Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies.

PURPOSE: A phase I study was conducted to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of a novel purine nucleoside, nelarabine, a soluble prodrug of 9-beta-D-arabinosylguanine (araG; Nelarabine), in pediatric and adult patients with refractory hematologic malignancies. PATIENTS AND METHODS: Between April 1994 and April 1997, 93 patients with refractory hematologic malignancies were treated with one to 16 cycles of study drug. Nelarabine was administered daily, as a 1-hour intravenous infusion for 5 consecutive days, every 21 to 28 days. First-cycle pharmacokinetic data, including plasma nelarabine and araG levels, were obtained on all patients treated. Intracellular phosphorylation of araG was studied in samples of leukemic blasts from selected patients. RESULTS: The MTDs were defined at 60 mg/kg/dose and 40 mg/kg/dose daily x 5 days in children and adults, respectively. Dose-limiting toxicity (DLT) was neurologic in both children and adults. Myelosuppression and other significant organ toxicities did not occur. Pharmacokinetic parameters were similar in children and adults. Accumulation of araGTP in leukemic blasts was correlated with cytotoxic activity. The overall response rate was 31%. Major responses were seen in patients with T-cell malignancies, with 54% of patients with T-lineage acute lymphoblastic leukemia achieving a complete or partial response after one to two courses of drug. CONCLUSION: Nelarabine is a novel nucleoside with significant cytotoxic activity against malignant T cells. DLT is neurologic. Phase II and III trials in patients with T-cell malignancies are encouraged.

Compound GW506U78 in refractory hematologic malignancies: relationship between cellular pharmacokinetics and clinical response.

PURPOSE: In vitro investigations with arabinosylguanine (ara-G) demonstrated potent cytotoxicity to T-lymphoblastoid cell lines. The goals of the present study were to evaluate GW506U78, a prodrug of ara-G, against human hematologic malignancies and to determine its pharmacokinetics in plasma and cells. PATIENTS AND METHODS: During a phase I multicenter trial of GW506U78, 26 patients were treated at M.D. Anderson Cancer Center (MDACC). Daily doses between 20 and 60 mg/kg were administered for 5 days. Parallel plasma and cellular pharmacokinetic studies were conducted. RESULTS: Complete (n=5) or partial remission (n=5) was achieved in T-cell acute lymphoblastic leukemia (T-ALL), T-lymphoid blast crisis, T-lymphoma, and B-cell chronic lymphocytic leukemia (B-CLL) (n=13). In contrast, patients with B-ALL, B-lymphoma, acute myelogenous leukemia (AMI), or T-CLL did not respond. Peak plasma concentrations of GW506U78 and ara-G were dose-dependent. The elimination of GW506U78 (half-life [t1/2]=17 minutes) was faster than the elimination of ara-G (t1/2=3.7 hours). Median peak concentrations of ara-GTP were 23, 42, 85, and 93 micromol/L at 20, 30, 40, and 60 mg/kg, respectively. T-lymphoblasts accumulated significantly (P=.0008) higher peak arabinsylguanosine triphosphate (ara-GTP) (median, 140 micromol/L; n=7) compared with other diagnoses (median, 50 micromol/L; n=9) and normal mononuclear cells (n=3). The ara-GTP elimination was slow in all diagnoses (median, > 24 hours). Responders accumulated significantly (P=.0005) higher levels of ara-GTP (median, 157 micromol/L) compared with patients who failed to respond (median, 44 micromol/L). CONCLUSION: GW506U78 is an effective prodrug and a potent agent for hematologic malignancies with major efficacy in T-cell diseases. The pharmacokinetics of ara-GTP in leukemia cells are strongly correlated with clinical responses to GW506U78.

Pharmacokinetics of nelarabine and 9-beta-D-arabinofuranosyl guanine in pediatric and adult patients during a phase I study of nelarabine for the treatment of refractory hematologic malignancies.

PURPOSE: To characterize the pharmacokinetics of nelarabine (506U78), the water-soluble prodrug of 9-beta-D-arabinofuranosyl guanine (ara-G), and ara-G in pediatric and adult patients with refractory hematologic malignancies. Ara-G is phosphorylated within leukemic cells to form ara-G triphosphate (ara-GTP), which acts to terminate DNA chain elongation, resulting in cell death. PATIENTS AND METHODS: The pharmacokinetics of nelarabine and/or ara-G were evaluated in 71 patients (25 pediatric and 46 adult patients) on the first day of therapy. Blood was collected at specified times for the determination of plasma nelarabine and ara-G concentrations. RESULTS: There were no statistically significant differences in the pharmacokinetics of nelarabine between any of the groups of patients. The harmonic mean half-life (t1/2) of nelarabine in pediatric and adult patients was 14.1 minutes and 16.5 minutes, respectively. The maximum concentrations (C(max)) of ara-G occurred at or near the end of the nelarabine infusion. The C(max) of ara-G ranged from 11.6 micromol/L to 308.7 micromol/L at nelarabine doses of 5 to 75 mg/kg and was linearly related to the nelarabine dose. No statistically significant differences were noted for the pharmacokinetic parameter estimates of ara-G between adult male and female patients. In children versus adults, the dose-normalized C(max), time of the C(max), and the steady-state volume of distribution of ara-G were similar. However, the clearance of ara-G was higher in pediatric patients (0.312 L.h(-1).kg(-1)) as compared with adult patients (0. 213 L.h(-1).kg(-1)) (P <.001). The t1/2 of ara-G was shorter in pediatric patients as compared with adult patients (2.1 hours v 3.0 hours; P <.01). CONCLUSION: Nelarabine is an effective prodrug of ara-G, allowing systemic concentrations of ara-G that result in clinical activity.

Implementation of a pharmacogenetic management service for postmyocardial infarction care in a community pharmacy.

AIM: The purpose of this study was to pilot a multisite, proof-of-concept model where community pharmacists could engage patients and physicians to provide pharmacogenetic (PGt) testing and clinical decision support. PATIENTS & METHODS: Patients with history of acute myocardial infarction and percutaneous coronary intervention with no prior history of CYP2C19 testing. RESULTS: Four community pharmacies provided pharmacogenetic testing and medication therapy management services to 30 patients, resulting in eight recommendations for antiplatelet therapy adjustment. CONCLUSION: Pharmacists involved in the study were able to facilitate antiplatelet therapy adjustments based on PGt data regardless of baseline antiplatelet drug selection. Whereas prior literature largely revolved around PGt management in the inpatient setting, this project supports the involvement of the community pharmacist in making PGt-based recommendations.

Clinical pharmacokinetics of cisatracurium besilate.

Cisatracurium besilate, one of the 10 stereoisomers that comprise atracurium besilate, is a nondepolarising neuromuscular blocking agent with an intermediate duration of action. Following a 5- to 10-sec intravenous bolus dose of cisatracurium besilate to healthy young adult surgical patients, elderly patients and patients with renal or hepatic failure, the concentration versus time profile of cisatracurium besilate is best characterised by a 2-compartment model. The volume of distribution (Vd) of cisatracurium besilate is small because of its relatively large molecular weight and high polarity. Cisatracurium besilate undergoes Hofmann elimination, a process dependent on pH and temperature. Unlike atracurium besilate, cisatracurium besilate does not appear to be degraded directly by ester hydrolysis. Hofmann elimination, an organ independent elimination pathway, occurs in plasma and tissue, and is responsible for approximately 77% of the overall elimination of cisatracurium besilate. The total body clearance (CL), steady-state Vd and elimination half-life of cisatracurium besilate in patients with normal organ function are approximately 0.28 L/h/kg (4.7 ml/min/kg), 0.145 L/kg and 25 minutes, respectively. The magnitude of interpatient variability in the CL of cisatracurium besilate is low (16%), a finding consistent with the strict physiological control of the factors that effect the Hofmann elimination of cisatracurium besilate (i.e. temperature and pH). There is a unique relationship between plasma clearance and Vd because the primary elimination pathway for cisatracurium besilate is not dependent on organ function. There are minor differences in the pharmacokinetics of cisatracurium besilate in various patient populations. These differences are not associated with clinically significant differences in the recovery profile of cisatracurium besilate, but may be associated with differences in the time to onset of neuromuscular block.

Population pharmacokinetics of gentamicin. Use of the nonparametric expectation maximisation (NPEM) algorithm.

A new nonparametric expectation maximisation (NPEM) algorithm for the estimation of population pharmacokinetic parameter values was evaluated. The algorithm, in the form of a personal computer program, was used to compute population pharmacokinetic parameter densities of gentamicin in a group of 9 patients with indicators of malnutrition. The 1-compartment parameter values for clearance (CL), volume of distribution (Vd) and elimination rate constant (k) were compared with values generated using a standard 2-stage (STS) approach. NPEM was used with a full data set (72 gentamicin concentrations) and a sparse data set (only peak and trough concentrations for each patient; 18 in total). There were no differences in parameter value estimations between the STS and NPEM with all the data (p greater than 0.05) or with the sparse data (p greater than 0.05). Mean parameter value estimates from the STS and NPEM (with sparse data) were used as a priori data sets in the USC*PACK gentamicin Bayesian program to predict concentrations in 8 subsequent patients with similar indicators of malnutrition. There were no differences in predicted gentamicin concentrations between STS (3.75 +/- 2.06 mg/L) and NPEM (3.75 +/- 2.17 mg/L). NPEM was able to generate population pharmacokinetic parameter values for gentamicin in a defined population of patients using sparse routine clinical data. It was also shown to function with only a single data point per patient.

Effect of nutritional status on organic anion clearance by the swine liver.

Hepatic dysfunction follows a wide range of insults. Impaired excretion of organic dyes such as bilirubin often occurs before other obvious clinical defects in metabolic processes. Indocyanine green (ICG) is excreted through pathways similar to those of bilirubin. To determine the effectiveness of ICG as a marker of hepatic dysfunction related to clinical malnutrition, pigs received 5 mg/kg ICG with simultaneous sampling from the hepatic vein, pulmonary artery, and aorta over 3 hours. Group I remained well nourished, group II was fasted to a weight loss equal to 20% of initial body weight, and group III was fasted to a 20% weight loss and then refed until the animals regained their initial weight. Both systemic and intrinsic hepatic clearance were depressed significantly with fasting but returned above baseline after refeeding. No significant difference appeared between systemic and intrinsic hepatic clearance. Extraction ratios were low in all groups. In outbred swine, ICG clearance reflects the function of hepatic organic anion excretion in vivo, and venous sampling reflects intrinsic hepatic clearance. The impairment of the carrier-mediated transport system is reversible with refeeding.

The effect of theophylline on estimated hepatic blood flow.

We observed the effect of aminophylline administration on estimated hepatic blood flow. Indocyanine green (ICG) 0.5 mg/kg was administered as an intravenous bolus dose before and after intravenous infusion of 7 mg/kg aminophylline. Venous blood was collected at timed intervals over 15 minutes to construct ICG concentration-time graphs. Pharmacokinetic values were calculated using non-compartmental methods. Estimated hepatic blood flow decreased from 790 +/- 190 to 665 +/- 100 ml/minute (p less than 0.05) after administration of aminophylline.

Pharmacokinetics of RheothRx injection in healthy male volunteers.

The objectives of this study were to evaluate the safety and tolerability of RheothRx (poloxamer 188) injection administered as an intravenous (i.v.) infusion to healthy male volunteers and to determine the pharmacokinetic profile of poloxamer 188. Thirty-six healthy male volunteers were enrolled in a randomized, double-blind, placebo-controlled, dose-escalation trial for RheothRx injection. The volunteers were randomized to three treatment groups (12 per treatment group, with eight receiving active therapy and four receiving placebo). In each treatment group, volunteers received RheothRx injection or placebo as an i.v. infusion on two occasions at least 3 weeks apart to make a total of six doses being studied (10, 30, and 45 mg/kg/h for 72 h, 60 mg/kg/h for 43.3 to 72 h, 60 and 90 mg/kg/h for 24 h). Serial plasma samples were collected during and up to 36 h after the end of the infusions; urine was collected over intervals from the start of the infusion until 36 h after the infusions were terminated. Plasma and urine samples were assayed for poloxamer 188 by gel-permeation chromatography. Pharmacokinetic parameter values were calculated by noncompartmental and compartmental methods. Poloxamer 188 was eliminated primarily by renal excretion. Estimates of clearance, elimination rate constant, and apparent volume of distribution at steady state values were independent of infusion rate. Poloxamer 188 displayed no apparent infusion rate dependence in its pharmacokinetics.

Therapeutic drug monitoring. Practical considerations for primary care physicians.

Primary care physicians who understand the complexities of drug dosing may be able to provide their patients with more effective pharmacologic therapy. Standard or empirical methods of dosing are appropriate for most agents. The evolution of pharmacokinetics and clinically useful drug assays has led to pharmacokinetic dosing, a more sophisticated and exact method of dosing certain agents.

Population pharmacokinetics: development of a medical intensive care unit-specific gentamicin dosing nomogram.

OBJECTIVE: This study was designed to develop a population-specific dosing nomogram for gentamicin in medical intensive care unit (MICU) patients using the population pharmacokinetic program nonparametric expectation maximization (NPEM). DESIGN: Observational clinical gentamicin dosing data were collected, entered into the USC*PACK database program PASTRX, and downloaded into the population pharmacokinetic program NPEM. NPEM generated population pharmacokinetic parameter values that were used to develop a gentamicin dosing nomogram. The nomogram was tested in the next 15 patients admitted to MICU to determine accuracy. Doses given per the MICU and the Hull-Sarubbi nomograms were compared with doses based on actual patient-specific pharmacokinetic parameter values. Reliability coefficients (intraclass correlation coefficients) were calculated to assess the agreement between observations. SETTING: Data were gathered from patients receiving gentamicin therapy in the MICU, Presbyterian University Hospital, Pittsburgh. PATIENTS: Baseline population pharmacokinetic parameter values were determined in 36 MICU patients receiving gentamicin therapy. Patients with renal failure receiving hemodialysis or another mechanical method of blood clearance or fluid removal were excluded. The population parameter values in the form of a dosing nomogram were then used prospectively to dose gentamicin in 15 patients. RESULTS: NPEM generated population parameter values similar to those previously published using the Sawchuk-Zaske method in ICU patients. The mean volume of distribution generated using NPEM was 0.34 +/- 0.12 L/kg. The relationship between creatinine clearance (Clcr) and elimination rate constant (Ke) was: Ke = 0.00218 x Clcr + 0.007. The nomogram-derived doses correlated with doses determined by using actual patient-specific pharmacokinetic values (p < 0.05). The Hull-Sarubbi derived doses, however, did not correlate with patient-specific doses (p > 0.05). Only one patient had a peak concentration < 6 mg/L. Two of 15 patients had trough concentrations prior to the first maintenance dose > 2 mg/L. CONCLUSIONS: The use of NPEM to generate population-specific pharmacokinetic parameter values has been previously described. Application of population-specific dosing nomograms can improve initial dosing regimens such that conventional therapeutic concentrations can be achieved early in therapy. This nomogram, however, does not preclude follow-up patient-specific pharmacokinetic analysis.

Estimation of the hepatic extraction ratio of indocyanine green in swine.

1. The hepatic extraction ratio of Indocyanine Green was measured directly by trans-hepatic catheterization in 14 outbred swine (eight well-fed, six malnourished). A specific two-compartment pharmacokinetic model was fitted to the arterial Indocyanine Green concentration-time data and used to estimate the hepatic extraction ratio of Indocyanine Green. 2. The specific two-compartment pharmacokinetic model was modified to represent more accurately the physiological process of Indocyanine Green removal. Simulations were performed using this new model to estimate the hepatic extraction ratio of Indocyanine Green in the swine. 3. Similarly to previous findings, our data showed that the original model consistently overestimated the hepatic extraction ratio of Indocyanine Green (i.e. the model estimate was compared with the true, directly measured value). 4. The comparison of the modified model and the original model clearly indicates the reason for the overprediction of the hepatic extraction ratio of Indocyanine Green by the latter. The simulations using the new model indicate that the percentage of binding of Indocyanine Green to its transport protein (glutathione S-transferase) for removal in the bile will affect the estimation of the hepatic extraction ratio of Indocyanine Green. Thus, the amount of Indocyanine Green available for removal is less than that assumed by the original model.

Importance of the organ-independent elimination of cisatracurium.

Cisatracurium, one of 10 isomers of atracurium, undergoes pH and temperature-dependent Hofmann elimination in plasma and tissues. The clearance of cisatracurium due to Hofmann elimination and organ elimination was estimated by applying a nontraditional two-compartment pharmacokinetic model with elimination occurring from both compartments to plasma cisatracurium concentration-time data from 31 healthy adult surgical patients with normal renal and hepatic function. The elimination rate constant from the central compartment, intercompartmental rate constants, and the volume of the central compartment were obtained from the model fit. The elimination rate constant from the peripheral compartment could not be independently estimated in vivo and was therefore fixed to the rate of degradation of cisatracurium in human plasma (pH 7.4 and 37 degrees C) and held constant in the model. Total body clearance, Hofmann clearance, organ clearance, and the volume of distribution at steady-state were derived from the model parameter estimates. Renal clearance was calculated from cisatracurium urinary excretion data from 12 of the 31 patients. Clearance values (mean +/- SD) were 5.20 +/- 0.86, 4.00 +/- 1.04, 1.20 +/- 0.71, and 0.85 +/- 0.32 mL.min-1.kg-1 for total body clearance, Hofmann clearance, organ clearance, and renal clearance, respectively. Hofmann clearance accounted for 77% of total body clearance. Organ clearance was 23% of total body clearance. Renal clearance, a component of organ clearance, was 16% of total body clearance. The organ-independent nature of the elimination of cisatracurium was characterized by a relationship between steady-state volume of distribution and total body clearance. The half-life is an independent variable and is not dependent on the total body clearance nor the steady-state volume of distribution. Hofmann elimination is the predominant pathway for cisatracurium elimination in humans.

Pharmacokinetics of cisatracurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia.

BACKGROUND: Cisatracurium, one of the ten isomers in atracurium, is a nondepolarizing muscle relaxant with an intermediate duration of action. It is more potent and less likely to release histamine than atracurium. As one of the isomers composing atracurium, it presumably undergoes Hofmann elimination. This study was conducted to describe the pharmacokinetics of cisatracurium and its metabolites and to determine the dose proportionality of cisatracurium after administration of 2 or 4 times the ED(95). METHODS: Twenty ASA physical status 1 or 2 patients undergoing elective surgery under nitrous oxide/opioid/barbiturate anesthesia were studied. Patients received a single rapid intravenous bolus does of 0.1 or 0.2 mg x kg-1 (2 or 4 times the ED(95), respectively) cisatracurium. All patients were allowed to recover spontaneously to a train-of-four ratio > or = 0.70 after cisatracurium-induced neuromuscular block. Plasma was extracted, acidified, and stored frozen before analysis for cisatracurium, laudanosine, the monoquaternary acid, and the monoquaternary alcohol metabolite. RESULTS: The clearances (5.28 +/- 1.23 vs. 4.66 +/- 0.67 ml x min(-1) x kg(-1) and terminal elimination half-lives (22.4 +/- 2.7 vs. 25.5 +/- 4.1 min) were not statistically different between patients receiving 0.1 mg x kg(-1) and 0.2 mg x kg(-1), respectively. Maximum concentration values for laudanosine averaged 38 +/- 21 and 103 +/- 34 ng x ml(-1) for patients receiving the 0.1 and 0.2 mg x kg(-1) doses, respectively. Maximum concentration values for monoquaternary alcohol averaged 101 +/- 27 and 253 +/- 51 ng x ml(-1), respectively. Monoquaternary acid was not quantified in any plasma sample. CONCLUSIONS: Cisatracurium undergoes Hofmann elimination to form laudanosine. The pharmacokinetics of cisatracurium are independent of dose after single intravenous doses of 0.1 and 0.2 mg x kg(-1).

Pharmacokinetics and pharmacodynamics of cisatracurium in patients with end-stage liver disease undergoing liver transplantation.

We determined the pharmacokinetics and pharmacodynamics of cisatracurium, one of the 10 isomers of atracurium, in 14 patients with end-stage liver disease undergoing liver transplantation and in 11 control patients with normal hepatic and renal function undergoing elective surgery. Blood samples were collected for 8 h after i.v. bolus administration of cisatracurium 0.1 mg kg-1 (2 x ED95). Plasma concentrations of cisatracurium and its metabolites were determined using an HPLC method with fluorescence detection. Pharmacokinetic variables were determined using non-compartmental methods. Neuromuscular block was assessed by measuring the electromyographic evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve using a Puritan-Bennett Datex (Helsinki, Finland) monitor. Pharmacodynamic modelling was completed using semi-parametric effect-compartment analysis. Volume of distribution at steady state was 195 (SD 38) ml kg-1 in liver transplant patients and 161 (23) ml kg-1 in control patients (P < 0.05), plasma clearance was 6.6 (1.1) ml kg-1 min-1 in liver transplant patients and 5.7 (0.8) ml kg-1 min-1 in control patients (P < 0.05), but elimination half-lives were similar: 24.4 (2.9) min in liver transplant patients vs 23.5 (3.5) min in control patients (ns). The time to maximum block was 2.4 (0.8) min in liver transplant patients compared with 3.3 (1.0) min in control patients (P < 0.05), but the clinical effective duration of action (time to 25% recovery) was similar: 53.5 (11.9) min in liver transplant patients compared with 46.9 (6.9) min in control patients (ns). The recovery index (25-75% recovery) was also similar in both groups: 15.4 (4.2) min in liver transplant patients and 12.8 (1.9) min in control patients (ns). After cisatracurium, peak laudanosine concentrations were 16 (5) and 21 (5) ng ml-1 in liver transplant and control patients, respectively. In summary, minor differences in the pharmacokinetics and pharmacodynamics of cisatracurium in liver transplant and control patients were not associated with any clinically significant differences in recovery profiles after a single dose of cisatracurium.