Mean Peak Plasma Concentration Research Articles

The Influence of MDR1 G2677T/A Genetic Polymorphisms on the Pharmacokinetics of Repaglinide in Healthy Chinese Volunteers

Aims: The aim of this study was to evaluate the pharmacogenetic variability in the disposition of repaglinide in healthy Chinese subjects. Methods: A single dose of 2 mg repaglinide was orally administered to 24 healthy Chinese subjects. The serum concentrations of repaglinide were measured by using liquid chromatography/tandem mass spectrometry. We determined the polymorphic alleles of MDR1 C1236T, MDR1 G2677T/A, MDR1 C3435T, CYP3A4*18, OATP1B1 G388A, and OATP1B1 T521C in each subject. Results: The area under the plasma concentration-time curve from time 0 to infinity (AUC_(0–inf)) of repaglinide was significantly higher in subjects possessing the MDR1 2677GT and 2677TT alleles than in those with the MDR1 2677GG and 2677TA alleles (p = 0.007). The mean AUCs and peak plasma concentration were higher in subjects with the 521TC allele than in those with the OATP1B1 521TT allele, and the OATP1B1 388A allele is associated with a reduced trend of pharmacokinetic exposure; however, these trends were not statistically significant. The pharmacokinetics of repaglinide was not associated with MDR1 C1236T, MDR1 C3435T, and CYP3A4*18. Conclusion: This study shows that the genetic polymorphisms of MDR1 G2677T/A might explain the variability in the pharmacokinetics of repaglinide in the Chinese population.

Effect of fluvoxamine on the pharmokinetics of zolpidem: A two‐treatment period study in healthy volunteers

1. Our objective was to evaluate a possible pharmacokinetic interaction between zolpidem and fluvoxamine in healthy volunteers. 2. The study consisted of two periods: Period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem; and Period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 100 mg fluvoxamine. Between the two periods, the subjects were treated for 6 days with a single daily dose of 100 mg fluvoxamine. 3. Pharmacokinetic parameters of zolpidem given in each treatment period were calculated using non-compartmental analysis and the data from two periods were compared to determine statistically significant differences. 4. In the two periods of treatments, the mean peak plasma concentrations (C(max)) were 56.4 ± 25.6 ng/mL (zolpidem alone) and 67.3 ± 25.8 ng/mL (zolpidem after pretreatment with fluvoxamine). The t(max), times taken to reach C(max), were 0.83 ± 0.44 and 1.26 ± 0.74 h, respectively, and the total areas under the curve (AUC(0-∞)) were 200.9 ± 116.8 and 512.0 ± 354.6 ng h/mL, respectively. The half-life of zolpidem was 2.24 ± 0.81 h when given alone and 4.99 ± 2.92 h after pretreatment with fluvoxamine. 5. Fluvoxamine interacts with zolpidem in healthy volunteers and increases its exposure by approximately 150%. The experimental data showed the pharmacokinetic interaction between zolpidem and fluvoxamine, and suggest that the observed interaction might be clinically significant, but its relevance has to be confirmed.

Pharmacokinetics of Clindamycin Administered Orally to Pigeons

To determine the plasma concentration of clindamycin in pigeons after oral administration, 12 rock pigeons (Columba livia) were used in a 2-phase study. In the first phase, 8 pigeons received clindamycin by gavage at 100 mg/kg as a single dose. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 3, 4, and 6 hours, and the plasma was separated, frozen, and subsequently analyzed by liquid chromatography-mass spectrometry for clindamycin and its active metabolites, N-demethylclindamycin (NCLD) and clindamycin sulfoxide. Clindamycin was rapidly absorbed with plasma concentrations peaking at 0.5 hours at 1.43 microg/mL. The terminal half-life (t(1/2)) was 1.25 hours, and the mean residence time was 2.49 hours. N-demethylclindamycin was detected in 7 of 8 birds (88%), whereas clindamycin sulfoxide was not found in any samples. In phase 2, clindamycin was administered to 3 birds by gavage at 100 mg/ kg q6h for 5 doses. Mean peak plasma concentrations were 2.46 and 0.64 microg/mL, with trough concentrations of 0.11 and 0.44 microg/mL for clindamycin and NCLD, respectively. No adverse effects were observed in any birds. Based on an additive antimicrobial effect of NCLD with clindamycin, an oral dosage of 100 mg/kg q6h in pigeons should reach effective plasma concentrations against common susceptible pathogens. If dose proportionality exists, lower doses and longer intervals likely produce subtherapeutic concentrations to treat systemic infections. How well birds would tolerate an extended oral dose regimen, how frequently birds fail to produce the active metabolite critical for an additive effect, and the application of these results to other avian species require further study.

Clinical Development of AVL-292; A Potent, Selective Covalent Btk Inhibitor for the Treatment of B Cell Malignancies,

Abstract 3485Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in the treatment of several B cell malignancies. Bruton’s tyrosine kinase (Btk) plays a key role in promoting B cell proliferation and survival through participation in the BCR signaling pathway and represents a promising new drug target. AVL-292 is a covalent, highly selective, orally active small molecule inhibitor of Btk currently being evaluated in a Phase 1b clinical trial in relapsed, refractory B cell malignancies including Chronic Lymphocytic Leukemia (CLL) and non-Hodgkin lymphomas. AVL-292 forms a covalent bond with Cys481 in Btk and potently inhibits Btk in biochemical (IC50 < 0.5nM) and cellular assays (EC50 1–10 nM) including anti-IgM stimulation of BCR signaling, B cell proliferation and activation. A quantitative pharmacodynamic assay to determine the level of AVL-292 bonded to Btk in vitro or in vivo was developed and this drug-target engagement by AVL-292 was shown to correlate directly with inhibition of Btk enzyme activity and substrate phosphorylation. To rationally determine the dose and dose frequency of AVL-292 most likely to benefit patients and to reduce the potential for sub-therapeutic dosing in initial oncology patient cohorts, AVL-292 was administered to healthy adult subjects in a double-blind, placebo controlled, single ascending dose study. This study assessed safety, pharmacokinetics, and quantitatively measured Btk protein levels and AVL-292-Btk engagement in freshly isolated peripheral B lymphocytes. In healthy human subjects, AVL-292 was found to be safe and well tolerated following oral administration at dose levels ranging from 0.5–7.0 mg/kg. AVL-292 plasma levels and pharmacodynamic measurement of Btk engagement was dose-proportional across cohorts. All subjects that received 1.0 mg/kg AVL-292 achieved >80% Btk engagement and mean peak plasma levels (Cmax 365 ng/mL) of AVL-292 were rapidly achieved (Tmax median 40 min). Subjects receiving 2.0 mg/kg AVL-292 had a mean peak plasma concentration of 542 ng/mL. All subjects demonstrated >84% Btk engagement at this dose, with 5 of 6 subjects achieving >98% drug-target engagement. Although AVL-292 plasma levels declined substantially by 8 hours, Btk engagement persisted throughout 24 hours, demonstrating that covalent inhibition of Btk with AVL-292 enables prolonged duration of activity without high levels of circulating drug. These results suggest that a once daily dosing schedule is sufficient for sustained Btk inhibition. Furthermore, the Btk protein level in circulating B lymphocytes from all study subjects was evaluated and the mean level was found to be 417.7 pg Btk/mg total protein. Interestingly, this finding in normal B cells correlates well with preclinical ex vivo analysis of Btk protein in primary CLL cells where comparable Btk protein levels were found. This suggests that the AVL-292 dose range and schedule identified for complete Btk engagement in this healthy volunteer trial is likely to inform appropriate dose selection in the subsequent phase 1b oncology study, allowing more rapid identification of a safe and clinically effective dose. Disclosures:Evans:Avila Therapeutics: Employment, Equity Ownership. Tester:Avila Therapeutics: Employment, Equity Ownership. Aslanian:Avila Therapeutics: Employment, Equity Ownership. Chaturvedi:Avila Therapeutics: Employment, Equity Ownership. Mazdiyasni:Avila Therapeutics: Employment, Equity Ownership. Sheets:Avila Therapeutics: Employment, Equity Ownership. Nacht:Avila Therapeutics: Employment, Equity Ownership. Stiede:Avila Therapeutics: Employment, Equity Ownership. Witowski:Avila Therapeutics: Employment, Equity Ownership. Lounsbury:Avila Therapeutics: Employment, Equity Ownership. Petter:Avila Therapeutics: Employment, Equity Ownership. Singh:Avila Therapeutics: Employment, Equity Ownership. Westlin:Avila Therapeutics: Employment, Equity Ownership.

Regadenoson, An Adenosine 2A Receptor Agonist, Is Safe and Inhibits Invariant NKT Cells in Sickle Cell Disease

Abstract 849▪FN2▪This icon denotes a clinically relevant abstractAdenosine 2A receptor (A2AR) agonists decrease pulmonary inflammation and injury in a murine model of sickle cell disease (SCD) by interrupting invariant NKT (iNKT) cell activation that occurs as a result of vaso-occlusion (Clin Immunol 2011). iNKT cells represent a subpopulation of T lymphocytes that rapidly generates pro-inflammatory cytokines upon activation and thereby may play a role in sustaining or propagating vaso-occlusion in human SCD. To evaluate the effects of A2AR activation in human SCD, we are conducting a dose-seeking and safety study of the FDA-approved, highly selective A2AR agonist regadenoson in patients with SCD ≥ 14 years of age. This is a multi-center, phase I clinical trial of infusional regadenoson that utilizes a 3+3 design and is comprised of four stages to determine maximum tolerated dose and safety during a 12 hour infusion in adults at baseline (defined as absence of increased pain, ED or hospital visit in the past 2 weeks) (stage 1), a 24 hour infusion in adults at baseline (stage 2), a 24 hour infusion in adults during a painful vaso-occlusive crisis (VOC) (stage 3), and a 24 hour infusion in children (≥ 14 years) during a painful VOC (stage 4). Three dose levels of infusional regadenoson have been evaluated thus far: 0.24 (level 0), 0.6 (level 1) and 1.44 mcg/kg/hour (level 2). Samples for plasma levels and iNKT cell activation are obtained at 0, 6, 12, 18 and 30 hours after start of infusion. Two methods are used to identify iNKT cells: 1) CD1d tetramers, loaded with the α-GalCer-like glycolipid PBS57 (defined as tetramer+CD3+), and 2) 6B11 antibody to the invariant T cell receptor (defined as CD45+6B11 high). NF-kB activation is measured using phospho-Ser536-p65 antibody (phospho-NF-kB). To date, 15 subjects have received infusional regadenoson. Regadenoson appears to be safe (devoid of cardiovascular or other side effects) and biologically active in reducing iNKT cell activation markers during a 12 hour infusion at dose levels 1 and 2, and we are currently evaluating the safety of a 24 hour infusion at dose level 2. No dose limiting toxicities occurred in the 15 subjects at dose levels 0, 1 or 2. Pharmacokinetic analyses showed mean peak plasma concentrations of regadenoson for dose levels 0, 1 and 2 were 0.37 ng/ml, 1.16 ng/ml and 2.19 ng/ml, respectively. Based on animal models, we suspect that biologically active plasma concentrations are approximately 1 ng/ml. At baseline, iNKT cells were activated in patients with SCD as defined by elevated levels of phospho-NF-kB expression and A2AR expression as assessed by anti-A2AR immunoreactivity. In particular, CD4+ iNKT cells showed increased phospho-NF-kB expression whereas CD4- iNKT cells were not activated. At dose levels 1 and 2, regadenoson decreased iNKT cell activation in patients with SCD. For example, when pre- and post-12 hour regadenoson infusion measurements were compared at dose level 2 (N=5), mean percent of cells expressing phospho-NF-kB in the activation gate was 40% (90% CI 23–58) at baseline and decreased by 53% at the end of infusion to 19% (90% CI 6–33). Similar results were found in measurements of A2ARs. We conclude that infusional regadenoson administered at 0.6 and 1.44 mcg/kg/hour is safe during a 12 hour infusion and decreases activation of iNKT cells. Our next steps are to determine whether infusions of a longer duration (24 and 48 hours) are safe and similarly biologically effective during a VOC. We then intend to conduct a clinical trial to measure the clinical efficacy of regadenoson infusion during VOC and acute chest syndrome episodes. Disclosures:Off Label Use: Regadenoson is an adenosine 2A receptor agonist that is FDA approved for use during myocardial stress imaging. We are examining the safety of regadenoson in patients with sickle cell disease. Nathan:Astellas: Research Funding.

A Sensitive Method for Determination of Platycodin D in Rat Plasma Using Liquid Chromatography/Tandem Mass Spectrometry and its Application to a Pharmacokinetic Study

Platycodin D (PD), a major component isolated from the root of Platycodon grandiflorum, is widely used in traditional Chinese medicine. A sensitive rapid analytical method was established and validated to determine the PD in rat plasma. This method was further applied to assess the pharmacokinetics of PD in rats following administration of a single dose. Liquid chromatography tandem mass spectrometry (LC/MS/MS) in multiple reaction monitoring mode (MRM) was used in the method, and tubeimoside I was used as the internal standard (IS). A simple protein precipitation based on methanol (MeOH) was employed. The combination of a simple sample cleanup and short chromatographic running time (4 min) increased the throughput of the method substantially. The method was validated over the range of 0.5-1000 ng/mL with a correlation coefficient > 0.99. The lower limit of quantification was 0.5 ng/mL for PD in plasma. Intra- and inter-day accuracies for PD were 90-115 % and 96-108 %, respectively, and the inter-day precision was less than 15 %. After a single oral dose of 10 mg/kg of PD, its mean peak plasma concentration ( CMAX) was 13.7 ± 4.5 ng/mL at 0.5 h. The area under the plasma concentration-time curve ( AUC0-24 H) was 35.4 ± 16.1 h·ng/mL, and the elimination half-life ( T1/2) was 1.48 ± 0.13 h. In case of intravenous administration of PD at a dosage of 0.5 mg/kg, the area under the plasma concentration-time curve ( AUC0-24 H) was 2203 ± 258 h · ng/mL, and the elimination half-life (T½) was 6.57 ± 0.70 h. Based on the results, the oral bioavailability of PD in rats at 10 mg/kg is 0.079 %.

A sensitive method for determination of furanodiene in rat plasma using liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study

Furanodiene, a sesquiterpene component extracted from the essential oil of the rhizome of Curcuma wenyujin Y.H. Chen et C. Ling (Wen Ezhu), is widely used in traditional Chinese medicine. A sensitive analytical method was established and validated for furanodiene in rat plasma, which was further applied to assess the pharmacokinetics of furanodiene in rats receiving a single dose of furanodiene. Liquid chromatography tandem mass spectrometry (LC/MS/MS) in multiple reaction monitoring mode was used in the method and costundide was used as internal standard. A simple protein precipitation based on methanol was employed. The simple sample cleanup increased the throughput of the method substantially. The method was validated over the range of 1-1000 ng/mL with a correlation coefficient >0.99. The lower limit of quantification was 1 ng/mL for furanodiene in plasma. Intra- and inter-day accuracies for furanodiene were 88-115 and 102-107%, and the inter-day precision less than 14.4%. After a single oral dose of 10 mg/kg of furanodiene, the mean peak plasma concentration of furanodiene was 66.9 ± 23.4 ng/mL at 1 h, the area under the plasma concentration-time curve (AUC(0-10 h)) was 220 ± 47.8 h ng/mL, and the elimination half-life was 1.53 ± 0.06 h. After an intravenous adminstration of furanodiene at a dosage of 5 mg/kg, the area under the plasma concentration-time curve was 225 ± 76.1 h⋅ng/mL, and the elimination half-life was 2.40 ± 1.18 h. Based on this result, the oral bioavailability of furanodiene in rats at 10 mg/kg is 49.0%.

Pharmacokinetics of sodium and trihydrate amoxicillin after intravenous and intramuscular administration in llamas (Lama glama)

The pharmacokinetics of amoxicillin following a single intravenous (i.v.) and intramuscular (i.m.) administration of a conventional sodium formulation and following a single i.m. administration of a trihydrate long acting suspension was investigated in adult llamas. On phase 1, in a cross-over design, six llamas received sodium amoxicillin (20mg/kg) by the i.v. and i.m. routes. On phase 2, six llamas received i.m. trihydrate amoxicillin suspension (15mg/kg). Amoxicillin plasma concentrations were determined using a microbiological assay. Significant differences were found for mean peak plasma concentration (40.4±12.1 versus 3.04±1.02μg/ml), mean elimination half-life (0.86±0.3 versus 9.96±3.1h) and mean residence time (1.37±0.5 versus 15.1±4.1h) following sodium and trihydrate i.m. amoxicillin, respectively. Bioavailability was similar for both sodium (1.44±0.2) and trihydrate (1.14±0.4) formulations. The results of the pharmacokinetic/pharmacodynamic indices of time above the minimal inhibitory concentrations (T>MIC) suggest that 20mg/kg sodium amoxicillin would produce a good therapeutic outcome in infections due to susceptible bacteria administered every 8–12h, while for 15mg/kg trihydrate amoxicillin, higher doses or more frequent intervals may be needed for treating low susceptibility bacteria in llamas.

Pharmacokinetic Interaction Between Zolpidem and Carbamazepine in Healthy Volunteers

The objective of this study was to evaluate the pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers. The study consisted of 2 periods: period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem, and period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 400 mg carbamazepine. Between the 2 periods, the participants were treated for 15 days with a single daily dose of 400 mg carbamazepine. Pharmacokinetic parameters of zolpidem administered in each treatment period were calculated using noncompartmental analysis. In the 2 periods of treatments, the mean peak plasma concentrations (C(max)) were 59 ng/mL (zolpidem alone) and 35 ng/mL (zolpidem after pretreatment with carbamazepine). The t(max), times taken to reach C(max), were 0.9 hours and 1.0 hour, respectively, and the total areas under the curve (AUC(0-∞)) were 234.9 ng·h/mL and 101.5 ng·h/mL, respectively. The half-life of zolpidem was 2.3 and 1.6 hours, respectively. Carbamazepine interacts with zolpidem in healthy volunteers and lowers its bioavailability by about 57%. The experimental data demonstrate the pharmacokinetic interaction between zolpidem and carbamazepine and suggest that the observed interaction may be clinically significant, but its relevance has to be confirmed.

PHARMACOKINETICS OF MOXIDECTIN IN THE SOUTHERN HAIRY-NOSED WOMBAT (LASIORHINUS LATIFRONS)

Sarcoptic mange, caused by Sarcoptes scabiei var. wombati, could be a significant threat to populations of southern hairy-nosed wombats (Lasiorhinus latifrons; SHNW) in Australia. Treatment is currently based on the off-label use of various parasiticidal drugs, with limited clinical efficacy trials. Our primary aim was to determine the pharmacokinetic parameters of a macrocyclic lactone, moxidectin, to assist in the development of effective treatment protocols. Pharmacokinetic parameters were determined in four female SHNW following a single subcutaneous injection of 0.2 mg/kg moxidectin. Blood samples were collected for 38 days following injection (August-September 2008), for analysis using liquid chromatography and tandem mass spectrometry. The mean peak plasma concentration occurred at 13.6 hr, with a mean peak plasma level of 98.6 ng/ml. The mean elimination half-life was 5.03 days, resulting in a mean area under the curve of 377 ng.day/ml. The peak plasma moxidectin concentration was higher than that seen in livestock species but the plasma elimination half-life was shorter. This study suggests that a single injection of 0.2 mg/kg moxidectin may not be sufficient to clear a mange infection in this species.

Toltrazuril sulfone sodium salt: synthesis, analytical detection, and pharmacokinetics in the Horse

Toltrazuril sulfone (ponazuril) is a triazine-based antiprotozoal agent with clinical application in the treatment of equine protozoal myeloencephalomyelitis (EPM). In this study, we synthesized and determined the bioavailability of a sodium salt formulation of toltrazuril sulfone that can be used for the treatment and prophylaxis of EPM in horses. Toltrazuril sulfone sodium salt was rapidly absorbed, with a mean peak plasma concentration of 2400 ± 169 (SEM) ng/mL occurring at 8 h after oral-mucosal dosing and was about 56% bioavailable compared with the i.v. administration of toltrazuril sulfone in dimethylsulfoxide (DMSO). The relative bioavailability of toltrazuril sulfone suspended in water compared with toltrazuril sulfone sodium salt was 46%, indicating approximately 54% less oral bioavailability of this compound suspended in water. In this study, we also investigated whether this salt formulation of toltrazuril sulfone can be used as a feed additive formulation without significant reduction in oral bioavailability. Our results indicated that toltrazuril sulfone sodium salt is relatively well absorbed when administered with feed with a mean oral bioavailability of 52%. Based on these data, repeated oral administration of toltrazuril sulfone sodium salt with or without feed will yield effective plasma and cerebrospinal fluid (CSF) concentrations of toltrazuril sulfone for the treatment and prophylaxis of EPM and other protozoal diseases of horses and other species. As such, toltrazuril sulfone sodium salt has the potential to be used as feed additive formulations for both the treatment and prophylaxis of EPM and various other apicomplexan diseases.

Erratum

British Journal of Clinical PharmacologyVolume 72, Issue 1 p. 182-182 Free Access Erratum This article corrects the following: A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours Xuexin He, Su Li, He Huang, Zhiming Li, Likun Chen, Sheng Ye, Jiajia Huang, Jing Zhan, Tongyu Lin, Volume 71Issue 6British Journal of Clinical Pharmacology pages: 860-870 First Published online: May 12, 2011 First published: 09 June 2011 https://doi.org/10.1111/j.1365-2125.2011.04030.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat REFERENCE 1 He X, Li S, Huang H, Li Z, Chen L, Ye S, Huang J, Zhan J and Lin T. A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours Br J Clin Pharmacol 2011; 71: 860– 70. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar In the above paper 1 the authors have identified the following error: CA4P should be CA4 on line 7 of the Results section in the abstract on page 860. The sentence should read as For CA4, at 50 mg m−2, mean (SD) peak plasma concentration (Cmax) was 0.99 (0.33) µm, area under the curve from time zero to time of last quantifiable concentration (AUC(0,t)) was 1.42 (0.30) µm h and terminal elimination half-life (t1/2) was 1.81 (0.61) h. At 65 mg m−2, Cmax was 1.73 (0.62) µm, AUC(0,t) was 3.19 (1.47) µm h and t1/2 was 1.90 (0.61) h. Volume72, Issue1July 2011Pages 182-182 ReferencesRelatedInformation

Plasma concentrations and behavioral, antinociceptive, and physiologic effects of methadone after intravenous and oral transmucosal administration in cats

To determine plasma concentrations and behavioral, antinociceptive, and physiologic effects of methadone administered via IV and oral transmucosal (OTM) routes in cats. 8 healthy adult cats. Methadone was administered via IV (0.3 mg/kg) and OTM (0.6 mg/kg) routes to each cat in a balanced crossover design. On the days of drug administration, jugular catheters were placed in all cats under anesthesia; a cephalic catheter was also placed in cats that received methadone IV. Baseline measurements were obtained ≥ 90 minutes after extubation, and methadone was administered via the predetermined route. Heart and respiratory rates were measured; sedation, behavior, and antinociception were evaluated, and blood samples were collected for methadone concentration analysis at predetermined intervals for 24 hours after methadone administration. Data were summarized and evaluated statistically. Plasma concentrations of methadone were detected rapidly after administration via either route. Peak concentration was detected 2 hours after OTM administration and 10 minutes after IV administration. Mean ± SD peak concentration was lower after OTM administration (81.2 ± 14.5 ng/mL) than after IV administration (112.9 ± 28.5 ng/mL). Sedation was greater and lasted longer after OTM administration. Antinociceptive effects were detected 10 minutes after administration in both groups; these persisted ≥ 2 hours after IV administration and ≥ 4 hours after OTM administration. Despite lower mean peak plasma concentrations, duration of antinociceptive effects of methadone was longer after OTM administration than after IV administration. Methadone administered via either route may be useful for perioperative pain management in cats.

Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa)

Recombinant activated factor VIIa (rFVIIa) is used to treat bleeds in hemophilia patients with inhibitors. A subcutaneous formulation could potentially improve its half-life and make it suitable for prophylactic treatment. A study was conducted to determine the safety of subcutaneously administered rFVIIa in patients with hemophilia and the pharmacokinetic profile (including bioavailability). This was a multicenter, open-label, cross-over comparison of single doses of intravenous rFVIIa 90μgkg(-1) and a new formulation of rFVIIa for subcutaneous injection at dose levels of 45, 90, 180, 270 and 360μgkg(-1) . Sixty subjects (12 per dose cohort) with hemophilia A or B were enrolled. Subcutaneously administered rFVIIa showed lower mean peak plasma concentrations and prolonged FVII activity (C(max) , 0.44-5.16IU mL(-1) [across doses]; t(1/2) , 12.4h; t(max) , 5.6h) compared with intravenously administered rFVIIa (C(max) , 51.7IUmL(-1) ; t(1/2) , 2.7h; t(max) , <10min). The absolute bioavailability of subcutaneous rFVIIa ranged from 21.1 to 30.1% across dose levels. Dose proportionality was observed within a 2-fold dose increase but not across the full dose range. No thromboembolic events, drug-related serious adverse events, severe injection-site reactions or neutralizing antibodies were reported (primary endpoint). Mild and moderate injection-site reactions were more frequent with subcutaneous than with intravenous injections. This phase I clinical trial did not identify safety concerns of prolonged exposure to rFVIIa administered subcutaneously in single doses to hemophilia patients.

A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours

• Three pharmacokinetic and safety studies for combretastatin A4 phosphate (CA4P), the first vascular disrupting agent, have been conducted in Western countries. • The maximum tolerated dose (MTD) was approximately 60-68 mg m(-2). • CA4P-related grade 3 or 4 adverse events were tumour pain, dyspnoea, hypoxia and syncope in patients who received doses ≥ 50 mg m(-2). • This is the first pharmacokinetic and safety study conducted in East Asian patients. • There appeared to be a trend that Chinese patients metabolized CA4 more rapidly and had greater neurotoxicity than patients in Western countries. • We observed favourable clinical responses in patients with refractory nasopharyngeal carcinoma. • CA4P-induced acute renal failure was seen in one dehydrated Chinese patient. This trial was conducted to evaluate the safety and pharmacokinetics of combretastatin A4 phosphate (CA4P) given intravenously as a single dose to Chinese patients with refractory solid tumours. METHODS Twenty-five patients were treated with single doses of CA4P according to a dose escalation scheme: 5, 10, 20, 33, 50, 65 and 85 mg m(-2) infused intravenously over 30 min. CA4P was generally well tolerated at ≤ 65 mg m(-2). Transient, moderate increases in the heart rate-corrected QT interval occurred at all doses. CA4P produced a transient dose-dependent increase in neural and gastrointestinal toxicities. Acute renal failure occurred in one dehydrated patient who had also taken paracetamol. There were seven episodes of dose-limiting toxicity at doses ≥65 mg m(-2), including two episodes of reversible ataxia at 85 mg m(-2).For CA4, at 50 mg m(-2),mean (SD) peak plasma concentration (C(max) was 0.99 (0.33) mM, area under the curve from time zero to time of last quantifiable concentration (AUC(0,t)) was 1.42 (0.30) mM h and terminal elimination half-life (t(1/2)was 1.81 (0.61) h. At 65 mg m-2,C(max) was 1.73 (0.62) mM,AUC(0,t) was 3.19 (1.47) mM h and t (1/2) was 1.90 (0.61) h [corrected]One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass. CONCLUSION Doses ≤ 65 mg m(-2) given as 30 min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50-65 mg m(-2) have been selected for further studies.

The pharmacokinetics of oral itraconazole in AIDS patients.

To test the hypothesis that absorption of orally administered itraconazole may be reduced in patients with the Acquired Immunodeficiency Syndrome (AIDS), 8 patients with AIDS were given two 100 mg capsules of itraconazole for 15 days. Plasma levels were measured by HPLC hourly for the first 8 h following ingestion, then at 24, 48, 72 and 96 h on days 1, 8 and 15. Peak plasma levels occurred after approximately 4 h. Mean peak plasma concentrations were 446 +/- 196 and 530 +/- 214 ng mL-1 at days 8 and 15. The area under the curve over 24 h (AUC0-24) was 2105 +/- 1241, 7679 +/- 3838 and 8748 +/- 4385 ng mL-1 h for days 1, 8 and 15, respectively. Steady-state was achieved after one week of dosing. There was no evidence of hepatotoxicity and one patient stopped itraconazole due to a rash. It may be concluded that the absorption of oral itraconazole capsules is reduced in AIDS patients, by a factor of approximately 50%, when compared with normal volunteers. AIDS patients may require higher doses of itraconazole than used in non-AIDS patients to achieve comparable plasma levels.

Pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers

Ivabradine is a novel heart rate-lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Our objective was to evaluate a possible pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers. The study consisted of two periods: Period 1 (Reference), when each volunteer received a single dose of 10 mg ivabradine and Period 2 (Test), when each volunteer received a single dose of 10 mg ivabradine and 400 mg carbamazepine. Between the two periods, the subjects were treated for 15 days with a single daily dose of 400 mg carbamazepine. Plasma concentrations of ivabradine were determined during a 12-h period following drug administration, using a high-throughput liquid chromatography with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment period were calculated using non-compartmental and compartmental analysis to determine if there were statistically significant differences. In the two periods of treatments, the mean peak plasma concentrations (C(max)) were 16·25 ng/mL (ivabradine alone) and 3·69 ng/mL (ivabradine after pretreatment with carbamazepine). The time taken to reach C(max), t(max), were 0·97 and 1·14 h, respectively, and the total areas under the curve (AUC(0-∞)) were 52·49 and 10·33 ng h/mL, respectively. These differences were statistically significant for C(max) and AUC(0-∞) when ivabradine was administered with carbamazepine, whereas they were not for t(max), half-life and mean residence time. T Carbamazepine interacts with ivabradine in healthy volunteers, and lowers its bioavailability by about 80%. This magnitude of effect is likely to be clinically significant.

A dose-finding, pharmacokinetic and pharmacodynamic study of a novel schedule of flavopiridol in patients with advanced solid tumors

Based on the promising activity and tolerability of flavopiridol administered with a pharmacokinetically-derived dosing schedule in chronic lymphocytic leukemia (CLL), we conducted a phase I study using this schedule in patients with advanced solid tumors. Flavopiridol was given IV as a 30-min loading dose followed by a 4-hr infusion weekly for 4 weeks repeated every 6 weeks. Dose-escalation was in cohorts of three patients using the standard 3+3 phase I study design. Blood samples were obtained for pharmacokinetic and pharmacodynamic studies. Thirty-four eligible patients with advanced solid tumors received a total of 208 doses (median 7, range 1-24). Total doses ranged from 40 to 105 mg/m(2). The primary dose limiting toxicity was cytokine release syndrome (CKRS). No antitumor responses were observed. The mean peak plasma concentration across all doses was 1.65 ± 0.86 μM. Area under the concentration-versus-time curve ([Formula: see text]) ranged from 4.31 to 32.2 μM[Symbol: see text]hr with an overall mean of 13.6 ± 7.0 μM[Symbol: see text]hr. Plasma flavopiridol concentrations and AUC increased proportionally with dose. There was no correlation between cytokine levels and clinical outcomes. The maximum-tolerated dose of flavopiridol is 20 mg/m(2) bolus followed by 20 mg/m(2) infusion over 4 h given weekly for 4 weeks on a 6-week cycle in patients with advanced solid tumors. Flavopiridol PK was notably different, and there was a higher frequency of CKRS, despite prophylactic steroids, seen in this patient group compared to previous studies with CLL using a similar dosing schedule.

Pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers

Our objective was to evaluate a possible pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers. The study consisted of two periods: Period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem and Period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 500 mg ciprofloxacin. Between the two periods, the subjects were treated for 5 days with a single daily dose of 500 mg ciprofloxacin. Plasma concentrations of zolpidem were determined during a 12-hour period following drug administration. Pharmacokinetic parameters of zolpidem administered in each treatment period were calculated using non-compartmental analysis and the data from two periods were compared to determine statistically significant differences. In the two periods of treatments, the mean peak plasma concentrations (Cmax) were 75.73±28.34 ng/ml (zolpidem alone) and 80.58±22.40 ng/ml (zolpidem after pre-treatment with ciprofloxacin). The tmax, times taken to reach Cmax, were 0.91±0.42 and 1.44±0.61 h, respectively, and the total areas under the curve (AUC0-∞) were 300.2±115.5 and 438.1±142.6 ng h/ml, respectively. The half-life of zolpidem was 2.39±0.53 h when administered alone and 3.34±0.87 h after pre-treatment with ciprofloxacin. These differences were statistically significant for Cmax, tmax, AUC0-∞, half-life and mean residence time. Ciprofloxacin interacts with zolpidem in healthy volunteers, raising its bioavailability by about 46%. This magnitude of effect is likely to be clinically significant.

A Pharmacokinetic Analysis of Diclofenac Potassium Soft-Gelatin Capsule in Patients After Bunionectomy

The clinical utility of diclofenac potassium, a nonsteroidal anti-inflammatory drug, may be lessened by inconsistent gastrointestinal absorption. Diclofenac potassium liquid filled soft-gelatin capsule (DPSGC) is an investigational formulation that uses ProSorb dispersion technology to facilitate rapid and consistent gastrointestinal absorption. In this study, the pharmacokinetic (PK) properties of DPSGC are investigated and compared with a commercially available oral diclofenac potassium tablet in patients after primary unilateral first metatarsal bunionectomy. In an open-label, randomized study, 53 patients received ProSorb-D 12.5 mg (the liquid equivalent of DPSGC), DPSGC 25 mg, DPSGC 50 mg, or immediate-release diclofenac potassium 50-mg tablet administered every 8 hours for a 24-hour inpatient period followed by 7 days of outpatient dosing. Diclofenac steady-state PK was evaluated over an 8-hour sampling period 4 days after surgery. Delayed and/or multiple peaks in the diclofenac plasma concentration-time course profiles occurred more frequently with the commercially available oral diclofenac potassium 50-mg tablet than with the other DPSGC formulations. PK data for ProSorb-D 12.5-mg liquid, DPSGC 25 mg, DPSGC 50 mg, and diclofenac potassium 50-mg tablet revealed mean peak plasma concentrations (Cmax) of 302, 749, 1006, and 902 ng/mL, respectively, whereas area under the plasma concentration curve values were 316, 595, 1029, and 1166 ng-hour/mL, respectively. Mean times to Cmax (tmax) were 0.49, 0.63, 0.95, and 1.26 h, respectively. When compared with absorption characteristics of diclofenac potassium 50-mg tablet, DPSGC was more rapidly and consistently absorbed after bunionectomy. These characteristics should be advantageous when rapid pain relief is desired.