David F. Kisor

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 [centered dot] min-1 [centered dot] 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. (Anesth Analg 1996;83:1065-71)

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.

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 ED95. 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 dose of 0.1 or 0.2 mg *symbol* kg sup -1 (2 or 4 times the ED95, respectively) cisatracurium. All patients were allowed to recover spontaneously to a train-of-four ratio greater or equal to 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 *symbol* min sup -1 *symbol* kg sup -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 *symbol* kg sup -1 and 0.2 mg *symbol* kg sup -1, respectively. Maximum concentration values for laudanosine averaged 38+/-21 and 103+/-34 ng *symbol* ml sup -1 for patients receiving the 0.1 and 0.2 mg *symbol* kg sup -1 doses, respectively. Maximum concentration values for monoquaternary alcohol averaged 101+/-27 and 253+/-51 ng *symbol* ml sup -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 *symbol* kg sup -1.

Ambient Temperature Effects on 3,4-Methylenedioxymethamphetamine-Induced Thermodysregulation and Pharmacokinetics in Male Monkeys

Changes in ambient temperature are known to alter both the hyperthermic and the serotonergic consequences of 3,4-methylenedioxymethamphetamine (MDMA). Metabolism of MDMA has been suggested to be a requisite for these neurotoxic effects, whereas the hyperthermic response is an important contributing variable. The aim of the present study was to investigate the interaction between ambient temperature, MDMA-induced thermodysregulation, and its metabolic disposition in monkeys. MDMA (1.5 mg/kg i.v.) was administered noncontingently at cool (18°C; n = 5), room (24°C; n = 7), and warm (31°C; n = 7) ambient temperatures. For 240 min following MDMA administration, core temperature was recorded and blood samples were collected for analysis of MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 3,4-dihydroxyamphetamine, and 3,4-methylenedioxyamphetamine (MDA). A dose of 1.5 mg/kg MDMA induced a hypothermic response at 18°C, a hyperthermic response at 31°C, and did not significantly change core temperature at 24°C. Regardless of ambient temperature, plasma MDMA concentrations reached maximum within 5 min, and HHMA was a major metabolite. Curiously, the approximate elimination half-life (t½) of MDMA at 18°C (136 min) and 31°C (144 min) was increased compared with 24°C (90 min) and is most likely because of volume of distribution changes induced by core temperature alterations. At 18°C, there was a significantly higher MDA area under the concentration-time curve (AUC) and a trend for a lower HHMA AUC compared with 24°C and 31°C, suggesting that MDMA disposition was altered. Overall, induction of hypothermia in a cool environment by MDMA may alter its disposition. These results could have implications for MDMA-induced serotonergic consequences.

Pharmacogenetics in the Community Pharmacy Thienopyridine Selection Post–Coronary Artery Stent Placement

Introduction: Although antiplatelet therapy is a mainstay of post–percutaneous coronary intervention therapy, pharmacogenetic (PGt) considerations of therapy are often ignored despite related Food and Drug Administration warnings. Pharmacists are well situated to provide PGt guidance, and the community pharmacy is one setting where PGt testing, interpretation, and recommendations can take place to ensure optimal therapeutic outcomes. Case Report: A 65-year-old man who had a myocardial infarction that was treated with PCI and stent placement was determined by a community pharmacist to be a candidate for PGt testing to ensure optimal antiplatelet therapy. The patient was seen in the pharmacy as a part of a medication therapy management encounter and underwent genetic testing. Results of the genetic testing indicated the need for modification of therapy. The community pharmacist interpreted the results and made the appropriate recommendation to the cardiologist who in turn modified antiplatelet therapy appropriately. Conclusion: This case describes the potential for collaboration between pharmacists and physicians to optimize antiplatelet therapy through PGt testing. Points of consideration for others looking to implement related PGt services are also discussed.

Nelarabine in the Treatment of Refractory T-Cell Malignancies

Nelarabine is a nucleoside analog indicated for the treatment of adult and pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) that is refractory or has relapsed after treatment with at least two chemotherapy regimens. After being first synthesized in the late 1970s and receiving FDA approval in 2005, the appropriate use of nelarabine for refractory hematologic malignancies is still being elucidated. Nelarabine is the prodrug of 9-β-D-arabinofuranosylguanine (ara-G) which when phosphorylated intracellularly to ara-G triphosphate (ara-GTP), preferentially accumulates in cancerous T-cells. Dose-dependent toxicities, including neurotoxicity and myelosuppression, have been documented and may, in turn, limit the ability to appropriately treat the diagnosed malignancy. This article will summarize the pharmacologic properties of nelarabine and will address the current place in therapy nelarabine holds based upon the results of the available clinical trials to date.

Nelarabine: A Nucleoside Analog with Efficacy in T-Cell and other Leukemias

OBJECTIVE: To present the pharmacology and pharmacokinetics of nelarabine, 9-β-D-arabinofuranosylguanine (ara-G) and intraleukemic cellular pharmacokinetics of 9-β-D-arabinofuranosylguanine triphosphate (ara-GTP) generated from the administration of nelarabine, and clinical and safety information relative to nelarabine use in the treatment of hematologic malignancies. DATA SOURCES: MEDLINE (1966—December 2004) was searched using the English-language key terms 2-amino-6-methoxypurine arabinoside, 506U78, and nelarabine. Data were also obtained from published abstracts. STUDY SELECTION AND DATA EXTRACTION: Clinical studies evaluating the pharmacokinetics of nelarabine, ara-G, and cellular ara-GTP and use of nelarabine, alone or in combination with other agents for the treatment of hematologic malignancies, were included in this review. DATA SYNTHESIS: Nelarabine is the water-soluble, 6-methoxy analog of 9-β-D-ara-G. Nelarabine is readily converted to ara-G by endogenous adenosine deaminase. The half-life of nelarabine is approximately 15 minutes compared with 2–4 hours for ara-G. The clearance of ara-G is higher in children than in adults (0.312 vs 0.213 L × h−1 × kg−1). Intracellular ara-GTP elimination is slow relative to nelarabine and ara-G. In pediatric and adult patients, neurologic toxicity is dose limiting. Severe myelosuppression was not consistently observed. Major responses were seen in patients with T-cell malignancies. Patients who responded had significantly higher intracellular ara-GTP concentrations compared with those who did not respond. CONCLUSIONS: Nelarabine is an effective ara-G prodrug. Nelarabine has significant activity against malignant T-cells and appears to be an important addition to treatments of various leukemias.

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.

Nelarabine: efficacy in the treatment of clinical malignancies

Nelarabine is a nucleoside analog prodrug of 9-beta-D-arabinofuranosylguanine. Nelarabine is indicated for the treatment of adult and pediatric patients with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma whose disease has not responded to, or has relapsed after treatment with, at least two chemotherapy regimens. Nelarabine was granted Orphan Medical Product Status in Europe in June 2005, and accelerated approval by the US FDA in October 2005. The most common adverse events associated with nelarabine are neurotoxic in nature and have been dose-limiting.

Pharmacokinetics/pharmacodynamics of cisatracurium in healthy adult patients

The pharmacokinetics of cisatracurium and its metabolites were evaluated in 56 healthy adult surgical patients with full sampling (17 blood samples collected over 8 h) after single intravenous bolus doses of cisatracurium and in 186 healthy adult surgical patients with sparse sampling (five to eight blood samples collected randomly over 2 h) after single intravenous bolus doses with or without maintenance doses or continuous infusions of cisatracurium. Plasma concentration-time and neuromuscular block data from the patients with full sampling were analyzed using compartmental and non-compartmental pharmacokinetic models and semiparametric effect compartment analyses. Data from all patients were pooled to determine the population pharmacokinetics/pharmacodynamics of cisatracurium. Results from in vitro and in vivo studies indicated that Hofmann elimination is the predominant pathway for the elimination of cisatracurium in humans. The pharmacokinetics of cisatracurium are independent of the dose from 0.1 to 0.4 mg/kg [two to eight times the dose producing 95% suppression (ED95) of the first evoked twitch response of the adductor pollicis muscle to a train of four stimulations]. Anaesthesia type, sex, estimated creatinine clearance and the presence of obesity were associated with statistically significant effects on the pharmacokinetic/pharmacodynamic parameters for cisatracurium. These covariates were not associated with any clinically significant changes in the predicted recovery profile of cisatracurium. Slight differences in onset were predicted in patients with renal impairment and in patients given inhalation anaesthesia.