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Pharmacokinetics of Ropivacaine in Patients with Chronic End-stage Liver Disease

Ropivacaine is mainly eliminated by hepatic metabolism. The authors studied the effect of chronic end-stage liver disease on the pharmacokinetics of ropivacaine. Thirteen patients with chronic end-stage liver disease and eight healthy volunteers received a single dose of 0.6 mg/kg ropivacaine intravenously over 30 min. Ropivacaine, 3-hydroxyropivacaine, and 2',6'-pipecoloxylidide were measured in venous plasma and urine. Peak ropivacaine plasma concentrations were similar. Patients with chronic end-stage liver disease had, on average, 60% lower total (P=0.001) and 56% lower unbound plasma clearance (P=0.002), 59% higher steady state volume of distribution (P=0.03), and 4.2-fold longer half-life (P<0.001) of ropivacaine. Of the variation in total ropivacaine clearance, 69% was accounted for by variation in albumin, 57% in prealbumin, 25% in international normalized ratio of plasma thromboplastin time, and 24% in galactose half-life. The patients excreted a larger fraction of the original dose as unchanged ropivacaine (2.1% vs. 0.3%; P<0.001) and a smaller fraction as 3-hydroxyropivacaine (11% vs. 27%; P=0.001). The fraction excreted as 2',6'-pipecoloxylidide (4.7% vs. 5.0%) was similar. Ropivacaine clearance is decreased in chronic end-stage liver disease. A normal dose can be considered for a single block in patients with liver impairment, because the peak plasma concentrations were essentially similar. When using a postoperative ropivacaine infusion in a patient with end-stage liver disease, the lowest effective dose should be used for the shortest possible time and the patient should be monitored closely, because systemic toxicity cannot be ruled out. Because of wide interindividual differences in pharmacokinetics in patients with liver disease, no definitive dosing instructions can be given.

Disposition Kinetics of Difloxacin After Intravenous, Intramuscular and Subcutaneous Administration in Calves

The pharmacokinetics of difloxacin (Dicural) was studied in a crossover study using three groups (n = 4) of male and female Friesian calves after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administrations of 5 mg/kg body weight. Drug concentration in plasma was determined by high-performance liquid chromatography using fluorescence detection. The plasma concentration-time data following i.v. administration were best fitted to a two-compartment open model and those following i.m. and s.c. routes were best fitted using one-compartment open model. The collected data were subjected to a computerized kinetic analysis. The mean i.v., i.m. and s.c. elimination half-lives (t(1/2beta)) were 5.56 +/- 0.33 h, 6.12 +/- 0.42 h and 7.26 +/- 0.6 h, respectively. The steady-state volume of distribution (V(dss)) was 1.12 +/- 0.09 L/kg and total body clearance (Cl(B)) was 2.19 +/- 0.1 ml/(min x kg). The absorption half lives (t(1/2ab)) were 0.38 +/- 0.027 h and 2.1 +/- 0.09 h, with systemic bioavailabilities (F) of 96.5% +/- 6.4% and 84% +/- 5.5% after i.m. and s.c. administration, respectively. After i.m. and s.c. dosing, peak plasma concentrations (C(max)) of 3.38 +/- 0.13 microg/ml and 2.18 +/- 0.12 microg/ml were attained after (t(max)) 1.22 +/- 0.20 h and 3.7 +/- 0.52 h. The MIC90 of difloxacin for Mannheimia haemolytica was 0.29 +/- 0.04 microg/ml. The AUC/MIC90 and C(max)/MIC90 ratios for difloxacin following i.m. administration were 120 and 11.65, respectively and following s.c. administration were 97.58 and 7.51, respectively. Difloxacin was 31.7-36.8% bound to calf plasma protein. Since fluoroquinolones display concentration-dependent activities, the doses of difloxacin used in this study are likely to involve better pharmacodynamic characteristics that are associated with greater clinical efficacy following i.m. administration than following s.c. administration.

Differential effect of chronic renal failure on the pharmacokinetics of lidocaine in patients receiving and not receiving hemodialysis

The effect of chronic renal failure (CRF) on the pharmacokinetics of lidocaine, a drug cleared almost exclusively by hepatic metabolism, has thus far only been evaluated in patients undergoing regular hemodialysis. This study had 2 objectives: (1) to investigate the effect of CRF on the pharmacokinetics of lidocaine in both patients undergoing hemodialysis and patients not undergoing hemodialysis and (2) to test the effects of plasma from the patients examined and of lidocaine metabolites possibly accumulated in vivo on lidocaine biotransformation in vitro. In a clinical investigation we studied the kinetics of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), after intravenous injection of 1 mg/kg lidocaine in 15 healthy volunteers (creatinine clearance [CL(cr)] >80 mL/min x 1.73 m(-2)), 10 subjects with moderate renal insufficiency (CL(cr) between 30 and 60 mL/min x 1.73 m(-2)), 10 subjects with severe renal insufficiency (CL(cr) <30 mL/min x 1.73 m(-2)), and 10 functionally anephric patients undergoing long-term hemodialysis. In experiments in vitro we determined the effects of plasma and GX on the formation rate of the primary lidocaine metabolite, MEGX, by use of human liver microsomes. In patients not undergoing hemodialysis, lidocaine kinetic parameters were altered in proportion to the degree of renal function impairment, but only in patients with severe renal insufficiency were differences statistically significant: clearance was about half that of control subjects (mean +/- SD, 6.01 +/- 2.54 mL/min x kg versus 11.87 +/- 2.97 mL/min x kg; P < .001), and half-life was approximately doubled (4.55 +/- 1.71 hours versus 2.24 +/- 0.55 hours, P < .001). No such alterations were observed in patients undergoing regular hemodialysis, whose values were similar to those of the control group. The steady-state volume of distribution and MEGX levels were independent of renal function, whereas GX levels were more than double those of control subjects (P < .05) in all CRF groups. No inhibitory effect of plasma was observed, for any of the subjects examined, on lidocaine biotransformation in vitro. GX was found to be a competitive inhibitor, but its apparent inhibition constant value (52 +/- 6 micromol/L) was 2 orders of magnitude higher than its concentrations in vivo. Our in vivo findings have both clinical and methodologic implications: (1) Lidocaine dose adjustment may be required in patients with severe renal insufficiency who are not receiving hemodialysis. (2) Results of studies evaluating the effect of CRF on metabolic drug disposition are not of general validity, unless both patients undergoing hemodialysis and patients not undergoing hemodialysis have been examined. Our in vitro observations exclude that impairment of lidocaine disposition is the result of direct inhibition of metabolizing enzymes by accumulated metabolites or uremic toxins. Alternative mechanisms, suggested by the results of recent in vitro studies, are discussed.

Teicoplanin Population Pharmacokinetic Analysis in Hospitalized Patients

The goal of this study was to build a population pharmacokinetic (PK) model to characterize the population PK parameters in our hospitalized patients. Teicoplanin serum concentrations from clinical routine were used. Antibiotic dose history and blood collection times were recorded and analyzed with NONMEM-V. Demographic and biologic data creatinine clearance (CLcr), weight (WT), and albumin (Alb) were tested for inclusion as covariates in the basic model. Intraindividual and residual variability were modeled. One hundred seven sparse samples (mainly trough levels), from 79 patients, were included. A 2-compartment PK model characterized by clearance (CL), central compartment volume of distribution (Vc), intercompartment clearance, and steady-state volume of distribution (VSS) with first-order elimination adequately described the data. CLcr and WT significantly influenced teicoplanin CL (CL = 0.57[0.15]*(1+0.0048[0.39]*(CLcr - averageCLcr)*WT) L/h). VSS was not affected by any covariate (VSS = 50.2[0.13]L). A negative trend between Alb and individual VSS estimates was observed without statistical significance. In a new data set, bias and precision resulted in mean values of -3.24% and 9.42%, respectively. In conclusion, CLcr and WT are significant covariates on teicoplanin CL. Results from predictive accuracy and precision show the usefulness of this model for implementation in a therapeutic drug monitoring program in the near future.

Preclinical Drug Metabolism and Pharmacokinetic Evaluation of GW844520, A Novel Anti-Malarial Mitochondrial Electron Transport Inhibitor

GW844520 is a potent and selective inhibitor of the cytochrome bc1 complex of mitochondrial electron transport in P. falciparum, the parasite primarily responsible for the mortality associated with malaria worldwide. GW844520 is fully active against the parasite including resistance isolates, showing no cross resistance with agents in use. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-malarial. GW844520 had low blood clearance of about 0.5–4% of hepatic blood flow and a steady-state volume of distribution of 2–4 times total body water in mouse, rat, dog, and monkey. Oral bioavailability was high (51–100%). Consistent with the in vivo data, GW844520 had low intrinsic clearance in liver microsomes and hepatocytes of animal and human origin, high passive cellular permeability and was not a P-glycoprotein substrate. GW844520 did not associate appreciably with blood cells but was highly bound to plasma proteins (>99%) in all species. GW844520 was a substrate and inhibitor of human CYP2D6 but not of CYP1A2, 2C9, 2C19, and 3A4. This conjunctive analysis supports continued evaluation of this compound in definitive pre-IND studies and exemplifies our strategy supporting the discovery of novel agents to treat diseases of the developing world.

MK-0457, a Novel Aurora Kinase and BCR-ABL Inhibitor, Is Active Against BCR-ABL T315I Mutant Chronic Myelogenous Leukemia (CML).

Background. MK-0457 (VX-680) is a small-molecule inhibitor of aurora kinases A, B, and C, and wildtype and mutant BCR-ABL, including the T315I variant. The T315I BCR-ABL mutation mediates high level resistance to imatinib, dasatinib and nilotinib. MK-0457 has in vitro activity against cells expressing wild-type or mutated BCR-ABL, including the T315I BCR-ABL mutation, at a concentration of ~1μM. A Phase I study of MK-0457 is being conducted in patients with refractory hematologic malignancies, including CML.Methods. After IRB approval, 15 consenting patients with refractory CML (median 5 prior regimens), ECOG performance status ≤2, and adequate organ function were enrolled using a standard dose escalation scheme with 3 patients/dose level until dose-limiting toxicity (DLT), followed by 6 patients/level. MK-0457 was administered by continuous 5-day intravenous infusion every 2 to 3 weeks. DLT was defined as grade 3 or higher non-hematologic toxicity during cycle 1. Pharmacokinetics (PKs) were collected pre-dose through 168 h and analyzed for MK-0457 by HPLC/mass spec. Steady state volume of distribution (Vdss), clearance (CL), maximal concentration (Cmax) and terminal half-life (t1/2) were determined by WinNonLin.Results. Fifteen CML patients received MK-0457 dosed at 8, 12, 16, 20, 24, 28, and 32 mg/m2/hr. All but three of these patients had a history of accelerated phase or blast crisis. Eleven of these patients carried the BCR-ABL T315I mutation. All eleven BCR-ABL T315I mutant CML patients demonstrated clinical signals of anti-leukemic activity. By conventional criteria, there was one major hematological response, four minor hematological responses, one complete cytogenetic response, two partial cytogenetic responses, and one minimal cytogenetic response. Some degree of molecular response, as measured by BCR-ABL:ABL transcript ratio, was detected in five of six patients for whom such data were available. The longest a patient was treated was for 15 cycles, and is still ongoing. The patients with the best clinical response had the largest magnitude inhibition of BCR-ABL in leukemia cells as measured by levels of phosphoCRKL, a substrate of the BCR-ABL fusion kinase. None of the patients without the BCR-ABL T315I mutation showed objective responses. Remarkably, no drug-related non-hematological toxicity was observed. Some patients had apparent myelosuppression, which is an expected mechanism-based side effect of Aurora kinase inhibition. Plasma concentrations reached steady state rapidly (i.e., within 24 h) and declined biexponentially after the end of infusion; after a rapid initial decay, a slower decaying terminal phase demonstrated a t1/2 ~15 h. Steady state plasma concentrations are ≥ 1μM at a dose level of ≥ 20 mg/m2/hr.Conclusion. MK-0457 is very well tolerated and achieves plasma levels similar to those causing efficacy in preclinical models of CML. MK-0457 is the first T315I BCR-ABL inhibitor to show activity against this highly refractory, poor prognostic subpopulation of CML. Further evaluation of MK-0457 alone and in combination with other BCR-ABL inhibitors in CML is warranted.

Gatifloxacin Pharmacokinetics in Healthy Men and Women

The sex-based pharmacokinetics of gatifloxacin were investigated. Healthy subjects (6 men, 6 women) received a single oral dose of gatifloxacin 400 mg. Blood and urine samples were collected, and gatifloxacin concentrations were determined by high-performance liquid chromatography. Pharmacokinetic parameters were estimated by fitting appropriate models to the serum concentration-time data using ADAPT II. Linear regression analysis was used to determine the influence of sex and weight on the oral clearance (CL(s)/F) and apparent steady-state volume of distribution (V(ss)/F) of gatifloxacin. Women had a significantly smaller V(ss)/F compared to men (93.5 +/- 21.3 L vs 128.8 +/- 16.2 L, P = .009); however, there was no significant difference when normalized for total body weight (TBW) or lean body weight (LBW). Neither CL(s)/F nor peak serum concentration (C(max)) was significantly different between sexes, although C(max) was 25% higher in women (P = .06). Regression analyses revealed that TBW (R(2) = .63) and LBW (R(2) = .65) were strong predictors of V(ss)/F. Given the smaller V(ss)/F, women may have slightly higher maximum concentrations, but these differences are unlikely to have clinical significance.

Transport, Metabolism, and in Vivo Population Pharmacokinetics of the Chloro Benztropine Analogs, a Class of Compounds Extensively Evaluated in Animal Models of Drug Abuse

Recently, extensive behavioral research has been conducted on the benztropine (BZT) analogs with the goal of developing successful therapeutics for cocaine abuse. The present study was conducted to characterize the contribution of dispositional factors in mediating the behavioral differences among the chloro BZT analogs and to identify cytochrome P450 enzymes involved in their metabolism. Bidirectional transport and efflux studies of four of the chloro BZT analogs were conducted. Screening with a panel of human and rat Supersomes was performed for 4',4''-diCl BZT. In addition, pharmacokinetic and brain distribution studies for 4'-Cl and 4',4''-diCl BZT in Sprague-Dawley rats were conducted. The permeability of the chloro analogs ranged from 8.26 to 32.23 and from 1.37 to 21.65 x 10(-6) cm/s, whereas the efflux ratios ranged from 2.1 to 6.9 and from 3.3 to 28.4 across Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) and Caco-2 monolayers, respectively. The P-glycoprotein (P-gp) inhibitor verapamil reduced the efflux ratios and enhanced the absorptive transport of the chloro BZT analogs. 4',4''-diCl BZT was a substrate of human CYP2D6 and 2C19 and rat 2C11 and 3A1. The brain uptake for 4'-Cl and 4',4''-diCl BZT was comparable and higher than previously reported for cocaine (brain-to-plasma partition coefficient = 4.6-4.7 versus 2.1 for cocaine). The rank order for t(1/2) was 4',4''-diCl BZT >> 4'-Cl BZT > cocaine and for steady-state volume of distribution was 4'-Cl BZT > 4',4''-diCl BZT >> cocaine. In conclusion, the chloro analogs differ significantly in their clearance and duration of action, which correlates to their behavioral profiles and abuse liability. Furthermore, these results suggest that the distinctive behavioral profile of these analogs is not due to limited brain exposure.

Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy.

Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (s.c.) doses of 2.25 microg/kg every week and s.c. doses of 6.75 microg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after s.c. doses of 0.5 microg/kg every week to 15 microg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important.

Pharmacokinetic Parameters of (R)-(−) and (S)-(+)-Flurbiprofen in Dairy Bovines

The aim of the study was to evaluate the pharmacokinetics of flurbiprofen (FBP) in different age groups and physiological status groups in dairy cattle. Ten Argentine Holstein bovines were divided into three different groups: 3 cows in early lactation, 3 cows in gestation and 4 newborn calves. Based on previous experience, all the animals received racemic FBP (50:50) at a dose of 0.5 mg/kg by intravenous administration. Blood samples were taken at predetermined times after administration of flurbiprofen. Plasma enantiomer concentrations were measured by HPLC. Total body clearance (ClB) of (S)-(+)-FBP was higher in calves than in cows (114.5, 136.4, 121.4, 128.9 microg/ml vs 22.0, 24.2, 46.5 microg/ml and 27.6, 25.3, 34.6 microg/ml). In calves the disposition kinetics showed stereoselective behaviour. Area under the concentration-time curve (AUC) was higher and Cl(B) and steady-state volume of distribution (V(ss)) were lower for (R)-(-)-FBP than for (S)-(+)-FBP. In cows, stereoselectivity was observed in Cl(B) and elimination half-life (t(1)/2) only in the early lactation group. In this study, enantioselective metabolic behaviour of FBP under the physiological situations studied was found. Hence, it is possible that both enantiomers of flurbiprofen may contribute to the drug's therapeutic effects, but further studies with the administration of separate enantiomers will be required to elucidate their metabolism.

A phase I clinical and pharmacokinetic (PK) trial of the aurora kinase (AK) inhibitor MK-0457 in cancer patients

3009 Background: The AKs are essential for mitotic progression, spindle formation, centrosome maturation, chromosomal segregation, and cytokinesis. Elevated expression occurs frequently in tumors. MK-0457 (VX-680) is a potent AK inhibitor, with Ki values of 0.66, 18 and 4.6 nM for AKs A, B and C, respectively. MK-0457 inhibits proliferation of transformed cells in vitro (IC50’s 15–113 nM), and induces colon and pancreatic cancer xenograft regressions. Methods: After IRB approval, consenting patients (pts) with refractory solid tumors (median 3 prior regimens, range 2–6) and adequate hematologic and organ function were enrolled using an accelerated dose escalation scheme with 1–2 pts/dose level until ≥ grade 2 toxicity, followed by 3–6 pts/level. MK-0457 was administered by continuous 5-day intravenous infusion every 28 days. Dose-limiting toxicity (DLT) was grade 3 non-hematologic or grade 4 hematologic toxicity ≥ 5 days, or grade 4 febrile neutropenia (FN) during cycle 1. PKs were collected pre-dose through 168 h and analyzed for MK-0457 and metabolites by HPLC/mass spec. Steady state volume of distribution (Vdss), clearance (CL), maximal concentration (Cmax) and terminal half-life (t1/2) were determined by WinNonLin. Results: 16 pts received MK-0457 dosed at 0.5, 1, 2, 4, 8, and 12 mg/m2/h. Median number of cycles was 2 (range 1–6). DLT was asymptomatic neutropenia ≥ 5 days at 12 mg/m2/h. At 8 mg/m2/h, 1 pt experienced FN in cycle 2; a second developed a grade 2 allergic reaction. Three pts achieved stable disease as best response, and two of them completed 6 cycles. Plasma concentrations reached steady state rapidly (i.e., within 24 h) and declined biexponentially after the end of infusion; after a rapid initial decay, a slower decaying terminal phase demonstrated a t1/2 ∼15 h. PK parameters include Vdss = 237 ± 107 (SD) L/m2 and CL = 517 ± 141 ml/min/m2. At 8 mg/m2/h, Cmax was ∼650 nM. Conclusion: MK-0457 is generally well tolerated and achieves plasma levels similar to those causing regressions in xenografts. CL is high and exposures achieved are roughly dose proportional. Because 8 mg/m2/h was well tolerated in heavily pre-treated pts, escalation to 10 mg/m2/h is underway. Baseline tumor samples will be assessed for predictive biomarkers at the recommended phase II dose. [Table: see text]

Phase I study of concurrent motexafin gadolinium (MGd) with radiation therapy for children with newly diagnosed brain stem gliomas (BSG): A Children’s Oncology Group study

9014 Background: MGd, a radiosensitizer that selectively accumulates in tumors, generates reactive oxygen species intracellularly. In preclinical experiments, MGd enhances RT-induced apoptosis. Methods: A multi-institutional Phase I dose escalation and pharmacokinetic (PK) study was performed in children with newly diagnosed BSG to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of MGd administered i.v. 2 to 5 hours prior to involved field radiotherapy (RT) (1.8 Gy/day, total 54 Gy). Cohort 1 received MGd, 1.7 mg/kg/dose M-F × 3 wks and cohort 2 received the same dose M, W and F × 6 wks. The 6 subsequent cohorts of 3 to 6 pts received MGd M-F × 6 weeks at doses of 1.9, 3.4, 4.4, 5.5, 7.1 and 9.2 mg/kg/dose. Serum for PK analysis, and MRI scans (MGd is detectable by MR), were obtained for analysis of drug accumulation and responses. Results: 44 pts (42 fully evaluable for toxicity) with a median age of 6 years (range 2–20) were enrolled. At the 9.2 mg/kg/dose, 2/2 pts experienced DLT. During subsequent expansion of the 7.1 and 5.5 mg/kg/dose cohorts, DLTs, including transaminitis, hypertension and urticaria, were observed in 2/5 and 2/6 pts. At the MTD of 4.4 mg/kg/dose, 1/6 pts had reversible grade 3 serum transaminase elevations. PK analysis showed biphasic elimination with a terminal t 1/2 of 6.4 h. At the MTD, serum MGd concentrations were &gt;250 ng/ml for 24 h. Serum clearance and steady-state volume of distribution were 0.0243 L/h/kg and 0.162 L/kg. MRI for intra-tumoral MGd distribution is ongoing. One patient had a CR and 4 had a PR. The estimated median survival is 10.3 months (95% confidence interval: 8.1 months-11.5 months). Conclusions: The recommended phase II dose of MGd for children with BSG is 4.4 mg/kg/d administered M-F × 6 weeks with involved field RT. A COG phase II trial is planned. [Table: see text]

Pharmacokinetics of the opioid antagonist N-methylnaltrexone and evaluation of its effects on gastrointestinal tract function in horses treated or not treated with morphine

To determine the pharmacokinetics and effects of the morphine antagonist N-methylnaltrexone (MNTX) on gastrointestinal tract function in horses when administered alone and in combination with morphine. 5 healthy adult horses. Horses were treated with MNTX (1 mg/kg, IV), and serial blood samples were collected for determination of drug pharmacokinetics. For evaluation of effects on the gastrointestinal tract when administered alone, MNTX was administered at a dosage of 0.75 mg/kg, IV, twice daily for 4 days. For evaluation of effects when administered concurrently with morphine, MNTX (0.75 mg/kg, IV, q 12 hours) and morphine (0.5 mg/kg, IV, q 12 hours) were administered for 6 days. Gastrointestinal variables evaluated were defecation frequency, weight of feces produced, fecal moisture content, intestinal transit time, and borborygmus scores. The time-concentration data for MNTX disposition best fit a 2-compartment model with a steady-state volume of distribution of 244.6 +/- 21.8 mL/kg, t1/2 of 47.04 +/- 11.65 minutes, and clearance of 11.43 +/- 1.06 mL/min/kg. Adverse effects were not observed at doses <or= 1 mg/kg. Administration of MNTX increased daily fecal weight. When administered concurrently with morphine, MNTX partially prevented the effects of morphine on the gastrointestinal tract by increasing defecation frequency, fecal weight, fecal moisture content, and borborygmus score, and by preventing increases in intestinal transit time. Because MNTX does not cross the blood-brain barrier, administration of the drug should not alter the analgesic effects of opioids and may attenuate the adverse gastrointestinal effects associated with use of opioids in horses.

Population pharmacokinetics of tipifarnib in healthy subjects and adult cancer patients

To characterize the population pharmacokinetics of tipifarnib. A total of 1083 subjects treated orally with a solution, capsule or tablet formulations of tipifarnib, given as a single dose or as multiple twice-daily doses (range 25-1300 mg) were combined with data from 1, 2 and 24 h intravenous infusions. A total of 3445 concentrations in the index data set were fitted by an open three-compartment linear disposition model with sequential zero-order input into the depot compartment, followed by a first-order absorption process, and lag time, using NONMEM V. The effect of patient covariates on tipifarnib pharmacokinetics was explored. The model was evaluated using goodness of fit plots and relative error measurements for 3894 concentrations in the test data set. Computer simulations were undertaken to evaluate the effect of covariates on tipifarnib pharmacokinetics. Tipifarnib oral bioavailability (26.7%) did not differ between the formulations. The absorption rate from the solution was faster than from the solid forms. Whereas the absorption rate and systemic clearance were more rapid in healthy subjects, the extent of absorption and the steady-state volume of distribution were comparable in cancer patients and healthy subjects. Systemic clearance in cancer patients (21.9 l h-1) exhibited a statistically significant relationship with total bilirubin. The typical volume of the central compartment in cancer patients (54.6 l 70 kg-1) was directly proportional to body weight. The clinical relevance of these covariates in cancer patients is questionable as there was a substantial overlap in simulated concentration-time profiles across a wide range of covariate values. A population PK approach has been used to integrate data gathered during clinical development and to characterize the pharmacokinetics of tipifarnib. Individualization of dose based on body weight or total bilirubin concentration in adult cancer patients is not warranted.

METABOLISM OF [14C]GEMOPATRILAT AFTER ORAL ADMINISTRATION TO RATS, DOGS, AND HUMANS

This study describes the pharmacokinetic parameters of gemopatrilat, a potent vasopeptidase inhibitor, in humans and the comparative biotransformation of the compound in rats, dogs, and humans after administration of a single oral dose of [14C]gemopatrilat. Gemopatrilat was rapidly absorbed in humans with an oral bioavailability of 49%. Within 5 h after dose, the mean concentrations of gemopatrilat were less than 1% of the mean Cmax values. The total area under the first-moment time curve extrapolated to infinity [AUC(INF)] value for gemopatrilat was only 2% of the AUC(INF) of radioactivity in plasma. Gemopatrilat showed a large apparent steady-state volume of distribution (2500 liters) and a prolonged terminal-phase decline in plasma concentration. These results are consistent with the idea that the free sulfhydryl group of gemopatrilat forms reversible disulfide linkages with plasma and tissue proteins and is thus eliminated from the body at a very slow rate. Approximately half of the drug-related radioactivity in 1-h plasma samples from rat, dog, and human was reduced chemically with dithiothreitol to gemopatrilat, suggesting that disulfide linkage occurred in all species. In addition, metabolites formed through S-methylation and amide hydrolysis were also detected in rat, dog, and human plasma. No gemopatrilat was detected in urine and fecal samples from all three species, indicating that the compound is extensively metabolized in vivo. The major metabolites identified in human urine and feces were also present in rat and dog. These data suggest that the metabolism of gemopatrilat in all three species were qualitatively very similar.

Pharmacokinetics and Pharmacodynamics of a 0.1 mg/kg Dose of Cisatracurium Besylate in Children During N2O/O2/Propofol Anesthesia

We studied the pharmacokinetics and pharmacodynamics of cisatracurium in 9 children (mean weight, 17.1 kg) aged 1-6 yr (mean, 3.75 yr) during propofol-nitrous oxide anesthesia. Neuromuscular monitoring was performed. Venous samples were taken before injection of a 0.1 mg/kg dose of cisatracurium and then at 2, 5, 10, 30, 60, 90, and 120 min. Cisatracurium plasma concentrations were determined by high performance liquid chromatography. Onset time was 2.5 +/- 0.8 min, recovery to 25% of baseline twitch height was 37.6 +/- 10.2 min, and the 25%-75% recovery index was 10.9 +/- 3.7 min. Distribution and elimination half-lives were 3.5 +/- 0.9 min and 22.9 +/- 4.5 min, respectively. Steady-state volume of distribution (0.207 +/- 0.031 L/kg) and total body clearance (6.8 +/- 0.7 mL/min/kg) were significantly larger than those published for adults. Pharmacodynamic results were comparable to those obtained in pediatric studies during halothane or opioid anesthesia with the exception of a longer recovery to 25% baseline. Although the plasma-effect compartment equilibration rate constant was twofold faster (0.115 +/- 0.025 min(-1)) than that published for cisatracurium in adults, the effect compartment concentration corresponding to 50% block was similar (129 +/- 27 ng/mL).

Repeated intravenous injection of recombinant human hepatocyte growth factor ameliorates liver cirrhosis but causes albuminuria in rats

Hepatocyte growth factor (HGF) is a promising agent for the treatment of liver cirrhosis because of its mitogenic and anti-fibrotic effects. We investigated the effect of recombinant human HGF (rh-HGF) on cirrhosis development; its pharmacokinetics and nephrotoxicity in rats with liver cirrhosis induced by 4-week treatment with dimethylnitrosamine (DMN). rh-HGF (0.3 mg/kg) was intravenously administered to rats once a day for 4 weeks in parallel with DMN treatment or twice a day for the last 2 weeks of DMN treatment. Repeated doses of rh-HGF increased the liver weight and serum albumin, and reduced serum ALT. The development of hepatic fibrosis was inhibited more efficiently by extended low-dose treatment with rh-HGF. In cirrhotic rats, serum levels of rh-HGF increased and clearance was decreased, leading to an increase in the area under the plasma-concentration time curve and a decrease in the steady-state volume of distribution. Repeated doses of rh-HGF led to increased urinary albumin excretion, but no rh-HGF-treated animals developed increased serum creatinine levels. Urinary albumin excretion returned to baseline after the cessation of rh-HGF. These results suggest that extended treatment with rh-HGF is required for the attenuation of cirrhosis, and repeated doses of rh-HGF cause adverse effects in extra-hepatic organs. These issues must be resolved before the widespread application of rh-HGF in the treatment of liver cirrhosis.

In Silico Human and Rat Vss Quantitative Structure−Activity Relationship Models

We present herein a QSAR tool enabling an entirely in silico prediction of human and rat steady-state volume of distribution (Vss), to be made prior to chemical synthesis, preceding detailed allometric or mechanistic assessment of Vss. Three different statistical methodologies, Bayesian neural networks (BNN), classification and regression trees (CART), and partial least squares (PLS) were employed to model human (N=199) and rat (N=2086) data sets. The results in prediction of an independent test set show the human model has an r2 of 0.60 and an rms error in prediction of 0.48. The corresponding rat model has an r2 of 0.53 and an rms error in prediction of 0.37, indicating both models could be very useful in the early stages of the drug discovery process. This is the first reported entirely in silico approach to the prediction of rat and human steady-state volume of distribution.

Target-mediated drug disposition and dynamics

Nonlinear pharmacokinetics and pharmacodynamics may result from several capacity-limited processes and often represent complicating factors in characterizing the pharmacological properties of drugs. Target-mediated drug disposition (TMDD) corresponds to a special case wherein a significant proportion of a drug (relative to dose) is bound with high affinity to a pharmacological target, such that this interaction is reflected in the pharmacokinetic properties of the drug. Dose-dependent effects on apparent pharmacokinetic parameters may manifest, including the steady-state volume of distribution and total systemic clearance. Although a few small molecular weight compounds have been identified to exhibit TMDD, the incidence of TMDD is likely to increase particularly among emerging biotechnology pharmaceuticals. The goal of this commentary is to describe the basic tenets of TMDD and discuss several mathematical modeling approaches for characterizing this phenomenon. Whereas traditional pharmacokinetic/pharmacodynamic models assume that the amount of the drug–target complex is negligible relative to the total amount of drug in the body, integrated mechanism-based models of TMDD incorporate the binding and stoichiometry of drug–target binding. These models may be utilized to infer the time-course of inaccessible system variables, such as the in vivo density of the drug–target complex, and provide a suitable platform for ascertaining the apparent pharmacodynamic implications of TMDD.

Clinical Pharmacokinetics of Anti-angiogenic Photodynamic Therapy with Benzoporphyrin Derivative Monoacid Ring-A in Dogs Having Naturally Occurring Neoplasms

The aim of this study was to examine the pharmacokinetics of clinically applied benzoporphyrin derivative monoacid ring-A (BPD-MA; Verteporfin), a second-generation photosensitizer, during a trial of photodynamic therapy (PDT) in nine dogs having naturally occurring neoplasms. After injecting BPD-MA at 0.5 mg/kg intravenously, its mean half-life (t1/2) was found to be 8.14 +/- 5.34 h, mean clearance (Cl) 35.13 +/- 9.62 ml/(h kg), the mean value of the volume of distribution (Vc) 0.08 +/- 0.01 l/kg and the mean steady state volume of distribution (Vss) 0.38 +/- 0.31 l/kg respectively. With the exception of a transitional increase in serum alkaline phosphatase activity, no other clinical abnormalities were observed. The t1/2 in dogs with naturally occurring tumours was longer than that in humans, but similar to that in rats. The values of Cl and Vss in dogs having naturally occurring neoplasms were lower than those in humans. It is suggested that the pharmacokinetics of BPD-MA in tumour-bearing dogs would be helpful in determining the protocol of a short drug-light interval PDT with BPD-MA that mainly targets the tumour vasculature.