Mean Total Body Clearance Research Articles

Penetration of Vancomycin into Noninfected Bone in Patients Undergoing Total Joint Arthroplasty Evaluated by a Minimal Physiologically Based Population Pharmacokinetic Modeling Approach.

Arthroplasty is a healthcare priority and represents high volume, high cost surgery. Periprosthetic joint infection (PJI) results in significant mortality, thus it is vital that the risk for PJI is minimized. Vancomycin is recommended for surgical prophylaxis in total joint arthroplasty (TJA) by current clinical practice guidelines endorsed by the Infectious Diseases Society of America. This study aimed to develop a new assay to determine vancomycin concentrations in serum and bone, and a minimal physiologically based population PK (mPBPK) model to evaluate vancomycin bone penetration in noninfected patients. Eleven patients undergoing TJA received 0.5-2.0 g intravenous vancomycin over 12-150 min before surgery. Excised bone specimens and four blood samples were collected per patient. Bone samples were pulverized under liquid nitrogen using a cryogenic mill. Vancomycin concentrations in serum and bone were analyzed by liquid chromatography-tandem mass spectrometry and subjected to mPBPK modeling. Vancomycin serum and bone concentrations ranged from 9.30 to 86.6 mg/L, and 1.94-37.0 mg/L, respectively. Average bone to serum concentration ratio was 0.41 (0.16-1.0) based on the collected samples. The population mean total body clearance was 2.12L/h/kg0.75. Inclusion of total body weight as a covariate substantially decreased interindividual variability in clearance. The bone/blood partition coefficient (Kpbone) was estimated at 0.635, reflecting the average bone/blood concentration ratio at steady-state. The model predicted median ratio of vancomycin area under the curve (AUC) for bone/AUC for serum was 44%. Observed vancomycin concentrations in bone were overall consistent with perfusion-limited distribution from blood to bone. An mPBPK model overall well described vancomycin concentrations in serum and bone.

Pharmacokinetic and pharmacodynamic properties of orally administered torasemide in healthy cats.

BackgroundIn people and dogs, torasemide has higher bioavailability, longer half‐life, and longer duration of action than equivalent doses of furosemide but data regarding pharmacological properties of torasemide in cats are limited.ObjectiveTo assess pharmacokinetic and pharmacodynamic parameters of torasemide in healthy cats, and to investigate the effects of a single administration of torasemide on indicators of diuresis, plasma creatinine concentration, blood pressure, electrolyte concentrations and markers of the renin‐angiotensin‐aldosterone system (RAAS).AnimalsSix clinically healthy adult European shorthair cats.MethodsRandomized 4‐period crossover design with 3 groups and 4 treatments. Pharmacokinetic parameters were obtained using a noncompartmental analysis, and the clinically effective dose was assessed using a Hill model.ResultsMean absolute bioavailability was estimated at 88.1%. Mean total body clearance was 3.64 mL/h/kg and mean terminal half‐life was 12.9 hours. Urine output significantly increased after torasemide administration (P < .001). The urine sodium : potassium ratio (uNa : uK) paralleled and was statistically correlated to urine output (P < .001). Administration of a single torasemide dose led to a significant dose‐dependent increase in urine aldosterone : creatinine ratio (uAldo : C; P < .001) and a transient decrease in plasma potassium concentration (P < .001) but did not affect blood pressure or plasma creatinine concentration.Conclusions and Clinical ImportanceA single torasemide dose leads to a significant increase in diuresis and renin‐angiotensin‐aldosterone system (RAAS) activation in healthy cats, with high absolute bioavailability, and without clinically relevant adverse effects. Pharmacokinetic parameters indicate that once daily dosing of 0.27 mg/kg may be appropriate in a clinical setting.

Pharmacokinetics and metabolism of mirogabalin, a novel α2δ ligand, in rats and monkeys

The purpose of this study was to investigate the pharmacokinetic behaviour of mirogabalin in rats and monkeys. Pharmacokinetic parameters of mirogabalin after its oral and intravenous administration were determined. Distribution study, mass balance study and metabolite identification were also conducted after the oral administration of [14C]mirogabalin. Plasma exposure (Cmax and AUCinf) increased dose-proportionally after the oral administration of mirogabalin at 1, 3 and 10 mg/kg to rats and monkeys. Mean total body clearance (CLtot) after intravenous administration at 3 mg/kg was 13.5 mL/min/kg in rats and 9.02 mL/min/kg in monkeys, and absolute bioavailability at 3 mg/kg was 97.6% in rats and 85.2% in monkeys. There was greater recovery of radioactivity in urine than that in faeces after the oral administration of [14C]mirogabalin. The main radioactive component in the plasma, urine and faeces was mirogabalin. A204-4455 (lactam form), an oxidised metabolite of mirogabalin, mirogabalin N-glucuronide and O-glucuronide of oxidised A204-4455 were detected as minor components in monkeys and rats. Mirogabalin administered orally was almost completely eliminated via urinary excretion. A small part of the orally administered dose of mirogabalin was metabolised via glucuronidation at the amine and carboxylic acid moiety and oxidation as the primary metabolic pathway.

Population Pharmacokinetics and Pharmacodynamic Target Attainment of Vancomycin in Neonates on Extracorporeal Life Support.

To evaluate the population pharmacokinetics and pharmacodynamic target attainment of vancomycin in neonates with a contemporary ¼-inch extracorporeal life support circuit with a Quadrox-iD Pediatric oxygenator (Maquet Cardiovascular, LLC, Wayne, NJ). Retrospective medical record review. Two free-standing tertiary/quaternary pediatric children's hospitals. Neonates receiving either veno-arterial or veno-venous extracorporeal life support and vancomycin for empiric or definitive therapy with resulting serum concentrations. None. Twelve patients with a median gestations age of 39 weeks (range 36-41 wk) and a median postnatal age of 9.5 days (range 0-28 d) accounted for 14 courses of vancomycin therapy while on extracorporeal life support and were included in the analysis. The median weight was 3.1 kg (range 2.2-4.41 kg) with five of 12 patients (41.7%) being female. Vancomycin concentrations were best described by an one-compartment model incorporating allometric scaling of estimated glomerular filtration rate on clearance. The mean total body clearance (mL/min/kg) for the population was 3.48 ± 1.31 mL/min/kg, and the mean total volume of distribution (L/kg) for the population was 1.2 ± 0.4 L/kg. The intermittent and continuous infusion dosing regimens that provided for the highest percentage of trough concentrations in the range of 10-20 mg/L were the 10 mg/kg/dose IV q8h, 12.5 mg/kg/dose IV q8-12h, 15 mg/kg/dose IV q12h, and 20 mg/kg/dose IV q12h, and the 20, 25, and 30 mg/kg/d continuous infusion regimens, respectively. All regimens allowed for an area under the concentration:minimum inhibitory concentration ratio of 400:1 for minimum inhibitory concentrations of less than or equal to 0.5 mg/L for a 90% PTA. None of the simulated regimens had a greater than 90% probability of achieving an area under the concentration:minimum inhibitory concentration ratio of 400:1 for vancomycin minimum inhibitory concentrations greater than or equal to 1 mg/L while maintaining trough concentrations in the range of 10-20 mg/L. To our knowledge, this is the first pharmacokinetic and pharmacodynamic study of neonates receiving vancomycin with a contemporary ¼-inch extracorporeal life support circuit including the Quadrox-iD Pediatric oxygenator (Maquet Cardiovascular, LLC). The data suggest differences in vancomycin pharmacokinetics compared with previous extracorporeal life support data, notably a more rapid clearance, which could result in lower vancomycin concentrations. Considering this, a more aggressive initial dosing regimen may need to be employed in infants on extracorporeal life support.

Evaluation of haemodialysis as a protective technique for preventing high daily dose amikacin nephrotoxicity: an experimental study in an ovine model

Changes in pharmacokinetic parameters of critically ill patients make the treatment of infections challenging, particularly when multidrug-resistant bacteria are involved. The aim of this study was to evaluate the ability of haemodialysis to reduce the exposure to high dose amikacin and prevent nephrotoxicity. Amikacin 50 mg/kg was administered intravenously to six adult sheep once-daily for four days. The sheep were divided into two groups according to the implementation (group 1) or not (group 2) of haemodialysis. In group 1, haemodialysis was performed for 4 h, initiated 2 h after starting amikacin infusion. Amikacin area under the curve (AUC) and trough concentrations (Cmin) were used as markers of amikacin-induced nephrotoxicity. The median haemodialysis amikacin clearance was 2.14 L/h (35.6 mL/min), 14% of the mean total body clearance for 24 h. Haemodialysis reduced Cmin (group 1: 0.3 µg/mL [0.3–1.1]; group 2: 1.4 µg/mL [1.1–3.9]; P = 0.0003). A trend towards reduced AUC with haemodialysis was observed (group 1: 1450 µg/mL⋅h [1311–1716]; group 2: 3126 µg/mL⋅h [2581–3171]; P = 0.10). In conclusion, haemodialysis seems interesting in reducing AUC and Cmin after the injection of high-dose of amikacin, parameters known to be involved in its induced nephrotoxicity, in an experimental ovine model.

Comparative Oral Bioavailability, Toxicokinetics, and Biotransformation of Enniatin B1 and Enniatin B in Broiler Chickens.

A toxicokinetic study of the Fusarium mycotoxins enniatin B1 (ENN B1) and enniatin B (ENN B) was performed in broiler chickens. Each animal received ENN B1 or B orally via an intracrop bolus and intravenously at a dose of 0.2 mg/kg body weight. Both enniatins were poorly absorbed after oral administration, with absolute oral bioavailabilities of 0.05 and 0.11 for ENNs B1 and B, respectively. Both enniatins were readily distributed to the tissues, with mean volumes of distribution of 25.09 and 33.91 L/kg for ENNs B1 and B, respectively. The mean total body clearance was rather high, namely, 6.63 and 7.10 L/h/kg for ENNs B1 and B, respectively. Finally, an UHPLC-HRMS targeted approach was used to investigate the phase I and II biotransformations of both mycotoxins. Oxygenation was the major phase I biotransformation pathway for both ENNs B1 and B. Neither glucuronide nor sulfate phase II metabolites were detected.

Phase 1 study of N 1,N 11-diethylnorspermine (DENSPM) in patients with advanced hepatocellular carcinoma

N(1),N(11)-diethylnorspermine (DENSPM), a synthetic analog of the naturally occurring polyamine spermine, can induce polyamine depletion and inhibit tumor cell growth. The objectives of this phase I study were to assess the safety, maximum-tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of DENSPM in advanced HCC. Patients with measurable advanced HCC, Child-Pugh A or B cirrhosis, CLIP score ≤3, and Karnofsky score ≥60 % were eligible. DENSPM was given as a short intravenous infusion on days 1, 3, 5, 8, 10, and 12 of each 28-day cycle. The starting dose of 30 mg/m(2) was escalated at a fixed increment of 15 mg/m(2) until the MTD was identified. The plasma pharmacokinetics of DENSPM for the first and last doses given in cycle 1 was characterized. Thirty-eight patients (male 79 %; median age 61 years; Child-Pugh A 84 %; ≥1 prior systemic therapy 45 %) were enrolled and treated. The most common adverse events (AEs) ≥grade 1 were fatigue (53 %), nausea (34 %), diarrhea (32 %), vomiting (32 %), anemia (29 %), and elevated AST (29 %). The most common grade 3-4 AEs were fatigue/asthenia (13 %), elevated AST (13 %), hyperbilirubinemia (11 %), renal failure (8 %), and hyperglycemia (8 %). The MTD was 75 mg/m(2). There were no objective responses, although 7/38 (18 %) patients achieved stable disease for ≥16 weeks. The overall mean (±SD) total body clearance for the initial dose, 66.3 ± 35.9 L/h/m(2) (n = 16), was comparable to the clearance in patients with normal to near normal hepatic function. Drug levels in plasma decayed rapidly immediately after the infusion but remained above 10 nM for several days after dosing at the MTD. N(1),N(11)-diethylnorspermine treatment at the MTD of 75 mg/m(2), given intravenously every other weekday for two consecutive weeks of each 28-day cycle, was relatively well tolerated in patients with advanced HCC including those with mild-to-moderate liver dysfunction. This administration schedule provided prolonged systemic exposure to potentially effective concentrations of the drug. Stable disease was seen in 18 % of patients receiving DENSPM treatment. Further evaluation of DENSPM monotherapy for advanced HCC does not appear to be justified because of insufficient evidence of clinical benefit in the patients evaluated in this study.

Pharmacokinetics and pharmacodynamics of d-chlorpheniramine following intravenous and oral administration in healthy Thoroughbred horses

The pharmacokinetics of d-chlorpheniramine (CPM), a histamine H1-receptor antagonist, and its ability to inhibit of histamine-induced cutaneous wheal formation, were studied in healthy Thoroughbred horses (n=5). Following an intravenous (IV) dose of 0.5mg/kg bodyweight (BW), plasma drug disposition was very rapid, with the mean terminal half-life and total body clearance calculated as 2.7h and 0.7L/h/kg, respectively. The observed maximal inhibition of wheal formation following IV doses of 0.1 and 0.5mg/kg BW were 37.8% and 60.6% at 0.5h, respectively. Oral administration of CPM (0.5mg/kg BW) resulted in a bioavailability of 38%, which induced a peak plasma drug concentration at 1h and a maximal inhibition of wheal formation (39%) at 2h. A pharmacokinetic/pharmacodynamic link model showed that CPM in horses has lower efficacy, much lower potency and slightly lower sensitivity than other reported antihistamines. These results indicated that CPM should be administered at frequent intervals or at large dose rates to maintain therapeutic concentrations in horses.

PHARMACOKINETICS OF ENROFLOXACIN AFTER SINGLE DOSE ORAL AND INTRAVENOUS ADMINISTRATION IN THE AFRICAN PENGUIN (SPHENISCUS DEMERSUS)

The pharmacokinetics of a single dose of enrofloxacin administered orally, both pilled and in fish, and i.v. to African penguins (Spheniscus demersus) at 15 mg/kg were determined. Plasma concentrations of enrofloxacin and its metabolite ciprofloxacin were measured via high-pressure liquid chromatography with mass spectrometry. An i.v. administration of enrofloxacin resulted in an extrapolated mean plasma concentration of 7.86 microg/ml at time zero. Plasma volume of distribution for i.v. administration was 3.00 L/kg, with a mean elimination half-life of 13.67 hr and a mean total body clearance rate of 3.03 ml/min/kg. Oral administration of enrofloxacin achieved a mean maximum plasma concentration of4.38 microg/ml at 4.8 hr after administration when pilled, whereas mean maximum plasma concentration was 4.77 microg/ml at 1.59 hr after administration when given in fish. Mean terminal elimination half-life was 13.79 hr pilled and 11.93 hr when given in fish. Low concentrations of ciprofloxacin were detected after both oral and i.v. enrofloxacin administration. Enrofloxacin administered to African penguins at 15 mg/kg p.o.q. 24 hr, whether in fish or pilled, is expected to achieve the surrogate markers of efficacy for bacteria with a minimum inhibitory concentration of 0.5 microg/ml or less; however, clinical studies are needed to determine efficacy.

Tolerability and Dose Proportional Pharmacokinetics of Pasireotide Administered as a Single Dose or Two Divided Doses in Healthy Male Volunteers: A Single-Center, Open-Label, Ascending-Dose Study

BackgroundPasireotide is a multireceptor-targeted somatostatin analogue with high binding affinity for somatostatin receptor subtypes SST 1, 2, 3, and 5. ObjectiveTo evaluate the safety profile, tolerability, and pharmacokinetic profile of pasireotide in single- and divided-dose regimens in healthy volunteers. MethodsA single-center, open-label, ascending-dose study was performed in healthy volunteers. Pasireotide, 900, 1200, and 1500 μg SC, was administered as either a single dose or as two divided doses given 12 hours apart, with a 7-day washout period between treatments. ResultsSeventeen men (median age, 26 years) were enrolled. Their median weight was 81 kg, and 65% were white. One participant dropped out because of a grade 2 adverse event; most other adverse events were mild and affected the gastrointestinal tract. Blood glucose concentration increased after pasireotide administration, but returned to normal within 10 hours. After single-dose administration, pasireotide plasma concentration peaked rapidly at 15 minutes to 1 hour after dosing, followed by a tri-exponential (α, β, and γ phases) decline over time. Mean t½ values during the α, β, and γ phases were approximately 2 to 3, 12 to 17, and 54 to 97 hours, respectively. In the single-dose cohort, the mean (SD) AUC∞ was 110 (29), 149 (42), and 188 (52) h · ng/mL in the 900-, 1200-, and 1500-μg groups, respectively. Time to reach Cmax was 0.69 (0.41), 0.59 (0.38), and 0.56 (0.18) hours in the 900-, 1200-, and 1500-μg groups, respectively. AUC∞ values were similar in the single-dose and divided-dose cohorts. Mean total body clearance was 8 to 9 L/h across the dosage groups and dosing regimens, indicating a linear pharmacokinetic profile between doses. ConclusionsWhen administered as a single- or divided-dose regimen, pasireotide had a favorable tolerability profile in this selected group of healthy male volunteers. Its pharmacokinetic profile indicated rapid absorption, low clearance, high volume of distribution, and a long terminal half-life.

Absolute Oral Bioavailability of Almorexant, a Dual Orexin Receptor Antagonist, in Healthy Human Subjects

Background/Aims: The aim of this single-center, open-label study was to assess the absolute bioavailability of an oral (tablet) versus intravenous formulation of almorexant in healthy subjects. Methods: A pilot phase in 3 healthy male subjects, which preceded the main study, consisted of a single 30-min intravenous infusion of 10 mg almorexant. Its objectives were to ensure the tolerability of the intravenous formulation and to select the intravenous dose for the main study. The main study was a randomized, two-way crossover study in 20 healthy subjects (10 males and 10 females). Subjects received a single oral dose of 200 mg almorexant and a single 30-min intravenous infusion of 20 mg almorexant. Results: All 23 subjects completed the study as planned. Almorexant was well tolerated; the main observed adverse events were somnolence and fatigue. A geometric mean total body clearance of 43 l/h (95% CI 39–47) and a volume of distribution of 683 liters (95% CI 552–845) were determined. The absolute oral bioavailability of almorexant was 11.2% (90% CI 9.6–13.1). Conclusion: Almorexant seems to possess a pronounced first-pass effect and metabolism.

Disposition of Human Recombinant Lubricin in Naive Rats and in a Rat Model of Post-traumatic Arthritis After Intra-articular or Intravenous Administration

We have recently demonstrated that intra-articular (IA) administration of human recombinant lubricin, LUB:1, significantly inhibited cartilage degeneration and pain in the rat meniscal tear model of post-traumatic arthritis. In this report, we show that after a single IA injection to naïve rats and rats that underwent unilateral meniscal tear, [(125)I]LUB:1 had a tri-phasic disposition profile, with the alpha, beta, and gamma half-life estimates of 4.5 h, 1.5 days, and 2.1 weeks, respectively. We hypothesize that the terminal phase kinetics was related to [(125)I]LUB:1 binding to its ligands. [(125)I]LUB:1 was detected on articular cartilage surfaces as long as 28 days after single IA injection. Micro-autoradiography analysis suggested that [(125)I]LUB:1 tended to localize to damaged joint surfaces in rats with meniscal tear. After a single intravenous (IV) dose to rats, [(125)I]LUB:1 was eliminated rapidly from the systemic circulation, with a mean total body clearance of 154 mL/h/kg and a mean elimination half-life (t (1/2)) of 6.7 h. Overall, LUB:1 has met a desired disposition profile of a potential therapeutic intended for an IA administration: target tissue (knee) retention and fast elimination from the systemic circulation after a single IA or IV dose.

Gender Differences in Pharmacokinetics of Antipyrine in a Simulated Weightlessness Rat Model

Gender differences in gastrointestinal physiology and hepatic metabolizing enzyme systems may potentially modify drug absorption and disposition during spaceflight. This study evaluated the effect of simulated weightlessness on gender-related pharmacokinetic differences of intravenously administered antipyrine, a marker compound for hepatic oxidative metabolism, using the tail-suspended (TS) rat model for microgravity. TS rats were suspended at a 45 degrees angle from the cage floor for 3 d prior to and for 8 h after antipyrine administrations. Control and TS jugular vein-cannulated male and female Sprague-Dawley rats received a 20 mg x kg(-1) intravenous dose of antipyrine. Serial blood samples (0.25 ml) were collected from each rat at 14 predetermined times. Plasma drug concentrations were measured by a HPLC method. Plasma antipyrine concentration-time data were analyzed using noncompartmental pharmacokinetic methods. Statistical comparisons were made using the nonparametric Mann-Whitney U-test. In male rats, simulated weightlessness appreciably and significantly reduced the mean total body clearance of antipyrine by 44.7% and increased the mean residence time of antipyrine by 58.3%, but had no significant effect on the apparent volume of distribution of the drug. In striking contrast to that observed in male rats, simulated weightlessness had no significant effect on the disposition kinetics of antipyrine in female rats. Significant gender difference exists in microgravity-induced changes in drug disposition, where simulated weightlessness apparently has more of an effect in male versus female rats in terms of hepatic enzymatic functions.

The Pharmacokinetics of Ropivacaine After Intraperitoneal Administration

Intraperitoneal local anesthetic administration provides perioperative analgesia during laparoscopic procedures. We compared the pharmacokinetics of intraperitoneal ropivacaine administered by instillation or nebulization. A crossover study was performed on 5 pigs under standardized general anesthesia with a carbon dioxide pneumoperitoneum of 12 mm Hg for 1 hour. Each animal, acting as its own control, was studied twice with an 8-day interval and received, in a randomized sequence, 3 mg/kg ropivacaine either by intraperitoneal instillation at the time of pneumoperitoneum exsufflation or by continuous nebulization in the carbon dioxide insufflation tubing. Arterial blood samples were taken every 10 minutes up to 120 minutes, and then hourly up to 6 hours. Ropivacaine concentrations were measured using high-performance liquid chromatography with ultraviolet-visible detection. The plasma-free fraction was evaluated after plasma ultracentrifugation. Pharmacokinetic parameters were calculated using both noncompartmental and compartmental analysis. The mean values were compared using the Student t test, or Wilcoxon test for paired series. The data were described by a 1-compartment model for both ropivacaine administration techniques, with a delay of 10 minutes for the nebulization group. The maximal ropivacaine concentrations were 0.96 μg/mL for the nebulization group and 0.92 μg/mL for the instillation group (P = 0.66). The ropivacaine absorption constant was lower in the nebulization group (0.043 vs 0.083 min(-1), P = 0.02). There were no differences in the elimination half-life, elimination constant, mean total body clearance, distribution volume, mean area under the curve, and mean residence time. The free fraction of ropivacaine was also similar in the 2 groups. The pharmacokinetic profile of ropivacaine nebulization is similar to direct intraperitoneal instillation, but with a lower absorption rate.

A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas

Ixabepilone is an epothilone, a novel class of non-taxane microtubule stabilizing agents. A phase I/II and pharmacokinetic trial of ixabepilone was conducted in patients with recurrent high-grade gliomas. Adult patients received ixabepilone as a 1-h infusion daily for 5days every 3weeks. A modified continual reassessment method was used to escalate doses, beginning at 5.0mg/m(2), in patients stratified by use or non-use of enzyme inducing antiepileptic drugs (EIAED). In the phase I study, the maximum tolerated dose (MTD) and pharmacokinetics of ixabepilone were determined for each group. The phase II study used a two-stage design to evaluate response rate. Secondary endpoints were survival and 6-month progression free survival. In the phase I trial, 38 patients (median age 54years) were enrolled. The MTD was 6.8mg/m(2) for patients not taking EIAEDs and 9.6mg/m(2) for those taking EIAEDs. The dose limiting toxicities in both groups were hematologic. Twenty-three patients (median age 54years) were enrolled in the first stage of the phase II trial. No objective responses were observed. Median overall survival was 5.8 (95% CI, 5.0-8.6) months and 6-month PFS rate was 4% (95% CI, 0-22%). The overall mean total body clearance for ixabepilone was significantly higher (P=0.003) in patients receiving EIAEDs (36±11l/h/m(2)) than those not (24±9.2l/h/m(2)). Patients on EIAEDs had a substantially higher MTD likely due to induction of cytochrome P450. Ixabepilone had no activity in patients with recurrent high-grade gliomas.

A phase I escalating single-dose and weekly fixed-dose study of cetuximab pharmacokinetics in Japanese patients with solid tumors

Cetuximab is a therapeutic immunoglobulin G1 monoclonal antibody that recognizes the epidermal growth factor receptor (EGFR). This phase I dose-escalation study was designed to assess the safety and pharmacokinetics (PK) of cetuximab in Japanese patients with EGFR-expressing, advanced, solid tumors and also to look for evidence of antitumor efficacy. Thirty patients were enrolled in the study; 29 with colorectal adenocarcinomas and one with an adenocarcinoma of the lung. Patients received an initial/weekly infusion of cetuximab at dose levels of 100/100 (dose level 1), 250/250 (dose level 2), 400/250 (dose level 3), 500/250 (dose level 4) or 400/250 (dose level 5) mg/m(2), for 7 or more weeks, with an interval between the initial and second infusion of 1 (dose level 5 representing the standard regimen) or 2 weeks (dose levels 1-4 of the non-standard regimens). No dose-limiting toxicities (DLTs) were observed during the evaluation period. All patients had at least one adverse event (AE). The most common cetuximab-related AEs were skin toxicity (93% of patients), including acneiform dermatitis (83% of patients). Two patients experienced cetuximab-related grade 3 AEs of skin toxicity and diarrhea after DLT evaluation. C (max) and AUC(0-infinity) after the initial infusion showed dose-proportional increases. Mean total body clearance (CL) values decreased with dose at the lower dose levels. At doses of >or=400 mg/m(2), CL values appeared to level off. Mean trough concentrations for dose level 5 were constant from week 4 (day 29) onward. Two patients (8%) achieved partial response (at 100/100 mg/m(2)). The overall disease control rate (partial response + stable disease) was 58%. The current study demonstrated that cetuximab PK and safety profiles are similar between Japanese and non-Japanese patient populations. It would appear that the standard dose of an initial 2-h infusion of 400 mg/m(2) followed thereafter by weekly 1-h infusions of 250 mg/m(2) for non-Japanese patients is feasible for future clinical studies in Japanese patients.

Propofol

Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. By Audrey Shafer, Van A. Doze, Steven L. Shafer, and Paul F. White. Anesthesiology 1988; 69:348-56. Reprinted with permission.The pharmacokinetic and pharmacodynamic properties of propofol (Diprivan) were studied in 50 elective surgical patients. Propofol was administered as a bolus dose, 2 mg/kg iv, followed by a variable-rate infusion, 0-20 mg/min, and intermittent supplemental boluses, 10-20 mg iv, as part of a general anesthetic technique that included nitrous oxide, meperidine, and muscle relaxants. For a majority of the patients (n = 30), the pharmacokinetics of propofol were best described by a two-compartment model. The propofol mean total body clearance rate was 2.09 +/- 0.65 l/min (mean +/- SD), the volume of distribution at steady state was 159 +/- 57 l, and the elimination half-life was 116 +/- 34 min. Elderly patients (patients older than 60 yr vs. those younger than 60 yr) had significantly decreased clearance rates (1.58 +/- 0.42 vs. 2.19 +/- 0.64 l/min), whereas women (vs. men) had greater clearance rates (33 +/- 8 vs. 26 +/- 7 ml x kg x min ) and volumes of distribution (2.50 +/- 0.81 vs. 2.05 +/- 0.65 l/kg). Patients undergoing major (intraabdominal) surgery had longer elimination half-life values (136 +/- 40 vs. 108 +/- 29 min). Patients required an average blood propofol concentration of 4.05 +/- 1.01 micrograms/ml for major surgery and 2.97 +/- 1.07 micrograms/ml for nonmajor surgery. Blood propofol concentrations at which 50% of patients (EC50) were awake and oriented after surgery were 1.07 and 0.95 microgram/ml, respectively. Psychomotor performance returned to baseline at blood propofol concentrations of 0.38-0.43 microgram/ml (EC50). This clinical study demonstrates the feasibility of performing pharmacokinetic and pharmacodynamic analyses when complex infusion and bolus regimens are used for administering iv anesthetics.

Acute renal failure alters the kinetics of pralidoxime in rats

There is a trend towards increasing doses of pralidoxime to treat human organophosphate poisonings that may have relevance in subpopulations. Indeed, pralidoxime is eliminated unchanged by the renal route. This study assesses the effect of renal failure on the kinetics of pralidoxime in a rat model of acute renal failure induced by potassium dichromate administration. On the first day, Sprague–Dawley rats received subcutaneously potassium dichromate (study) or saline (control). Forty-eight hours post-injection, animals received pralidoxime methylsulfate (50 mg/kg of pralidoxime base) intramuscularly. Blood specimens were sampled during 180 min after the injection. Urine was collected daily during the 3 days of the study. Plasma pralidoxime concentrations were measured by liquid chromatography with electrochemical detection. There was a 2-fold increase in mean elimination half-life and a 2.5-fold increase in mean area under the curve in the study compared to the control group. The mean total body clearance was halved in the study compared to the control group. Our study showed acute renal failure does not modify the distribution of pralidoxime but significantly alters its elimination from plasma. These results suggest that dosages of pralidoxime should be adjusted in organophosphate-poisoned humans with renal failure when using high dosage regimen of pralidoxime.

Phase I and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas

Karenitecin is a highly lipophilic camptothecin analogue with a lactone ring that is relatively resistant to inactivating hydrolysis under physiologic conditions. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of karenitecin in adults with recurrent malignant glioma (MG), to describe the effects of enzyme-inducing antiseizure drugs (EIASDs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Karenitecin was administered intravenously over 60 min daily for 5 consecutive days every 3 weeks to adults with recurrent MG who had no more than one prior chemotherapy regimen. The continual reassessment method was used to escalate doses, beginning at 1.0 mg/m(2)/day, in patients stratified by EIASD use. Treatment was continued until disease progression or treatment-related dose-limiting toxicity (DLT). Plasma pharmacokinetics was determined for the first daily dose of karenitecin. Thirty-two patients (median age, 52 years; median KPS score, 90) were accrued. Seventy-eight percent had glioblastoma, and 22% had anaplastic glioma. DLT was reversible neutropenia or thrombocytopenia. The MTD was 2.0 mg/m(2) in daggerEIASD patients and 1.5 mg/m(2) in -EIASD patients. The mean (+/-SD) total body clearance of karenitecin was 15.9 +/- 9.6 liters/h/m(2) in daggerEIASD patients and 10.2 +/- 3.5 liters/h/m(2) in -EIASD patients (p = 0.02). No objective responses were observed in 11 patients treated at or above the MTD. The total body clearance of karenitecin is significantly enhanced by the concurrent administration of EIASDs. This schedule of karenitecin, a novel lipophilic camptothecin analogue, has little activity in recurrent MG.

Pharmacokinetics of diclofenac and its interaction with enrofloxacin in sheep

The pharmacokinetics of diclofenac was investigated in sheep given diclofenac alone (1 mg kg −1, i.v. or i.m.) and in combination with enrofloxacin (5 mg kg −1, i.v.). The plasma concentration–time data following i.v. administration of diclofenac was best described by a two compartment open pharmacokinetic model. The elimination half-life ( t 1/2 β ), area under concentration–time-curve (AUC), volume of distribution (Vd area), mean residence time (MRT) and total body clearance (Cl B) were 1.03 ± 0.18 h, 12.17 ± 1.98 μg h ml −1, 0.14 ± 0.02 L kg −1, 1.36 ± 0.16 h and 0.10 ± 0.02 L kg −1 h −1, respectively. Following i.m. administration of diclofenac alone and in conjunction with enrofloxacin, the plasma concentration–time data best fitted to a one compartment open model. The t 1/2 β , AUC, Vd area, MRT and Cl B were 1.33 ± 0.10 h, 7.32 ± 1.01 μg h mL −1, 0.13 ± 0.01 L kg −1 and 0.07 ± 0.01 L kg −1 h −1, respectively. Co-administration of enrofloxacin did not affect Vd area and MRT but absorption rate constant ( K a), β, t 1 / 2 K a , t 1/2 β , AUC, AUMC, Cl B and bioavailability ( F) were significantly increased. This may be due to direct inhibition of cytochrome P 450 isozymes by enrofloxacin. A dose of 1.4 mg kg −1 of diclofenac administered every 6 h may be appropriate for use in sheep.