), 18% during 33 courses administered at full doses. No clinical antitumor effects were observed in 18 patients evaluable for therapeutic response. The addition of ara-C to a nonmyelosuppressive dose schedule of FU results in potentiated marrow suppression, and the antitumor effect for the combination is less than would have been predicted for either drug alone.     

The pharmacokinetics of high-dose carboplatin in pediatric patients with cancer.

Carboplatin disposition was studied in 18 pediatric patients with cancer over a dosage range of 400 to 700 mg/m2 given on an alternate-day schedule (total doses of 1200 to 2100 mg/m2) with high-dose etoposide. Median age was 7.7 years, hepatic functions were normal, and serum creatinine levels were less than or equal to 1.0 mg/dl. Carboplatin pharmacokinetics were determined by atomic absorption spectroscopy. Median pharmacokinetic parameters for ultrafilterable platinum were as follows: clearance 45.8 ml/min/m2 (range, 25.5 to 65.3 ml/min/m2) and a terminal half-life of 3.6 hours (range, 2.1 to 14.2 hours). Carboplatin clearance (CL) values and volume of distribution (VC) were highly correlated to body size (CL = 55 x Body surface area in [BSA, in square meters] - 6.7, r2 = 0.73; VC = 5 x BSA [in square meters] + 0.26, r2 = 0.69). However, carboplatin doses normalized to BSA still resulted in twofold to threefold variability in area under the concentration-time curve. Carboplatin CL was significantly lower in those subjects (n = 9) who had previously received cumulative cisplatin doses of greater than or equal to 960 mg/m2 (p less than 0.05) but was not influenced by age, gender, or diagnosis.     

Preclinical and clinical evidence for disappearance of long-circulating characteristics of polyethylene glycol liposomes at low lipid dose

This study describes the effect of the lipid dose of (99m)Tc-polyethylene glycol (PEG) liposomes in the low-dose range (0. 02-1.0 micromol/kg) on the pharmacokinetics and biodistribution in rats, rabbits, and humans. The biodistribution and pharmacokinetics of (99m)Tc-PEG liposomes at various dose levels were studied in rats and rabbits with a focal Escherichia coli infection. Scintigraphic images were recorded on a gamma camera. In addition, the role of macrophages in the biodistribution of a low-dose PEG liposome injection was studied. Finally, the pharmacokinetics of (99m)Tc-PEG liposomes at two lipid dose levels was studied in four patients. At a dose level of 0.03 micromol/kg, the blood level in rats at 4 h postinjection was significantly lower than at the highest dose level (1.1 micromol/kg). The same effect was observed in rabbits where enhanced clearance was observed at a dose level of 0.02 micromol/kg. The circulatory half-life decreased from 10.4 to 3.5 h (at 1.0 and 0. 02 micromol/kg, respectively). At the lowest dose level, liposomes were mainly taken up by the liver and to a lesser extent by the spleen. Injection of a low dose of PEG liposomes in macrophage-depleted rabbits resulted in normal pharmacokinetics, suggesting involvement of macrophages in the effectuation of the rapid elimination of the liposomes from the circulation. Most importantly, the rapid clearance of low-dose PEG liposomes was also observed in humans when relatively low lipid doses were administered. This study showed that at very low lipid doses the biodistribution of PEG liposomes is dramatically altered.     

Disposition of and clinical response to salicylates in patients with rheumatoid disease

The disposition of salicylic acid (SA) and its metabolites and the clinical response to long-term aspirin treatment at varying doses were assessed in patients with rheumatoid disease. Steady-state kinetics of SA (total and unbound), salicyluric acid (SUA), gentisic acid (GA), and clinical status were estimated weekly in 10 patients with rheumatoid arthritis. Eight received a soluble aspirin form and two received an enteric-coated form. The starting dose of aspirin in each patient was 1.8 gm (soluble) or 1.95 gm (enteric-coated) daily. Weekly increments in dose were made until a satisfactory clinical outcome was achieved. The final aspirin dose range was 3.6 to 8.1 gm daily, which resulted in mean steady-state plasma SA concentrations (CpSA) from 56 to 375 mg/l. Since the mean total CpSA increased approximately proportionately over the dose range, there was little change in total SA clearance. By contrast, increasing aspirin dosage resulted in decreased clearance and disproportionate increases in unbound SA (CpuSA). The maximum velocity of conversion of SA to SUA (Vm) increased significantly, from 57.3 +/- 11.7 mg/hr at an aspirin dose of 1.8 gm/day to 71.4 +/- 19.4 mg/hr at the next highest dose (2.7 to 3.6 gm/day), with no further change with increasing dosage. Km ranged from 0.4 to 1.2 mg/l for CpuSA and from 5.5 to 17.2 for total CpSA. Renal clearance of SUA (ClSUA) ranged from 124 to 893 ml/min and correlated with creatinine clearance. ClGA ranged from 23 to 164 ml/min, and ClSA ranged from 0.1 to 17.1 ml/min; neither correlated with creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") and its major metabolites in squirrel monkeys at plasma concentrations of MDMA that develop after typical psychoactive doses

At certain doses, the psychoactive drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") destroys brain serotonin axon terminals. By causing increases in plasma MDMA concentrations that exceed those predicted by the increase in dose, nonlinear pharmacokinetics has the potential to narrow the range between safe and neurotoxic doses of MDMA. The present study sought to determine whether the pharmacokinetics of MDMA in nonhuman primates are nonlinear and, if they are, to identify plasma concentrations of MDMA at which nonlinear accumulation of MDMA occurs. Four different oral doses of MDMA were tested in the same six squirrel monkeys in random order. At each dose, pharmacokinetic parameters for MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 3,4-methylenedioxyamphetamine were determined. Doses were selected to be equivalent to 0.4, 0.8, 1.6, and 2.8 mg/kg doses in humans. The maximal concentration (C(max)) and area under the curve (AUC) of MDMA increased nonlinearly with dose, whereas the C(max) and AUC of the metabolites HHMA and HMMA remained relatively constant. Nonlinear MDMA pharmacokinetics occurred at plasma MDMA concentrations of 100 to 300 ng/ml and above. The half-life (T(1/2)) of MDMA and its metabolites also increased with dose. These results firmly establish nonlinear pharmacokinetics for MDMA in squirrel monkeys and indicate that nonlinear MDMA accumulation occurs at plasma MDMA concentrations that develop in humans taking typical doses. By raising MDMA concentrations and prolonging its action, nonlinear pharmacokinetics and T(1/2) prolongation, respectively, may influence the likelihood and severity of MDMA toxicities (including brain serotonin neurotoxicity).     

Dose ranging study and constant infusion evaluation of ciprofloxacin.

We evaluated the pharmacokinetics of 100- and 200-mg doses of ciprofloxacin, with the 200-mg dose administered either as a 30-min infusion or as a 100-mg loading dose followed by a 4-h constant infusion of 25 mg/h in six normal volunteers. No significant differences were seen in the dose-normalized area under the curve when the 100- and 200-mg 30-min administrations were compared. Differences that approached statistical significance were seen when data from either of these trials were compared with data from the constant-infusion arm. Serum clearances averaged 23.0 +/- 9.1 liters/h per 1.73 m2 for the 100-mg dose and 23.7 +/- 5.1 liters/h per 1.73 m2 for the 200-mg dose. Renal clearance accounted for approximately two-thirds of the serum clearance in each instance. Half-lives were slightly longer than 4 h. For the constant-infusion arm, serum clearance was 28.9 +/- 2.7 liters/h per 1.73 m2, with renal clearance accounting for 58% of serum clearance. Although no nonlinearities were apparent in the 100- to 200-mg dose range, larger doses, particularly in the multiple-dosing situation, may uncover nonlinearity in the disposition of ciprofloxacin.     

Intrapleural administration of cisplatin and etoposide to treat malignant pleural effusions in patients with non-small cell lung cancer

BACKGROUND: To determine the efficacy, toxicity and pharmacokinetics of intrapleural cisplatin (CDDP) and etoposide as a treatment for malignant pleural effusions (MPE) in patients with non-small cell lung cancer (NSCLC). METHODS: Seventy patients with MPE associated with NSCLC were enrolled in this study. In 68 patients, a catheter was inserted into the pleural cavity, within 24 h after complete drainage of the pleural effusion, CDDP (80 mg/m2) and etoposide (80 mg/m2) were simultaneously administered successfully via the catheter and the catheter was clamped. Seventy-two hours later, the catheter was unclamped to allow drainage. The catheter was removed when the accumulated intrapleural fluid decreased to 20 ml or less per day. RESULTS: The pharmacokinetic profiles showed high maximum concentrations of CDDP (free form, 88 microg/ml) and etoposide (182. 4 microg/ml) in intrapleural fluids. CDDP did not remain for a long period (free form, beta-phase half-life = 10.51 h) in the fluids, while etoposide persisted for a long period (beta-phase half-life = 62.53 h). The overall response rate was 46.2%, the median survival time 32.3 weeks, the 1-year survival rate 28.7% and the 2-year survival rate 12.8%. The most serious adverse reactions were WHO grade 3 anemia (3 patients), grade 3 nausea and vomiting (17 patients), grade 3 constipation (1 patient), grade 3 pulmonary toxicity (1 patient), grade 4 fever (1 patient), grade 3 infection (1 patient) and grade 3 mental disorder (1 patient). CONCLUSION: Intrapleural administration of CDDP and etoposide was an effective and acceptable regimen for patients with MPE due to NSCLC.     

Pharmacokinetics and pharmacodynamics of glyceryl trinitrate and its two dinitrate metabolites in conscious dogs

The pharmacokinetics and pharmacodynamics of nitroglycerin (GTN) and its dinitrate metabolites, 1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate (1,2-GDN and 1,3-GDN), were examined in a seven-way crossover study in six conscious dogs. The mean apparent clearance after a low GTN i.v. dose (0.025 mg/kg) was 1440 ml/min/kg (S.D. = 630), which decreased to 686 ml/min/kg (S.D. = 317) after a high GTN i.v. dose (0.25 mg/kg), demonstrating dose-dependent pharmacokinetics. Bioavailability of oral GTN (0.25 mg/kg) was very low (0.015 +/- 0.019). The formation of dinitrate metabolites was rapid and extensive after i.v. and oral dosing of GTN. The pharmacokinetics of 1,2-GDN and 1,3-GDN were very similar. The dinitrates exhibited longer half-lives (approximately 45 min) and lower apparent clearances (approximately 16 ml/min/kg) than those found for GTN. The apparent fractional GTN clearances to 1,2-GDN (CLapp,m1) and 1,3-GDN (CLapp,m2) were also determined. The CLapp,m1 decreased significantly (P less than .05) in going from the low GTN dose (1030 +/- 620 ml/min/kg) to the high dose (425 +/- 145 ml/min/kg). In contrast, CLapp,m2 remained unchanged (low dose: 107 +/- 55 ml/min/kg; high dose: 115 +/- 37 ml/min/kg). The duration of systolic blood pressure decrease after low i.v. GTN doses was very short (approximately 15 min) and significantly longer (approximately 90 min) for high i.v. GTN doses. GTN is about 10 to 12 times more efficient than 1,2-GDN and 1,3-GDN in terms of the maximal systolic blood pressure decrease produced by a therapeutic dose. Oral GTN is pharmacodynamically active and this effect can be attributed to the formation of high levels of dinitrate metabolites.     

Pharmacokinetics of cefotaxime.

The pharmacokinetics of cefotaxime after intramuscular injection and intravenous infusion were determined. The mean peak serum level after the 500-mg intramuscular dose was 11.7 micrograms/ml, and it was 20.5 micrograms/ml after a 1,000-mg dose. The serum half-life was 1.2 and 1.3 h, respectively for the two doses. The apparent fractional volumes of distribution of 32 and 37 liters were not significantly different for the two doses, and the fractional serum clearance was approximately 315 ml/min per 1.73 m2 for both doses. The mean peak serum level after 1,000 mg administered by intravenous infusion over 30 min was 41.1 micrograms/ml. The half-life was 1.13 h, apparent volume of distribution was 33 liters, serum clearance 341 ml/min per 1.73 m2, and renal clearance was 130 ml/min per 1.73 m2. The pharmacology of cefotaxime is similar to the pharmacology of other cephalosporin antibiotics, but the low inhibitory levels which it has against gram-positive and gram-negative bacteria suggest that lower dosage regimens should be possible.     

Pharmacokinetics of Metronidazole as Determined by Bioassay

The pharmacokinetics of metronidazole, a drug effective in vitro against most anaerobic bacteria and promising in treating anaerobic infections, are described. Serum and urine levels after single and multiple doses in 10 adult male volunteers were measured by an agar well diffusion bioassay using clostridial species as the test organisms under anaerobic conditions. Peak serum levels averaged 11.5 mug/ml and 6.2 mug/ml after single 500-mg and 250-mg doses, respectively. Renal clearance was only 10.2 ml/min per 1.73 m(2), and less than 20% of the administered dose was recovered in the urine as active drug in 24 h. The average serum half-life was 8.7 h, and there was no protein binding as determined by an ultrafiltration method. With multiple doses of metronidazole (500 mg four times a day and 250 mg three times a day), blood levels increased progressively for the first few doses and then leveled off, with no significant accumulation occurring between 3 and 7 days. On 250 mg three times a day, serum levels just before the 8 a.m. dose (12 h after the preceding dose) on the third day averaged 3.9 mug/ml, and before the 8 p.m. dose, 5.7 mug/ml. For the higher, 500-mg dose (four times a day) regimen, the corresponding minimum serum levels were 13.1 mug/ml at 8 a.m. and 21.3 mug/ml at 8 p.m. Peak levels would have been about 10 mug/ml higher, and since the minimum inhibitory concentrations of most anaerobes including Bacteroides fragilis are less than 6 mug/ml, these concentrations should be highly effective therapeutically, even for severe infections.     

Trimethoprim pharmacokinetics in children with renal insufficiency

We studied the pharmacokinetics of trimethoprim in 14 children (two neonates) with renal insufficiency. They were 1 week to 16.4 years old and had glomerular filtration rates (GFR) between 10.8 to 72.3 ml/min/1.73 m2. The half-life (t1/2) of trimethoprim was inversely related to the GFR. The relation followed a power curve (correlation of t1/2 with GFR: r = -0.86; P less than 0.001). The slower elimination rate was mainly the result of lowered renal clearance of trimethoprim. The volume of distribution (Varea) was, in most patients, in the upper normal range for children. In some of the patients, chiefly infants with severe renal insufficiency, the Varea was larger than normal. In some individuals the pharmacokinetics of trimethoprim deviated from that to be expected from the GRF. We recommend reduced daily doses of trimethoprim if the GFR is less than 30 ml/min/1.73 m2. The reduction should be proportional to the reduction in GFR and primarily take the form of a prolonged dose interval.     

Single-dose pharmacokinetics of 3-O-demethylfortimicin A in humans after intravenous and intramuscular administration.

The pharmacokinetics of 3-O-demethylfortimicin A were evaluated in 16 healthy adult male volunteers after bolus intramuscular (i.m.) and 30-min intravenous (i.v.) infusion administration of doses ranging from 0.25 to 16 mg/kg. Mean calculated peak levels of the drug in plasma after the 0.25-, 0.5-, 1-, 2-, 4-, 8-, and 16-mg/kg i.m. doses were 1.1, 1.9, 3.5, 4.9, 11.0, 21.8, and 41.3 micrograms/ml, respectively, occurring about 60 min after dosing. The biphasic decline in levels of the drug in plasma after i.v. administration was not apparent after i.m. dosing, presumably because absorption of the drug from the injection site obscured the alpha elimination phase. Mean calculated peak levels for the 1-, 2-, 4-, 8-, and 16-mg/kg 30-min i.v. infusions were 5.9, 12.2, 20.1, 36.7, and 66.4 micrograms/ml, respectively. A statistically significant trend of increasing apparent volume of distribution with increasing dose size was noted for the i.m. dose group only. Plasma drug clearance was dose level and route independent, with an excellent linear relationship between the area under the plasma drug level curve and the dose. The mean 0- to 48-h urinary recoveries of 3-O-demethylfortimicin A after the i.m. injections and i.v. infusions were 90 and 102%, respectively. After the i.m. dosings, the half-life of the drug in plasma averaged 2.0 h, and after the i.v. dosings it averaged 2.7 h. The results of the study indicated that most of the drug was cleared by renal mechanisms.     

Pharmacokinetics and pharmacodynamics of sotalol in a pediatric population with supraventricular and ventricular tachyarrhythmia

OBJECTIVE: This pharmacokinetic-pharmacodynamic study was designed to define the steady-state relationship between pharmacologic response and dose or concentration of sotalol in children with cardiac arrhythmias, with an emphasis on neonates and infants. METHODS: The treatment consisted of an upward titration with unit doses of 10, 30, and 70 mg of sotalol per square meter of body surface area. The patients received 3 doses at each dose level. The dosing interval was 8 hours. The Class III and beta-blocking activities of sotalol were derived from the QT and R-R intervals, respectively, of the surface electrocardiogram, which was recorded at 6 scheduled times before and after the third, sixth, and ninth doses. During these three dose intervals, 4 scheduled blood samples were also collected. Drug concentrations were measured with a validated nonstereoselective liquid chromatographic tandem mass spectrometric detection assay. Pharmacokinetic and pharmacodynamic parameters were obtained with standard methods. RESULTS: Twenty-one centers enrolled 25 patients in the study: 7 were neonates, 9 were infants, and 11 were children between the ages of 2 years and 12 years. The area under the drug concentration-time curve increased proportionately with dose. The apparent oral clearance of sotalol was linearly correlated with body surface area and creatinine clearance. The smallest children (body surface area <0.33 m2) displayed greater drug exposure than the larger children. The increase of QTc and R-R intervals was dose dependent. At the 70-mg/m(2) dose level, the mean (+/- standard deviation) maximum increase for the QTc interval was 14% +/- 7% and the average Class III effect during a dose interval was 7% +/- 5%. At the same dose level, the mean maximum increase of the R-R interval was 25% +/- 15% and the average beta-blocking effect during a dose interval was 12% +/- 13%. The effects tended to be larger in the smallest children. The Class III response and the plasma concentrations of sotalol were linearly related. The treatment was well tolerated. CONCLUSIONS: The steady-state pharmacokinetics of sotalol were dose proportionate. Pharmacologically important beta-blocking effects were observed at the 30-mg/m2 and 70-mg/m2 dose levels. Important Class III effects were seen at the 70-mg/m2 dose level. The Class III effect was linearly related to the drug concentration.     

Multiple-dose pharmacokinetics of ofloxacin, a new broad-spectrum antimicrobial agent

Twelve healthy male volunteers received 14 oral doses of ofloxacin (300 mg each), and the concentrations of the unchanged drug were measured at various times in serum and urine over a period of 15 days. Serum and urine ofloxacin concentrations were determined in specific assays using high-pressure liquid chromatography (HPLC); urine levels were also determined by means of a microbiological assay. A washout period of 72 hours followed the first and 14th doses, allowing comparison of serum pharmacokinetics at the beginning and end of the multiple-dose regimen. Doses 2 to 14 were administered at 12-hour intervals. Maximum serum concentration (Cmax), concentration at 12 hours after dosing (C12), and area under the serum concentration-time curve (0 to 72 hours) were all 1.3 to 1.7 times greater after the 14th dose than after the initial dose. A 1.6-fold increase in C12 was already evident after the third dose; C12 remained more or less constant thereafter. Thus it is concluded that ofloxacin rapidly attained steady-state serum levels under a multiple-dose regimen, at levels only slightly above those following a single dose. High serum Cmax levels (4.6 and 5.9 micrograms/ml after the first and 14th doses, respectively) and long serum half-lives (6.0 and 7.3 hours after the first and last doses, respectively) indicated long-lasting, clinically relevant serum ofloxacin concentrations after oral administration. Serum ofloxacin levels 24 hours after the last dose were in the range of 0.3 to 0.7 microgram/ml, above the minimal inhibitory concentration (MIC90) for most bacterial strains. Cumulative urinary recovery remained high throughout the study. After 14 doses of ofloxacin (total, 4.2 gm), 88% of the unchanged drug was recovered in the urine; urinary concentrations remained above 1 microgram/ml, far above the MIC90 for most bacterial strains, for at least 108 hours after the final dose. High renal clearance values relative to total clearance (98%) confirmed the importance of the renal elimination route. Determinations of ofloxacin in urine using a microbiological assay were in close agreement with the HPLC determinations for all samples obtained throughout the study. Thus no detectable appearance of active metabolites occurred under the multiple-dose regimen. Ofloxacin was well tolerated; mild, probably drug-induced side effects were reported by three subjects, but they did not require any countermeasures.     

Safety, pharmacokinetics, and biological pharmacodynamics of the immunocytokine EMD 273066 (huKS-IL2): results of a phase I trial in patients with prostate cancer

This phase 1 clinical trial was conducted to evaluate the safety and to determine the maximum tolerated dose (MTD) of the immunocytokine EMD 273066 huKS-IL2 and, secondarily, to assess its pharmacokinetics, immunogenic potential, and immunologic activity in patients with androgen-independent prostate cancer (n = 22). EMD 273066 was administered in 3-day cycles (separated by 4 weeks) of once-daily, 4-hour intravenous infusions at a dose determined by an escalation protocol (0.4, 0.7, 1.4, 2.8, 4.3, 6.4, or 8.5 mg/m/d). Approximately 2/3 of patients received a second cycle of treatment. The results show that the MTD of EMD 273066 [ie, one dose level below that producing dose-limiting toxicity (DLT) in at least 33% of patients in a dosing group] was 6.4 mg/m/d. EMD 273066 was generally well tolerated up to a dose of 4.3 mg/m/d. No DLTs, defined as drug-related toxicities >OR= Grade 3 occurring during the first treatment cycle, were observed among patients in the 0.4-, 0.7-, 1.4-, or 4.3-mg/m/d dosing groups. Four patients treated with 2.8, 6.4, or 8.5 mg/m/d EMD 273066 experienced DLTs. Titers of both antiimmunocytokine and anti-FcIL-2 antibody responses were observed after the first dose cycle and either decreased or remained stable during a second course of treatment. No hypersensitivity reactions were observed. EMD 273066 exhibited immunologic activity as demonstrated by increases in lymphocyte counts, natural killer cell number and specific activity, and antibody-dependent cellular cytotoxicity activity. On average, Cmax, which was dose-dependent, was achieved within 1 hour after infusion. Mean t(1/2) which was independent of dose, ranged from 4.0 to 6.7 hours across doses. A zero-compartment body model with one-order kinetics best described the concentration-time profiles. These data demonstrate that the novel immunocytokine EMD 273066 is well tolerated at doses above a level of observed systemic biologic activity in patients with androgen-independent prostate cancer.     

Interpatient and intrapatient variability in vinblastine pharmacokinetics

We analyzed interpatient and intrapatient differences in vinblastine pharmacokinetics in 24 patients treated with a bolus dose of vinblastine followed by prolonged (2 to 36 weeks) continuous infusion via an implantable pump. The bolus vinblastine serum clearance was 552 +/- 182 ml/min/m2, with a terminal half-life of 29.2 +/- 11.2 hours. After steady state was achieved (2 weeks), the infusion clearance was 646 +/- 221 ml/min/m2. Interpatient differences in serum albumin levels were correlated with both the bolus clearance (r = 0.49) and the initial (first month) infusion clearance (r = 0.39). The infusion clearance decreased over the duration of the infusion (726 vs. 489 ml/min/m2; P = 0.001;months 1 vs. 4). Analysis of intrapatient changes in vinblastine clearance demonstrated a positive correlation with albumin (P less than 0.01) and negative correlation with dose (P less than 0.05). These results are consistent with a nonlinear pharmacokinetic model. We conclude that interpatient and intrapatient differences in vinblastine pharmacokinetics can be attributed partially to changes in hepatic function and nonlinear elimination at higher doses.     

Spontaneous locomotor activity and pharmacokinetics of intravenous methamphetamine and its metabolite amphetamine in the rat

The purpose of these studies was to better understand the behavioral effects and pharmacokinetics of an i.v. bolus dose of (+)-methamphetamine [(+)-METH] in a rat model of (+)-METH abuse. We characterized the behavioral effects after increasing (+)-METH doses (0.1, 0.3, and 1.0 mg/kg) and the pharmacokinetics of (+)-METH (and its metabolite (+)-amphetamine [(+)-AMP)]) at the lowest and highest of these doses in adult male Sprague-Dawley rats. The doses and route of administration were selected to mimic aspects of human use on a dose/body weight basis. Although the 0.1 mg/kg dose did not cause statistically significant increases in locomotor activity compared with saline controls, the higher doses (0.3 and 1.0 mg/kg) caused statistically significant increases in locomotor activity (p <.05), which lasted for up to 3 h at the highest dose. After the 1.0 mg/kg dose, the volume of distribution at steady state was 9.0 liters/kg, the total clearance was 126 ml/min/kg, and the average distribution and elimination half-lives were 9.2 and 63.0 min, respectively. Because the pharmacokinetic values after the 0.1 mg/kg dose were not different from those after the 1.0 mg/kg dose, the pharmacokinetics of (+)-METH were considered to be independent of the dose over this 10-fold range. (+)-AMP serum concentrations after the 1.0 mg/kg dose peaked from 10 to 30 min, and exhibited a T(1/2lambdaz) of 98.5 min. The statistically longer T(1/2lambdaz) of (+)-AMP (p <.05) suggested that the (+)-AMP terminal elimination rate and not the (+)-AMP metabolic formation rate is the rate-limiting step in (+)-AMP elimination following i.v. (+)-METH dosing.     

Clinical pharmacology of flavopiridol following a 72-hour continuous infusion

BACKGROUND: Flavopiridol, a novel flavone derivative, inhibits cyclin-dependent kinase-1. We initiated a Phase I trial in patients with refractory solid tumors to determine the maximum tolerated dose and characterize the adverse effect profile. OBJECTIVE: To characterize the clinical pharmacology of flavopiridol. METHODS: Serial plasma samples were collected and analyzed by HPLC using electrochemical detection. The pharmacokinetics were analyzed by noncompartmental analysis. Enterohepatic recirculation was studied by analyzing fecal samples, with an attempt to correlate cholecystokinin and post-infusional peak concentrations. The plasma protein binding was studied using equilibrium dialysis. RESULTS: Seventy-six patients were treated with flavopiridol at 13 dose levels for a total of 504 cycles of treatment. The average steady-state concentration was 26.5 and 253 nM at 4 and 122.5 mg/m2, respectively. The clearance ranged from 49.9 to 2943 mL/min, with nonlinearity at doses >50 mg/m2/d. A post-infusional increase in plasma flavopiridol concentrations was noted in a subset of patients and generally occurred between 3 and 24 hours after the end of infusion. Flavopiridol was found in fecal matter, suggesting enterohepatic recirculation. There was nonsaturable plasma protein binding of flavopiridol (fu = 6%). CONCLUSIONS: The dose-limiting toxicity for the Phase I trial of flavopiridol was secretory diarrhea. We failed to identify a clear relationship between dose or concentration and diarrhea. At 50 and 78 mg/m2/d, the mean steady-state plasma concentrations were 278 and 390 nM. These concentrations were well above those noted for in vitro antiproliferative activity. Nonlinear elimination was observed at doses above 50 mg/m2/d, and postinfusional peaks appear to be related to enterohepatic recirculation.