High Total Body Clearance Research Articles

Pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite following intravenous administration in cattle.

This study investigated the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl metabolite (M-I) after single-dose intravenous (IV) administration (10mg/kg) of PTX in six healthy cattle. The safety of PTX was evaluated by clinical observation and biochemical analysis. Plasma concentrations of PTX and M-I were simultaneously determined by reverse-phase high performance liquid chromatography. Pharmacokinetic parameters were calculated using non-compartmental methods. Salivation and discomfort were observed for 2h following the drug administration. Serum direct bilirubin, total bilirubin, and phosphorus levels at 24h following the drug administration were significantly different from the control values (0h) (P < 0.05). Pharmacokinetic variables of PTX were characterized by a short terminal elimination half-life (1.05 ± 0.19h), a large volume of distribution (6.30 ± 1.76L/kg), and high total body clearance (5.31 ± 1.27L/h/kg). The mean ratio between the area under the concentration-time curves of M-I and PTX was 1.34. These results indicate that single-dose administration of PTX at 10mg/kg IV in cattle resulted in therapeutic concentrations similar to those observed in humans and horse. However, further studies are necessary to determine the safety and pharmacokinetics following repeated administrations of PTX.

High body clearance and low oral bioavailability of alantolactone, isolated from Inula helenium, in rats: extensive hepatic metabolism and low stability in gastrointestinal fluids

Alantolactone (ALA) is a major bioactive sesquiterpene lactone present in the roots of Inula helenium L. (Asteraceae) which has been used widely in traditional medicine against various diseases such as asthma, cancer and tuberculosis. The pharmacologic activities of alantolactone have been well characterized, yet information on the physicochemical and pharmacokinetic properties of alantolactone and their mechanistic elucidation are still limited. Thus, this study aims to investigate the oral absorption and disposition of alantolactone and their relevant mechanisms. Log P values of alantolactone ranged from 1.52 to 1.84, and alantolactone was unstable in biological samples such as plasma, urine, bile, rat liver microsomes (RLM) and simulated gastrointestinal fluids. The metabolic rate of alantolactone was markedly higher in rat liver homogenates than in the other tissue homogenates. A saturable and concentration-dependent metabolic rate profile of alantolactone was observed in RLM, and rat cytochrome P450 (CYP) 1A, 2C, 2D and 3A subfamilies were significantly involved in its hepatic metabolism. Based on the well-stirred model, the hepatic extraction ratio (HER) was estimated to be 0.890-0.933, classifying alantolactone as a drug with high HER. Moreover, high total body clearance (111±41ml/min/kg) and low oral bioavailability (0.323%) of alantolactone were observed in rats. Taken together, the present study demonstrates that the extensive hepatic metabolism, at least partially mediated by CYP, is primarily responsible for the high total body clearance of alantolactone, and that the low oral bioavailability of alantolactone could be attributed to its low stability in gastrointestinal fluids and a hepatic first-pass effect in rats. Copyright © 2016 John Wiley & Sons, Ltd.

Molecular Design of Bisphosphonate-Modified Proteins for Efficient Bone Targeting In Vivo.

To establish a rational molecular design for bisphosphonate (BP)-modified proteins for efficient bone targeting, a pharmacokinetic study was performed using a series of alendronate (ALN), a nitrogen-containing BP, modified proteins with various molecular weights and varying degrees of modification. Four proteins with different molecular weight—yeast glutathione reductase (GR; MW: 112,000 Da), bovine serum albumin (BSA; MW: 67,000 Da), recombinant human superoxide dismutase (SOD; MW: 32,000 Da), and chicken egg white lysozyme (LZM; MW: 14,000 Da)—were modified with ALN to obtain ALN-modified proteins. Pharmacokinetic analysis of the tissue distribution of the ALN-modified and unmodified proteins was performed after radiolabeling them with indium-111 (111In) by using a bifunctional chelating agent. Calculation of tissue uptake clearances revealed that the bone uptake clearances of 111In-ALN-modified proteins were proportional to the degree of ALN modification. 111In-GR-ALN and BSA-ALN, the two high-molecular-weight proteins, efficiently accumulated in bones, regardless of the degree of ALN modification. Approximately 36 and 34% of the dose, respectively, was calculated to be delivered to the bones. In contrast, the maximum amounts taken up by bone were 18 and 13% of the dose for 111In-SOD-ALN(32) and LZM-ALN(9), respectively, because of their high renal clearance. 111In-SOD modified with both polyethylene glycol (PEG) and ALN (111In-PEG-SOD-ALN) was efficiently delivered to the bone. Approximately 36% of the dose was estimated to be delivered to the bones. In an experimental bone metastasis mouse model, treatment with PEG-SOD-ALN significantly reduced the number of tumor cells in the bone of the mice. These results indicate that the combination of PEG and ALN modification is a promising approach for efficient bone targeting of proteins with a high total-body clearance.

Abstract 4517: Plasma and tumor pharmacokinetics of IV LMP744, a novel indenoisoquinoline topoisomerase I inhibitor, in a canine phase I study

Abstract Introduction: LMP744 (NSC706744) is one of 3 indenoisoquinolines being evaluated in pet dogs with lymphoma to define their safety, pharmacokinetics, and pharmacodynamic modulation (COTC007b). LMP744 forms stable DNA-topoisomerase I (Top1) cleavage complexes and induces unique DNA cleavage sites relative to approved Top1 poisons; LMP744 is not a substrate for ABC transporters and does not have the stability issues inherent to camptothecins. Here we report the plasma and tumor pharmacokinetics of LMP744 administered IV daily x 5 to patient dogs. Methods: Eligibility included: dogs &amp;gt;15 kg with histologically confirmed non-Hodgkin's lymphoma with nodal presentation (stage 2 or greater) and minimal nodes size for biopsy of 3 cm in the longest dimension, performance status of Grade 0 or 1 and informed owner consent. Dose levels (DL) explored were 25, 50, 75, 100, and 125 mg/m2/day through a 3+3 dose escalation study design. LMP744 was administered over 1 h IV daily x 5, Q28D. LMP744 was quantitated with a validated LC-MS/MS assay, and plasma pharmacokinetic parameters determined non-compartmentally with PK Solutions and plasma and tumor parameters compartmentally with ADAPT5 through iterated two stage (ITS) and maximum likelihood solution with the expectation maximization algorithm (MLEM). Results: All 18 dogs had useable pharmacokinetic data. Non-compartmental analysis suggested linear relationships between plasma Cmax and tumor C2h vs. dose. LMP744 distributed extensively to tumor tissue and mean tumor concentrations were at least 2 orders of magnitude higher than plasma concentrations at equivalent time points of 2, 6 and 120 h. Compartmental modeling with a 3 compartment linear model resulted in a good fit to the plasma data. The parameters and%CVs respectively for Clt, Vc, Cld1, Vp1, Cld2, Vp2 were 57.5 L/h/m2 (29%), 136 L/m2 (24%), 234 L/h/m2 (24%), 1180 L/m2 (27%), 30.8 L/h/m2 (63%), 5140 L/m2 (67%). Sequential plasma half-lives were 16.5 min, 13 h, and 183 (31%) h, respectively. In line with the long t1/2, plasma accumulation was observed on this daily times-5 schedule. Conclusion: The plasma pharmacokinetics of LMP744 in dogs display triphasic behavior, a relatively high total body clearance at 57.5 L/h/m2, and a terminal half-life of 183 h. The favorable biodistribution to tumor may be a valuable distinction to consider in the translation of this novel indenoisoquinoline to the clinic. Support: N01-CM-2011-00015, N01-CM-42202 and P30-CA-47904 Note: This abstract was not presented at the meeting. Citation Format: Julie L. Eiseman, Julianne Holleran, David L. McCormick, Miguel Muzzio, Joseph M. Covey, Chand Khanna, Christina Mazcko, Yves Pommier, Melissa Paolini, Amy Leblanc, Jenna H. Burton, James H. Doroshow, Joseph E. Tomaszewski, Jan H. Beumer. Plasma and tumor pharmacokinetics of IV LMP744, a novel indenoisoquinoline topoisomerase I inhibitor, in a canine phase I study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4517. doi:10.1158/1538-7445.AM2015-4517

Abstract 4632: Plasma and tumor pharmacokinetics of IV LMP400, a novel indenoisoquinoline topoisomerase I inhibitor, in a canine phase I study

Abstract Introduction: LMP400 is one of 3 indenoisoquinolines that are being evaluated in pet dogs with lymphoma to define their safety, pharmacokinetics, and pharmacodynamic modulation (COTC007b). LMP400 forms stable DNA-topoisomerase I (Top1) cleavable complexes and induces unique DNA cleavage sites relative to approved Top1 poisons; LMP400 is not a substrate for ABC transporters and does not have the stability issues that most camptothecin analogs do. Here we report the plasma and uncoupled tumor pharmacokinetics of LMP400 administered IV daily x 5 to patient dogs. Methods: Eligibility included: dogs &amp;gt;15 kg with histologically confirmed non-Hodgkin's lymphoma with nodal presentation (stage 2 or greater) and minimal nodes size for biopsy of 3 cm in the longest dimension, performance status of Grade 0 or 1 and informed owner consent. Dose levels (DL) explored were 8, 16, 24, and 40 mg/m2/day through a 3+3 dose escalation study design. LMP400 was administered over 1 h IV daily x 5, Q28D. LMP400 was quantitated with a validated LC-MS/MS assay (PMID: 20236781), and plasma pharmacokinetic parameters determined non-compartmentally with PK Solutions and plasma and tumor parameters compartmentally with ADAPT5 through iterated two stage (ITS) and maximum likelihood solution with the expectation maximization algorithm (MLEM). Results: All fifteen dogs had useable pharmacokinetic data. Non-compartmental analysis suggested linear relationships between plasma Cmax and AUC vs. dose and tumor C2h vs. dose. Plasma terminal half-life was 11.9 ± 5.0 h and the CL was 26.7 L/h/m2. In line with the t1/2, slight plasma accumulation was observed on this daily times 5 schedule. Compartmental modeling with a 2 compartment linear model resulted in a good fit to the data. The parameters and %CVs respectively for Ke, Vc, Kcp, Kpc, Kct and Ktc were 0.181 h-1 (42.6%), 108 L/m2 (32.7%), 0.250 h-1 (30.1%), 0.0602 h-1 (67%), 0.0632 h-1 (3.65%), and 0.649 h-1 (42.2%). Plasma compartmental CL and half-life were 19.5 L/h/m2 and 29.7 h. Conclusion: The plasma pharmacokinetics of LMP400 in dogs display biphasic behavior, a relatively high total body clearance at 19.5 L/h/m2, and a terminal half-life of 29.7 h. LMP400 distributed to the tumors and mean tumor concentrations were at least 10-fold higher than plasma concentrations at equivalent time points of 2, 6 and 120 h. This favorable biodistribution to tumor (lymph node) may be a valuable distinction to consider in the translation of this novel indenoisoquinoline to the clinic. Support: N01-CM-2011-00015, N01-CM-42202 and P30-CA-47904 Citation Format: Julie L. Eiseman, Julianne Holleran, David L. McCormick, Miguel Muzzio, Joseph M. Covey, Chand Khanna, Christina Mazcko, Yves Pommier, Melissa Paoloni, James D. Doroshow, Joseph E. Tomaszewski, Jan H. Beumer. Plasma and tumor pharmacokinetics of IV LMP400, a novel indenoisoquinoline topoisomerase I inhibitor, in a canine phase I study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4632. doi:10.1158/1538-7445.AM2014-4632

Bioavailability and pharmacokinetics of oral and injectable formulations of methadone after intravenous, oral, and intragastric administration in horses

To characterize the bioavailability and pharmacokinetics of oral and injectable formulations of methadone after IV, oral, and intragastric administration in horses. 6 healthy adult horses. Horses received single doses (each 0.15 mg/kg) of an oral formulation of methadone hydrochloride orally or intragastrically or an injectable formulation of the drug orally, intragastrically, or IV (5 experimental treatments/horse; 2-week washout period between each experimental treatment). A blood sample was collected from each horse before and at predetermined time points over a 360-minute period after each administration of the drug to determine serum drug concentration by use of gas chromatography-mass spectrometry analysis and to estimate pharmacokinetic parameters by use of a noncompartmental model. Horses were monitored for adverse effects. In treated horses, serum methadone concentrations were equivalent to or higher than the effective concentration range reported for humans, without induction of adverse effects. Oral pharmacokinetics in horses included a short half-life (approx 1 hour), high total body clearance corrected for bioavailability (5 to 8 mL/min/kg), and small apparent volume of distribution corrected for bioavailability (0.6 to 0.9 L/kg). The bioavailability of methadone administered orally was approximately 3 times that associated with intragastric administration. Absorption of methadone in the small intestine in horses appeared to be limited owing to the low bioavailability after intragastric administration. Better understanding of drug disposition, including absorption, could lead to a more appropriate choice of administration route that would enhance analgesia and minimize adverse effects in horses.

Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers

The pharmacokinetics and metabolism of BIBF 1120, an oral triple angiokinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), were studied in healthy male volunteers (n = 8) who had received a single oral dose of 100 mg [14C]-radiolabelled BIBF 1120 administered as solution.BIBF 1120 was well-tolerated and rapidly absorbed; median time to reach maximum plasma concentrations was 1.3 h and gMean terminal half-life was 13.7 h. A relatively high apparent total body clearance and volume of distribution possibly indicated a high tissue distribution.Plasma concentrations of BIBF 1120 plus carboxylate metabolite BIBF 1202 were lower than the total [14C]-radioactivity in plasma, indicating presence of additional metabolites. Total recovery in excreta was 94.7% 1 week post-dose; mass balance was considered complete after 96 h. BIBF 1120 and metabolites were mainly excreted via faeces.The major metabolic pathway for BIBF 1120 was methyl ester cleavage to BIBF 1202. Subsequently, the free carboxyl group of BIBF 1202 was glucuronidated to 1-O-acylglucuronide. Pathways of minor importance were oxidative N-demethylation to yield BIBF 1053, and oxidation of the piperazine moiety and conjugation. Glucuronidation of the parent drug and formylation of the secondary aliphatic amine of the piperazine ring played a minor role.

The role of floxuridine in metastatic liver disease

Liver metastases are mainly supplied by the hepatic artery. Sustained high levels of intratumoral drug are achievable with certain drugs given via the hepatic artery. Floxuridine (FUDR) is an ideal drug for hepatic arterial infusion (HAI) due to its short half life, steep dose response curve, high total body clearance, and high hepatic extraction. HAI FUDR has consistently shown higher response rates than systemic chemotherapy alone, and some studies have shown a survival advantage. HAI FUDR in combination with systemic chemotherapy has evolved over the years and may be used in palliative, neoadjuvant, and adjuvant settings. The dramatic responses observed with HAI FUDR plus modern era systemic chemotherapy offer the possibility of resection and cure in selected patients. The high hepatic extraction of FUDR limits systemic side effects. Toxicity includes biliary and gastrointestinal ulcers.

Pharmacokinetics (PK) of [14C]-BIBW 2992 after administration of a single dose of 15 mg [14C]-BIBW 2992 oral solution in healthy male volunteers

14607 Background: BIBW 2992 is a novel oral, potent and irreversible inhibitor of EGFR and HER2. This study investigated the PKs and the mass balance of a single oral dose of [14C]-radiolabelled BIBW 2992 in healthy male volunteers. Safety and tolerability of BIBW 2992 were also investigated. Methods: This was a Phase I, open label, single dose study with [14C]-radiolabelled BIBW 2992 performed at one study centre in 8 healthy male subjects receiving one single dose of 15 mg of BIBW 2992 containing 2.25 MBq of [14C]-radiolabelled BIBW 2992. Observation period for the collection of samples of blood, urine and feces was at least 120 hours. Plasma and urine concentrations of BIBW 2992 were analyzed using high performance liquid chromatography coupled to tandem mass spectrometry. [14C]-radioactivity levels in plasma, whole blood, urine and feces were analyzed by Liquid Scintillation Counting methods. Results: The major route of elimination of total [14C]-radioactivity was found to be via feces (85.4%) with an overall recovery of [14C]-radioactivity of 89.5%. For BIBW 2992 as well as for [14C]-plasma and whole blood radioactivity, maximum plasma concentrations were reached around 6 hours after dosing. The gMean terminal half-life (t1/2) was 33.9 hours for BIBW 2992, 118 hours for [14C]-radioactivity in plasma and 195 hours for [14C]-radioactivity in whole blood. A relatively high apparent total body clearance (CL/F) for BIBW 2992 was determined. The gMean CL/F values for the [14C]- radioactivity in plasma and whole blood were low. BIBW 2992 as well as [14C]-radioactivity in plasma and in whole blood exhibited a high apparent volume of distribution (Vz/F) during the terminal phase. BIBW 2992 was generally tolerated with only mild adverse events of short duration (all CTCAE Grade 1) reported. Conclusions: BIBW 2992 was safe and well tolerated at a single dose of 15 mg. The major route of elimination of BIBW 2992 is via feces. The data suggest the presence of one or more metabolites of BIBW 2992 in plasma and in whole blood with a longer terminal half-life than BIBW 2992. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim Pharma GmbH & Co. KG

The Increase in Total and Unbound Propofol Concentrations During Accidental Hemorrhagic Shock in Patients Undergoing Liver Transplantation

To the Editor: Hemorrhagic shock increases the sedative effects of propofol (1,2), so that a patient in hemorrhagic shock should receive only 10%–20% of the propofol dose that a healthy patient would receive (3). However, the mechanism of increase of end-organ sensitivity remains unclear. We demonstrate increases in total and unbound propofol in four patients with advanced cirrhosis who became hemodynamically unstable as a result of massive blood loss during surgery. After IRB approval and with written informed consent from patient, we induced anesthesia with vecuronium 0.1 mg/kg, and propofol 2 mg/kg and maintained anesthesia with 60% air, 0.5%–1.5% isoflurane in oxygen, fentanyl 30 g/kg, and propofol infusion of 2 mg/kg/h. After propofol injection, we collected arterial blood samples to measure blood propofol concentration. We used high-performance liquid chromatography to measure total and unbound propofol concentrations, as reported previously (4). Table 1 shows systolic arterial blood pressure, heart rate, total propofol, fraction unbound, and unbound propofol. After hemorrhagic shock, all patients were infused with lactated Ringer’s solution and mannitol adenine phosphate or were administered dopamine. All patients were adequately resuscitated within 60 min. Total propofol concentrations increased two-fold during hemorrhagic shock, as did the unbound fraction of propofol. The unbound propofol concentrations increased four-fold during hemorrhagic shock.Table 1: Hemodynamic Data and Propofol ConcentrationsThe total propofol concentration likely increased because of the physiological response to shock in our patients. Specifically, shock likely resulted in substantial reductions in hepatic and renal blood flow. Because the clearance of propofol is highly sensitive to liver and renal blood flow (4,5), the propofol clearance decreased during shock, increasing the concentrations during the infusion. This is consistent with effects of experimental hemorrhagic shock on total propofol concentrations in an animal study (1,2,6). However, relatively little attention has been given to hemorrhagic shock’s effect on unbound propofol concentrations. Propofol is a drug with a large distribution volume, high total body clearance (7), and a high degree of binding to plasma albumin, erythrocytes and lipoproteins (8,9) (unbound fraction of <3%). Therefore, the change of unbound fraction is clinically important as we reported previously (3,10). The unbound drug concentration is responsible for a drug’s pharmacological effects, as it is the unbound concentration that equilibrates between the blood and tissues. As the unbound propofol increased four-fold in our patients, this implies that the propofol dose requirements for these patients could be decreased by about 75%, consistent with Shafer’s analysis (3). Daisuke Takizawa, MD Department of Anesthesiology Saitama Cardiovascular and Pulmonary Center Osato-gun, Saitama 360-0105, Japan Department of Anesthesiology Gunma University Graduate School of Medicine 3-39-22 Showa-machi, Maebashi 371-8511, Japan [email protected] Eri Takizawa, MD Department of Anesthesiology Gunma University Graduate School of Medicine 3-39-22 Showa-machi, Maebashi 371-8511, Japan Sohtaro Miyoshi, PhD Fuminori Kawahara, PhD Haruhiko Hiraoka, PhD Department of Anesthesiology Saitama Cardiovascular and Pulmonary Center Osato-gun, Saitama 360-0105, Japan

Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs

ObjectiveTo determine the plasma concentration and define the pharmacokinetic characteristics of fentanyl (10 μg kg−1) administered as a single intravenous (IV) injection followed by: (a) no further drug; or (b) a constant rate infusion (CRI) of fentanyl 10 μg kg−1 hour−1 lasting 1, 3 or 4 hours in dogs. AnimalsFourteen healthy adult beagles (seven males and seven females). Experimental designRandomized cross-over design. Materials and methodsDogs were randomly assigned to four treatment groups. Drugs were administered to each dog in a randomized cross-over design with at least a 14-day washout interval between experiments. All dogs received an IV loading dose of fentanyl (10 μg kg−1). One group received no further fentanyl. In others, the loading dose was followed by a CRI of fentanyl (10 μg kg−1 hour−1) for 1, 3 or 4 hours. Blood samples were collected and plasma fentanyl concentrations determined using high-performance liquid chromatography–mass spectrometry. Plasma pharmacokinetic estimates were obtained by plotting plasma concentrations versus time data and by fitting the change in concentration to a pharmacokinetic model, using a purpose-built program written by the Graduate School of Pharmaceutical Sciences (Kyoto University) in Visual Basic (VBA) on Excel (Microsoft Corporation). ResultsPlasma fentanyl concentration decreased rapidly after single IV injection: the plasma concentration–time curve best fitted a two-compartment model. Pharmacokinetic variables for IV injection were characterized by a short distribution half-time (t1/2α was 4.5 minutes), a relatively long elimination half time (t1/2β was 45.7 minutes), a large volume of distribution (approximately 5 L kg−1) and high total body clearance (77.9 mL minute−1 kg−1). Stable plasma fentanyl levels were obtained in all CRI groups although pharmacokinetic variables were influenced by the duration of administration. Conclusions and Clinical relevanceWhile this study clarified the pharmacokinetic features of rapid IV fentanyl injection and CRI in dogs, the plasma concentration achieving analgesia was not and so further research is needed. Further studies on the effects of other sedatives and/or anaesthetics on fentanyl's disposition are also required as the drug is commonly used with other agents.

What's old is new again: patients receiving hepatic arterial infusion chemotherapy.

Hepatocellular carcinoma (HCC) ranks as the eighth most common cancer in the world. Although uncommon in North America, the incidence of HCC in the United States has increased by 70% since the 1980s (Yu, Yuan, Govindarajan, & Ross, 2000). The most frequent causes of malignant hepatic disease in the United States are metastases from melanoma and primary tumors of the gastrointestinal tract, breast, and lung. Surgical resection and systemic chemotherapy are the standard treatments for this disease. However, surgery is not an option for patients with advanced disease, and the response rate from systemic chemotherapy remains low. An alternative therapy for patients with HCC or cancers with liver metastases is hepatic arterial infusion of chemotherapy directly into the liver. This method allows a high total body clearance and hepatic extraction to generate high hepatic and low systemic exposures. Nursing care of patients receiving hepatic arterial infusion of chemotherapy includes patient education and monitoring for complications.

Phase I clinical and pharmacokinetic studies of the taxoid derivative RPR 109881A administered as a 1-hour or a 3-hour infusion in patients with advanced solid tumors

PurposeTo define the maximum tolerated dose (MTD), the recommended phase II dose, the optimal infusion duration and pharmacokinetics of the semisynthetic taxoid derivative RPR 109881A, given as a 1-h or 3-h infusion every 3 weeks. Patients and methodsRPR109881A was administered as a 1-h i.v. infusion to 34 patients (study 1) with oral steroids as pre-medication. In a subsequent study, 29 patients were treated at the recommended dose or at the dose immediately below (study 2); the first 14 patients received RPR 109881A as a 3-h infusion, while the subsequent 15 were randomized to receive the drug as a 1-h or 3-h infusion. The pharmacokinetics of RPR109881A was studied in plasma and urine and for selected patients in some biological fluids (cerebrospinal fluid, pleural effusion, ascitis). ResultsIn study 1, the dose was escalated from 15 to 105 mg/m2, at which dose two of five patients presented dose-limiting toxicities with febrile neutropenia (FN) after the first cycle, thus defining the MTD. The dose of 90 mg/m2, at which grade 3/4 neutropenia was almost universal with FN in 18%, was recommended for phase II. At 90 mg/m2 the incidence of diarrhea, fatigue and alopecia were 59, 29 and 70%, respectively. The results of study 2 were comparable to those of study 1, thus recommending the 1-h infusion duration for phase II evaluation. RPR 109881A exhibited a high total body clearance, a large distribution volume and long terminal half-life of 20 h. RPR 109881A was detected in cerebrospinal fluid shortly after the end of 1-h infusion. Three objective responses were observed in non-small-cell lung cancer (NSCLC) patients, including a patient with brain metastases. ConclusionsThe antitumor activity in NSCLC, the reproducible profile of toxicity and above all the ability to cross the blood–brain barrier make RPR 109881A worthy of further disease-oriented clinical development.

Intrahepatic arterial infusion of chemotherapy: Pharmacologic principles

Hepatic arterial (HA) infusional chemotherapy possesses a number of constraints not found with systemic chemotherapy. The drug used should have activity in a dose-responsive way without significant hepatic toxicity. The drug must also possess suitable pharmacokinetic properties, namely, a high total body clearance and hepatic extraction, so as to generate high hepatic and low systemic exposures. Of the drugs examined for HA use, 5-fluoro-2'-deoxyuridine (FUDR, floxuridine) demonstrates the best properties. In HA infusional therapy, the catheter is positioned to deliver drug directly to the liver only and must be connected to a reliable pumping mechanism. Surgical implantation of catheters and pumps provides a safe and reliable means to infuse HA FUDR. HA FUDR delivery via an implanted system in the treatment of colorectal liver metastases represents the largest application of HA therapy and provides a basis for future advances when combined with other regional and systemic treatments. Semin Oncol 29:119-125. Copyright 2002, Elsevier Science (USA). All rights reserved.

Pharmacokinetic Profile of the Induction Dose of Propofol in Patients with Severe Burns

The pharmacokinetics of propofol were studied in nine severely burnt patients undergoing general anaesthesia with enflurane/fentanyl for escarectomy. All patients received an intravenous bolus dose of propofol 2 mg/kg, and blood concentrations of propofol were measured over the subsequent 12 hours using high performance liquid chromatography with fluorescent detection. Propofol blood concentrations, showing a very rapid initial decline and a long terminal elimination phase, were best fitted by a triexponential function describing a 3-compartment open mamillary model with rapid distribution from the central compartment, extensive redistribution and elimination from the central compartment. When compared with nonburnt normal controls, the patients with burns showed lower propofol blood concentrations, lower baseline albumin blood levels (p ≤ 0.001), smaller areas under the concentration-time curve (p ≤ 0.001), larger volumes of distribution (p ≤ 0.001), and higher total body clearance (p ≤ 0.001). Pathophysiological systemic responses to the burn injury and particularly the presence of oedema and changes in albumin concentrations were probably responsible for the significant alterations in the disposition kinetics of propofol in the patients with burns.

Topical Application of Eosin to Burns Produces Interference in Measurement of Serum Vancomycin by Fluorescence Polarization Immunoassay

Vancomycin, a gram-positive bactericidal agent, represents the drug of choice for infections caused by methicilin-resistant Staphylococcus aureus , common microorganisms implicated in infections and systemic sepsis in burned patients. Even though the toxicity of the current method of preparation of vancomycin has been reduced by an improved purification method (1), the concentration of vancomycin in the blood should be monitored closely in burned patients to maintain adequate anti-infective concentrations in patients with particularly high total body clearance and volume of distribution. This monitoring can be performed by determining the peak and trough serum concentrations of vancomycin. For this purpose, different analytical techniques are available, mainly immunoassays such as the fluorescence polarization immunoassay (FPIA) developed by Abbott Diagnostic Laboratories (Chicago, IL) (2) on the TDx analyzer and the enzyme-multiplied immunotechnique assay (Emit) developed by Syva–Behring Laboratories (San Jose, CA). FPIA is a fast, reliable, and automated technique frequently used in large laboratories. However, in a few selected situations some interferences may occur. One possible interference has been reported to be due to accumulating vancomycin degradation products in renal failure (3)(4), which could result in overestimated concentrations. However, a recent study conducted in patients with renal dysfunction did not report any substantial differences in the vancomycin concentrations obtained by FPIA and Emit during the first week after the onset of the treatment (5). Recently, we have been able to detect another origin of interference in the FPIA vancomycin assay. Some serum specimens displayed unusually high blank values (>100-fold increase) as compared with routine blank data in the vancomycin FPIA. All of these serum specimens originated from burned patients treated simultaneously with intravenous (i.v.) vancomycin and topical eosin. Indeed, a rational approach in the treatment of burn injuries involves topical wound therapy …

A method using a liquid chromatographic-electrospray-mass spectrometric assay for the determination of antimigraine compounds: preliminary pharmacokinetics of MDL 74,721, sumatriptan and naratriptan, in rabbit

MDL 74,721 (I), sumatriptan(II) and naratriptan(III) are new 5-HT 1-like agonists that have potential as a novel treatment for migraine. Liquid chromatographic-electrospray-mass spectrometric (LC-ESI-MS) assays have been developed to compare the pharmacokinetics of these three antimigraine compounds. The concentration of each parent drug was determined using a solid-phase extraction method and LC-ESI-MS analysis demonstrating the high sensitivity and specificity of the methods down to subnanogram levels in rabbit plasma samples. Pharmacokinetic parameters evaluated after administration of single intravenous and oral doses were very similar and the ANOVA analysis did not show any statistically significant differences for t 1 2 , C max , V or AUC (normalised). The pharmacokinetic parameters showed short t 1 2 (range 1.14-1.9 h) either after intravenous (iv) or oral (po) administration and high total body clearance (CL) after the po dose both probably due to extensive and rapid metabolism of the parent drugs as suggested by the low values for bioavailability (range 13.4–22.8%).

Pharmacokinetic Rationale for Chemotherapeutic Drugs Combined with Intra-Arterial Degradable Starch Microspheres (Spherex®)

To enhance the effectiveness of regional treatment in patients with liver carcinoma, cytotoxic drugs may be combined with alternative therapeutic strategies such as partial vascular blockade using degradable starch microspheres (DSM). When DSM combined with a cytotoxic drug are infused through the hepatic artery, the steep drug concentration gradient to the tumour tissue results in higher tissue drug concentrations which may elicit an increased antitumour response. The co-injected drug should therefore possess an extensive extravascular distribution and possess a suitable dose-response relationship. Furthermore, the drug of choice should also have a high total body clearance with a large component of clearance outside the target compartment, should not interact with the spheres and should be given without inducing any back-flow. Under these assumptions, a reduced systemic exposure of a co-injected drug could be translated into an increased regional extraction ratio induced by the blood flow reduction.

The acetylcholinesterase oxime reactivator HI‐6 in man: Pharmacokinetics and tolerability in combination with atropine

In a double-blind, placebo-controlled, single-dose ascending pharmacokinetics and tolerance study, we evaluated the bispyridinium oxime HI-6 dichloride monohydrate (62.5, 125, 250, and 500 mg), administered intramuscularly with atropine sulphate, 2 mg, in 24 healthy male volunteers. The plasma HI-6 peak concentration (Cmax) and area under the concentration-time curve (AUC) demonstrated linear pharmacokinetics with low intradose variability, suggestive of uniformity of effect among subjects. HI-6 (500 mg) attained plasma drug concentrations that appeared adequate for practical use as an antidote. The mean +/- SD time to maximum plasma HI-6 concentration (tmax = 0.69 +/- 0.21 h, n = 16), and absorption half-life (t/2a = 0.17 +/- 0.05 h) indicated rapid onset of effect. The volume of distribution (Vd = 0.25 +/- 0.04 L kg-1 TBW) approximated the extracellular fluid volume. A high total body clearance (CL = 252 +/- 52 mL min-1) and short apparent elimination half-life (t/2e = 1.15 +/- 0.19 h) were expected for this polar quaternary ammonium drug. The renal clearance CLr = 137 +/- 33 mL min-1), which approximated the expected glomerular filtration rate, and 24 h urinary excretion of unchanged drug (55 +/- 10%) indicated substantial non-renal elimination. Blood pressure, heart rate, respiratory rate, electrocardiographic parameters, mental acuity, and vision were not altered. Adverse events and changes in serum, urine, and semen laboratory tests were mild. The pharmacokinetics, safety, and apparent efficacy of HI-6 suggest it may be a superior oxime antidote against nerve agent poisoning.

Pharmacokinetics and haemodynamic response after an intravenous bolus injection of clonidine in children

SummaryThe pharmacokinetics and haemodynamic response after an intravenous bolus injection of clonidine (2.5 μg·kg−1) were investigated in paediatric patients. Plasma levels of clonidine were determined by radioimmunoassay in eight ASA 1 paediatric patients (age: 33 months (SD 13), weight: 15.1 kg (SD 3.4), body surface area: 0.625 m2 (SD 0.109)). A considerably shorter terminal half‐life (mean 6.13 h (SD 1.33), harmonic mean: 5.55 h, 95% confidence interval 4.60–7.63), a smaller distribution volume (0.96 1·kg−1 (SD 0.43)) and a higher total body clearance (4.85 ml·kg−1 min−1 (SD 1.00)) were found in comparison with previously reported adult studies. The haemodynamic response was investigated during isoflurane anaesthesia in twelve ASA 1 children (age: 31 months (SD 11), weight: 14.4 kg (SD 3.1)) premedicated with rectal midazolam and atropine. A significant reduction in mean arterial blood pressure (MABP) was observed (P= 0.0032). The MABP was found to be reduced by 26.3% (SD 13.6) compared with baseline and the time for 75% of the expected blood pressure reduction to occur was 21.3 min (SD 25.6). A consistent finding in all patients was a harmonic undulation of the blood pressure implying a dampened sine wave response. A small but significant decrease in heart rate (127 bpm (SD 19) vs 119 bpm (SD 20), P= 0.006) was observed immediately after injection following which the heart rate gradually returned to the previous baseline. The observed changes in heart rate and blood pressure responses were of a moderate magnitude. The use of clonidine as a premedicant or adjunct to general anaesthesia in children appears to be appropriate from both a pharmacokinetic and haemodynamic standpoint.