Total Body Clearance Research Articles

Pharmacokinetics and metabolism of brexpiprazole, a novel serotonin-dopamine activity modulator and its main metabolite in rat, monkey and human

The pharmacokinetics of brexpiprazole were investigated in the in vitro and in vivo. The total body clearance of brexpiprazole in rat and monkey was 2.32 and 0.326 L/h/kg, respectively, after intravenous administration, and oral availability was 13.6% and 31.0%, respectively. Dose-dependent exposures were observed at dose ranges between 1–30 mg/kg in the rat and 0.1–3 mg/kg in the monkey. Brexpiprazole distributed widely to body tissues, and Vd,z were 2.81 and 1.82 L/kg in rat and monkey, respectively. The serum protein binding of brexpiprazole was 99% or more in animals and human. Uniform distribution character among the species was suggested by a traditional animal scale-up method. A common main metabolite, DM-3411 was found in animals and humans in the metabolic reactions with the liver S9 fraction. CYP3A4 and CYP2D6 were predominantly involved in the metabolism. The affinity of DM-3411 for D2 receptors was lower than that of brexpiprazole, and neither DM-3411 nor any metabolites with affinity other than M3 were detected in the brain, demonstrating that brexpiprazole is only involved in the pharmacological effects. Overall, brexpiprazole has a simple pharmacokinetic profile with good metabolic stability, linear kinetics, and no remarkable species differences with regard to metabolism and tissue distribution.

Pharmacokinetics, bioavailability, and tissue disposal profiles of Tiamulin fumarate in Nile tilapia (Oreochromis niloticus) following oral and intravenous administrations

Tiamulin fumarate (TIF) is a pleuromutilin antibiotic and has high activity against animal bacterial pathogens including aquatic bacterial pathogens. However, its pharmacokinetic profiles, tissue distribution characteristics and bioavailability in aquatic animals remain unknown. The objective of this study was to investigate the pharmacokinetics and tissue distribution regularities of TIF in tilapia (Oreochromis niloticus) following a single oral (PO) dose of 20mg/kg body weight (bw) and a single intravenous (IV) dose of 5mg/kg bw at 22±1°C, respectively. TIF concentrations in tilapia plasma and tissues were determined using the isotope dilution HPLC-HESI-MS/MS procedure, which was validated according to the guidelines defined by US Food and Drug Administration. TIF was well distributed throughout the body compartments of tilapia judged by the apparent volume of distribution (Vd ) >1L/kg (6.69L/kg PO and 1.78L/kg IV). TIF had a short mean residence time (MRT; 22.82h PO and 14.61h IV) and quick total body clearance (CLb ) (0.62Lkg-1 h-1 PO and 0.60Lkg-1 h-1 IV). The total area under the curve (AUCtot ) of plasma were 32.25μgh-1 ml-1 (PO) and 8.30μgh-1 ml (IV), respectively, and the oral absolute bioavailability (F%) of TIF was calculated to be approximately 97.1%. For tissue distribution, high concentrations of TIF were found in kidney, and the longest MRT was recorded in bile. The withdrawal time (WT) of TIF in muscle, skin, liver, kidney, gill, and bile was 3.75 (4) and 1.79 (2), 1.77 (2) and 2.06 (3), 6.41 (7) and 1.97 (2), 6.95 (7) and 3.98 (4), 4.92 (5) and 2.36 (3), and 7.06 (8) and 6.16 (7) days after PO and IV administration, respectively. The present investigations indicated that TIF was quickly absorbed, well distributed, rapidly eliminated in tilapia, and it could serve as reference data for establishing use regimen and provide useful information for the further development of TIF in aquaculture.

Pharmacokinetics and bioavailability of tildipirosin following intravenous and subcutaneous administration in horses.

This study was designed to investigate the safety and pharmacokinetic (PK) profile of tildipirosin in horses after intravenous (i.v.) and subcutaneous (s.c.) injection of a single dose at 4mg/kg of body weight (b.w.). A total of 12 healthy mixed breed horses were used in the study. Horses were monitored for systemic and local adverse effects, and whole blood samples were collected for hematology and plasma biochemistry analysis at time (0) and at 6, 24, and 72h after drug administration. For PK analysis, blood samples were collected at pre-determined times before and after tildipirosin administration. Plasma concentrations of tildipirosin were determined using ultra-high-performance liquid chromatography-ultraviolet detection method (UHPLC-UV). All horses tolerated the i.v. injection of tildipirosin without showing any systemic adverse effects. However, a non-painful, soft swelling appeared at the s.c. injection site in 5 horses (41.7%). On average, tildipirosin reached a maximum plasma concentration (Cmax ) of 1257ng/ml (geometric mean) between 0.5 and 1.5h after s.c. administration (Tmax ). The geometric mean values for total body clearance (Cl), the apparent volume of distribution based on the terminal phase (Vz ), and the apparent volume of distribution at steady-state (Vss ) were 0.52 L/kg·h, 22 L/kg, and 10.0 L/kg, respectively. Data collected in this study suggests that tildipirosin can be used safely in horses with caution.

Comparative pharmacokinetic profile of cimicoxib in dogs and cats after IV administration

Cimicoxib is a selective COX-2 inhibitor (coxib) registered for the treatment of pain and inflammation in dogs. Pharmacokinetics of some coxibs have been described in dogs and cats. In cats, total body clearance values are lower and terminal half-lives of the coxibs are longer than those in dogs. The aim of this work was to evaluate if this is also the case for cimicoxib. For this purpose, blood pharmacokinetics and urinary excretion after IV administration were compared between these species. The in vitro metabolism of cimicoxib was also evaluated using canine and feline microsomes.In canine and feline microsomes, the formation rate of demethyl-cimicoxib, a phase 1 metabolite, was decreased in presence of quinidine, a specific human cytochrome P450 (CYP)2D6 inhibitor. IC50 values were 1.6 μM and 0.056 μM with canine and feline microsomes, respectively. As quinidine was about 30 times more potent in feline microsomes, the affinity of cimicoxib to the enzyme was considered to be about 30 times lower than that in canine microsomes. Total body clearance (ClB) of cimicoxib, was 0.50 L/h kg in dogs and 0.14 L/h kg in cats (P < 0.01) and terminal half-life, T½λz, was 1.92 and 5.25 h, respectively (P < 0.01). Dose eliminated in urine was 12.2% in dogs and 3.12% in cats (P < 0.01). Conjugated demethyl-cimicoxib represented 93.7% of this amount in dogs and 67.5% in cats. Thus cimicoxib, like other veterinary coxibs, was eliminated more slowly in cats. Both CYP2D15 (the canine ortholog of CYP2D6) and UDP-glucuronyltransferase enzyme systems have reduced ability to produce metabolites of cimicoxib in cats.

Unraveling the Contribution of Fluid Therapy to the Development of Augmented Renal Clearance in a Piglet Model.

Augmented renal clearance (ARC) observed in the critically ill pediatric population has received an increased attention over the last years due to its major impact on the disposition and pharmacokinetics of mainly renally excreted drugs. Apart from an important inflammatory trigger, fluid administration has been suggested to contribute to the development of ARC. Therefore, the primary objective of this study was to evaluate the effect of continuous intravenous fluid administration on renal function using a conventional piglet animal model and to quantify the impact of fluid administration on the pharmacokinetics of renally excreted drugs. At baseline, twenty-four piglets (12 treatment/12 control; 7 weeks old, all ♂) received the marker drugs iohexol (64.7 mg/kg body weight (BW)) and para-aminohippuric acid (10 mg/kg BW) to quantify glomerular filtration rate and effective renal plasma flow, respectively. In addition, the hydrophilic antibiotic amikacin (7.5 mg/kg BW) was administered. Following this baseline measurement, the treatment group received fluid therapy as a constant rate infusion of 0.9% saline at 6 mL/kg/h over 36 h. After 24 h of fluid administration, the marker drugs and amikacin were administered again. When comparing both groups, a significant effect of fluid administration on the total body clearances of iohexol (p = 0.032) and amikacin (p = 0.0014) was observed. Clearances of iohexol and amikacin increased with on average 15 and 14%, although large interindividual variability was observed. This led to decreased systemic exposure to amikacin, which was manifested as decrease in area under the plasma concentration-time curve from time 0 h to infinity from 34,807 to 30,804 ng.h/mL. These results suggest that fluid therapy is a key factor involved in the development of ARC and should be taken into account when administering mainly renally excreted drugs. However, further research is necessary to confirm these results in children.

1318. Pharmacokinetics and Safety of Cefepime-Taniborbactam (formerly Cefepime/VNRX-5133) in Subjects with Renal Impairment

BackgroundTaniborbactam is a novel, non-ß-lactam, ß-lactamase inhibitor with activity against serine (Class A, C, D) and metallo (Class B) ß-lactamases including epidemiologically important carbapenemases. Both cefepime and taniborbactam are predominantly renally excreted and are likely to require dose adjustment in patients with renal impairment and end-stage renal disease (ESRD). The current study was designed to evaluate the pharmacokinetics and safety in patients with renal impairment and ESRD.MethodsThis was a Phase 1, open-label study in subjects with normal renal function (eCLCR ≥ 90 mL/min) matched to subjects with mild, moderate, and severe renal impairment (eGFR 60-89, 30-59, and < 30 mL/min/1.73m2, respectively), and patients with ESRD on hemodialysis. Subjects received a single dose of cefepime 2 g and taniborbactam 500 mg; subjects with ESRD received a single dose before HD and after a 9 day washout period, following HD. PK parameters including AUC0-inf and total body clearance (CL) were evaluated. Safety assessments included adverse events (AEs), vital signs, clinical laboratory evaluations, electrocardiograms, and physical examinations.ResultsThirty-three subjects were enrolled; 67% male, 58% white and 39% black/African Americans. Median age and BMI were 55.0 years and 29.5 kg/m2, respectively. For both cefepime and taniborbactam, exposures increased, and CL decreased with increasing renal impairment (see Table). The hemodialysis extraction ratio was 49.7% and 47.4% for taniborbactam and cefepime respectively. No safety signals were observed and there were no serious adverse events.Table ConclusionCefepime and taniborbactam CL is similarly reduced with varying degrees of renal impairment. Dialysis removes a high fraction of both drugs. Dose adjustments recommended for cefepime are appropriate for taniborbactam.DisclosuresBrooke Geibel, BS, Venatorx Pharmaceuticals (Employee, Shareholder) James A. Dowell, PhD, Venatorx Pharmaceuticals (Independent Contractor) Thomas C. Marbury, MD, Venatorx Pharmaceuticals (Independent Contractor) William Smith, MD, Venatorx Pharmaceuticals (Independent Contractor) Paul C. McGovern, MD, Venatorx Pharmaceuticals (Employee) Cynthia Richards, MD, Venatorx Pharmaceuticals (Independent Contractor) Tim Henkel, MD, PhD, Venatorx Pharmaceuticals (Employee, Shareholder)

1317. Pharmacokinetics (PK) of Ampicillin-Sulbactam (SAM) during Orthotopic Liver Transplantation (OLT)

BackgroundSAM is used as surgical prophylaxis during OLT due to its broad spectrum activity against Gram-positive,-negative and anaerobic pathogens. SAM resistance among Gram-negatives is rising, making dosage selection paramount to preventing surgical site infections. Current guidelines recommend a 3g dose, consisting of 2g ampicillin (AMP) and 1g sulbactam (SUL), every 2h. There are no data; however, describing SAM PK during OLT to support an optimized dosing regimen.MethodsThis was a single-center PK study of OLT patients receiving SAM for surgical prophylaxis at a dose selected by the anesthesiologist. Patients were excluded if they were undergoing simultaneous liver and kidney transplantation and had a CrCL < 30 mL/min at start of surgery. Up to 24 blood samples, along with times of pertinent events, were collected throughout the OLT. AMP and SUL plasma concentrations were determined. Population PK analyses were conducted in Pmetrics using R. Akaike information criterion (AIC) and visual inspection determined best model fit. Individual PK parameters were simulated to describe free AMP time above the MIC90 (fT >MIC90) of 32 mg/L.ResultsFive patients were enrolled. Participants had a mean ± SD age of 64 ± 7 years, body weight 82 ± 8 kg, CrCL of 75 ± 35 mL/min, and received various SAM doses (1.5-3g q2-3h). A 2 compartment model fitted the data better than a 1 compartment model for both AMP (AIC: 396 vs. 423) and SUL (AIC: 334 vs. 347). Final models included fractional clearance (CLf) terms on typical total body clearance (CLθ) to account for the placement of the portal vein clamp. AMP PK parameters (AIC: 372) were: CLθ, 9.7 ± 2.6 L/h; CLf, 0.73 ± 0.49; volume of central compartment (Vc), 7.2 ± 1.4 L; intercompartment constants (k12 and k21), 4.08 ± 3.28 and 2.63 ± 2.9 h-1, respectively. Final SUL PK parameters (AIC: 314) were: CLθ, 8.3 ± 2.5 L/h; CLf, 0.92 ± 0.55; Vc, 7.3 ± 1.6 L; k12, 4.60 ± 4.41 h-1, and k21, 4.07 ± 3.31 h-1. Exposures ranged from 58-96% with only 3g q2h providing nearly 100% fT >MIC90.ConclusionThis is the first study to describe intra-operative SAM PK in OLT recipients and the effect of portal vein clamp on AMP and SUL clearance. These data will help guide optimized SAM dosing regimens for OLT surgery based on local MIC distributions for targeted pathogens.Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials))

Intravenous Infusion of Fentanyl Has No Effect on Blood Concentration of Tacrolimus in Patients Receiving Hematopoietic Stem-Cell Transplantation.

Both tacrolimus (TAC) and fentanyl are frequently used in patients receiving allogeneic hematopoietic stem-cell transplantation. A recently published report demonstrated that fentanyl can reduce the total body clearance of TAC; however, most patients in this study were administered concomitantly with azole antifungal agents, which are known to be strong inhibitors of CYP3A. Hence, the exact effect of fentanyl on TAC pharmacokinetics was unclear. In the current study, the authors retrospectively investigated the pharmacokinetic interaction between TAC and fentanyl in patients who were not concomitantly administered drugs that affect TAC metabolism. Patients with continuous infusion of TAC and fentanyl after hematopoietic stem-cell transplantation at the Tokyo Medical and Dental University between January 2014 and December 2018 were enrolled. The total body clearance of TAC was compared before and after the initiation or discontinuation of fentanyl. Thirty patients (24 men and 6 women; median age, 11 years) were screened for their eligibility. Twenty-eight patients were enrolled for evaluating the effects of the fentanyl initiation on TAC pharmacokinetics; 2 patients were excluded because of the absence of data related to the TAC blood concentrations or the concomitant use of azole antifungals. Twenty patients were enrolled for investigating the effects of fentanyl discontinuation on TAC pharmacokinetics, whereas 10 patients were excluded because of the absence of data related to the blood concentration of TAC or the additional administration of azole antifungals. Furthermore, the total body clearance of TAC was not significantly affected by the initiation or discontinuation of fentanyl, although there were large interindividual variations. In addition, the results remained the same even when the analysis was performed independently for adults and children. Intravenous infusion of fentanyl does not affect the pharmacokinetics of TAC.

Comparative pharmacokinetics of seven bioactive components in normal, sham-operated, and myocardial ischemia-reperfusion injury rats after oral administration of the Salvia Miltiorrhiza-Moutan Cortex herb pair.

Recently the Salvia Miltiorrhiza-Moutan Cortex (SM-MC) herb pair is considered as a promising Chinese medicinal mixture exhibiting a range of pharmacological activities, including treating cardiovascular disease due to its unique composition. In this study, we conducted the comparative pharmacokinetic analysis of seven main bioactive components of SM-MC in a different model rat. A straightforward ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) strategy that could simultaneously evaluate the levels of seven compounds was used to ensure the reliability of these pharmacokinetic analyses in rat plasma. The rat plasma samples were collected from normal, sham-operated, and myocardial ischemia-reperfusion injury (MIRI) groups at predetermined time points after the administration of SM-MC. The main pharmacokinetic parameters were detected and calculated. We successfully assessed the maximum concentration (Cmax ), time to Cmax (Tmax ), the elimination rate constant (λz ), total half-life (t1/2 ), total body clearance (CL), and the area under the concentration-time curve from 0 to last sampling time (AUC0-t ) and extrapolated to infinity (AUC0-∞ ). To sum up, an optimized UPLC-MS/MS approach that could be used to rapidly, simultaneously, and sensitively detect seven bioactive compounds derived from SM-MC extract preparations was successfully developed, which may offer a pharmacokinetic basis for preclinical and clinical studies of SM-MC herb pair for treating MIRI.

Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of danofloxacin in Lohi sheep

Background: Danofloxacin is exclusively used in animals worldwide because of its broad antimicrobial spectrum but not still used in Pakistan. The current study aimed to investigate the pharmacokinetic behavior and pharmacokinetic/pharmacodynamic integration of danofloxacin in order to optimize the dosage regimen in indigenous species of sheep (Lohi) under local environment of Pakistan. Methods and materials: Eight, healthy, adult and non-lactating sheep of Lohi breed with a weight of 35–50 kg were selected. Danofloxacin at a dose of 2.5 mg/kg was injected intravenously to each animal. 2 mL of blood was collected at specific time interval. Plasma was separated by centrifugation. In vitro plasma protein binding was determined at different concentrations of danofloxacin (50, 100, 150, 200, 250 μg/mL) in pooled sheep plasma by ultrafiltration method. Danofloxacin concentration was determined by HPLC technique. Different concentrations of danofloxacin (0.5–8 μg/mL) were used to determine in vitro bacterial killing against bacterial isolate of Mannheimia haemolytica WOO221 during 24 h incubation period. A range of danofloxacin dilutions (0.02–16 μg/mL) were employed to determine the MIC90 value against the tested strain of Mannheimia haemolytica WOO221. The sigmoid Emax equation was used to determine the three antibacterial levels of danofloxacin in Lohi sheep. Results: The average unbound drug was 19.2% in plasma of sheep. The distribution half life was (0.21 ± 0.004 h) and Vdarea of 6.41 ± 0.0.94 L/Kg. Total body clearance was 1.15 ± 0.19 L/h/Kg with elimination half life of 0.54 ± 0.27 L/h. Concentration dependent in vitro activity of danofloxacin was observed. Danofloxacin concentration (8 μg/mL) showed the maximum antibacterial activity by decreasing the bacterial count to 2 CFU/mL after 12 h incubation period. The MIC90 of tested strains was calculated as 0.125 μg/mL. Our in vitro results on the tested strains show that a high AUC24/MIC leads of 88 lead to a complete eradication of bacteria in vitro. Whereas AUC24/MIC of 73 and 39 correspond to a bactericidal and bacteriostatic action on the strain tested in vitro. Conclusion: Based upon a first step of investigation of PK/PD parameters, a dose of 10 mg/kg body weight every 24 h time interval can be used for further investigation of an optimal dosage in Lohi sheep.

Differential Effects of 1α,25-Dihydroxyvitamin D3 on the Expressions and Functions of Hepatic CYP and UGT Enzymes and Its Pharmacokinetic Consequences In Vivo.

The compound 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is the active form of vitamin D3 and a representative ligand of the vitamin D receptor (VDR). Previous studies have described the impacts of 1,25(OH)2D3 on a small number of cytochrome P450 (CYP) and uridine diphosphate-glucuronyltransferase (UGT) enzymes, but comparatively little is known about interactions between several important CYP and UGT isoforms and 1,25(OH)2D3 in vitro and/or in vivo. Thus, we investigated the effects of 1,25(OH)2D3 on the gene and protein expressions and functional activities of selected CYPs and UGTs and their impacts on drug pharmacokinetics in rats. The mRNA/protein expressions of Cyp2b1 and Cyp2c11 were downregulated in rat liver by 1,25(OH)2D3. Consistently, the in vitro metabolic kinetics (Vmax and CLint) of BUP (bupropion; a Cyp2b1 substrate) and TOL (tolbutamide; a Cyp2c11 substrate) were significantly changed by 1,25(OH)2D3 treatment in liver microsomes, but the kinetics of acetaminophen (an Ugt1a6/1a7/1a8 substrate) remained unaffected, consistent with Western blotting data for Ugt1a6. In rat pharmacokinetic studies, the total body clearance (CL) and nonrenal clearance (CLNR) of BUP were significantly reduced by 1,25(OH)2D3, but unexpectedly, the total area under the plasma concentration versus time curve from time zero to infinity (AUC) of hydroxybupropion (HBUP) was increased probably due to a marked reduction in the renal clearance (CLR) of HBUP. Additionally, the AUC, CL, and CLNR for TOL and the AUC for 4-hydroxytolbutamide (HTOL) were unaffected by 1,25(OH)2D3 in vivo. Discrepancies between observed in vitro metabolic activity and in vivo pharmacokinetics of TOL were possibly due to a greater apparent distribution volume at the steady-state (Vss) and lower plasma protein binding in 1,25(OH)2D3-treated rats. Our results suggest possible drug-drug and drug-nutrient interactions and provide additional information concerning safe drug combinations and dosing regimens for patients taking VDR ligand drugs including 1,25(OH)2D3.

In situ self-assembly of near-infrared-emitting gold nanoparticles into body-clearable 1D nanostructures with rapid lysosome escape and fast cellular excretion

The integration of strong near-infrared (NIR) emission, rapid lysosome escape, fast cellular excretion, and efficient total body clearance is highly desired for nanoparticles (NPs) to achieve synergistic functions in both molecular imaging and delivery. Herein, using a well-designed cyclopeptide (CP) that can spontaneously assemble into controllable nanofibers as template, a facile strategy is reported for in situ self-assembly of NIR-emitting gold NPs (AuNPs) into ordered and well-controlled one-dimensional (1D) nanostructures (AuNPs@CP) with greatly enhanced NIR emission (∼ 6 fold). Comparing with the unassembled AuNPs, the AuNPs@CP are observed to enter living cells through endocytosis, escape from lysosome rapidly, and excrete the cell fast, which shows high gene transfection efficiencies in construction of cell line with ∼ 7.5-fold overexpression of p53 protein. Furthermore, the AuNPs@CP exhibit high in vivo diffusibility and total body clearance efficiency with minimized healthy organ retention, which are also demonstrated to be good nanovectors for plasmid complementary deoxyribonucleic acid 3.1 (pcDNA3.1)(+)-internal ribosome entry site (IRES)-green fluorescent protein (GFP)-p53 plasmid with efficient p53 gene over-expression in tumor site. This facile in situ strategy in fabricating highly luminescent 1D nanostructures provides a promising approach toward future translatable multifunctional nanostructures for delivering, tracking, and therapy.

Pharmacokinetic and pharmacodynamic integration for optimal dosage of cefquinome against Streptococcus equi subsp. equi in foals

Cefquinome is administered in horses for the treatment of respiratory infection caused by Streptococcus equi subsp. zooepidemicus, and septicemia caused by Escherichia coli. However, there have been no attempts to use cefquinome against Streptococcus equi subsp. equi (S. equi), the causative agent of strangles. Hence the objective of this study was to calculate an optimal dosage of cefquinome against S. equi based on pharmacokinetics and pharmacodynamics integration. Cefquinome (1.0 mg/kg) was administered by intravenous and intramuscular routes to six healthy thoroughbred foals. Serum cefquinome concentrations were determined by high-performance liquid chromatography. The in vitro and ex vivo antibacterial activity were determined from minimum inhibitory concentrations (MIC) and bacterial killing curves. The optimal dosage was calculated from the integration of pharmacokinetic parameters and area under the curve (AUC24h/MIC) values. Total body clearance and volume of distribution of cefquinome after intravenous administration were 0.06 L/h/kg and 0.09 L/kg, respectively. Following intramuscular administration, a maximum concentration of 0.73 μg/mL at 1.52 h (Tmax) and a systemic bioavailability of 37.45% were observed. The MIC of cefquinome against S. equi was 0.016 μg/mL. The ex vivo AUC24h/MIC values representing bacteriostatic, and bactericidal activity were 113.11, and 143.14 h, respectively. Whereas the %T > MIC for bactericidal activity was 153.34%. In conclusion, based on AUC24h/MIC values and pharmacokinetic parameters, cefquinome when administered by intramuscularly at a dosage of 0.53 mg/kg every 24 h, would be effective against infection caused by S. equi in foals. Further studies may be necessary to confirm its therapeutic efficacy in a clinical environment.

Population pharmacokinetic and exposure-response analyses of d-amphetamine after administration of lisdexamfetamine dimesylate in Japanese pediatric ADHD patients

Lisdexamfetamine dimesylate, a prodrug of d-amphetamine, has been approved for treatment of attention-deficit/hyperactivity disorder (ADHD). The purposes of this study were constructing a population pharmacokinetic model of d-amphetamine after dosing of lisdexamfetamine dimesylate and assessing influential factors on the pharmacokinetics of d-amphetamine in Japanese pediatric patients with ADHD. Additionally, the exposure-response relationship was evaluated for Japanese pediatric patients with ADHD using a clinical rating scale, the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score as a response index. A total of 1365 points of plasma d-amphetamine concentrations from pediatric patients (6–17 years) with ADHD in clinical studies conducted in Japan and the US were employed for the population pharmacokinetic analysis. The plasma concentrations of d-amphetamine in pediatric patients with ADHD were well described by a one-compartment model with first-order absorption and lag time. The effects of body weight and ethnicity (Japanese or non-Japanese) on apparent total body clearance and the effect of body weight on apparent volume of distribution were incorporated into the final model. No clear exposure-dependent reduction was evident from the ADHD RS-IV total score, whereas the reductions were greater for the lisdexamfetamine dimesylate treatment groups compared with the placebo group regardless of exposure to d-amphetamine.

Pharmacokinetic and pharmacodynamic analysis of neutropenia following nab-paclitaxel administration in Japanese patients with metastatic solid cancer.

To develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for neutropenia following nab-paclitaxel administration and identify factors associated with drug disposition and changes in neutrophil counts in patients with solid cancer. PK/PD analysis by nonlinear mixed effects approach was performed using the data from 27 patients who participated in phase I studies of nab-paclitaxel monotherapy conducted in Japan. The patients were treated with either weekly (80, 100, or 125mg/m2) or every 3weeks (200, 260, or 300mg/m2). The observed paclitaxel concentrations in whole blood and neutrophil counts in the first cycle were used for PK/PD analysis. Covariate analysis was performed to identify factors affecting PK and the decrease in neutrophil counts. The developed 3-compartment, non-linear PK model described relationships of body surface area with total body clearance and volume of distribution for the peripheral compartment. Covariate factors affecting neutrophil counts were age and serum albumin level. Simulation based on the developed PK/PD model showed a substantial impact of age and serum albumin level on the time course of neutrophil counts after nab-paclitaxel administration. Advanced age was related to greater decrease in neutrophil counts, and serum albumin level, inversely related to change in neutrophil counts. We have developed a novel PK/PD model for nab-paclitaxel in which age and serum albumin level were considered clinically important covariate factors. This model needs to be further validated using a larger patient population.

Effect of Chronic Kidney Disease on Hepatic Clearance of Drugs in Rats.

The pharmacokinetics of some hepatically cleared drugs have been reported to fluctuate in patients with renal impairment, but the definitive factors have not been clarified. We compared the pharmacokinetics of some drugs with different hepatic elimination processes in a chronic kidney disease (CKD) rat model, to optimize their administration during kidney injury. We chose indocyanine green (ICG), midazolam (MDZ), and acetaminophen (APAP) as reference drugs to determine changes in hepatic clearance pathways in presence of CKD. Drugs were intravenously administered via the jugular vein to the CKD model rats, previously established by adenine administration, and then, blood, bile, and urine samples were collected. The plasma concentration of ICG, which is eliminated into the bile without biotransformation, increased; and its total body clearance (CLtot) significantly decreased in the CKD group compared to the control group. Moreover, the plasma concentrations of MDZ and APAP, metabolized in the liver by CYP3A and Ugt1a6 enzymes, respectively, were higher in the CKD group than in the control group. The biliary clearances of APAP and its derivative APAP-glucuronide increased in the CKD group, whereas their renal clearances were markedly decreased with respect to those in the control group. Altogether, plasma concentrations of some hepatically eliminated drugs increased in the CKD rat model, but depending on their pharmacokinetic characteristics. This study provides useful information for optimizing the administration of some hepatically cleared drugs in CKD patients.

Pharmacokinetics of Cefquinome on Single Intravenous Administration in Marathwadi Buffalo Calves by Microbiological Assay Technique

Experiment was performed on six healthy Marathwadi buffalo calves of either sex of age above 6 months and weighing between 80 to 120 kg to study the different pharmacokinetic parameters after single intravenous administration @ 2 mg/kg body weight by microbiological assay technique. After intravenous administration of the drug, blood samples (4 ml each) of buffalo calves were collected from external jugular vein using disposable needles in clot activator tubes at different time intervals. The schedule of blood collection for pharmacokinetic studies after intravenous administration was at 0, 5, 10, 15, 30 min and 1, 2, 4, 6, 8, 10, 12 and 24 hrs. The serum levels of cefquinome were estimated by microbiological assay technique using large glass plate. Different Pharmacokinetic parameters were calculated as described by different scientists. The peak serum concentration, elimination half life, volume of distribution, total body clearance, absorption half life and area under curve values found were 1.74 ± 0.151 mcg/ml at 2.5 min of sampling time, 1.97±0.14 h, 3.97 ± 0.83 L/kg (Vd(B)) and 2.86 ± 0.34L/kg (Vdss), 1.11 ± 0.13 L/kg.h−1, 0.10 ± 0.02 h, and 1.93 ± 0.23 μg/ml/hr respectively. The bioavailability of cefquinome in buffalo calves was found to be 100 %. It may be concluded that the elimination half life of cefquinome was 2.54 h in Marathwadi buffalo calves indicating the repeating of doses at 12 to 15 h intervals in Marathwadi buffalo calves and the loading dose would be double than the maintenance dose of cefquinome after intravenous administration.

Pharmacokinetics of Ceftiofur Sodium in Black-bone Silky Fowl after One Single Intravenous and Intramuscular Injection

Background: Ceftiofur is a third-generation cephalosporin antibiotic developed exclusively for veterinary applications. Although not approved in China, ceftiofur is being used extensively in an extra-label manner to treat poultry infections. Black-bone silky fowl is a unique chicken breed which is different from the common chicken breeds in both morphology and other physiology. These differences may result in varied pharmacokinetic profiles. Therefore, the present study aimed to investigate the pharmacokinetics of ceftiofur (measured by ceftiofur and its active metabolites concentrations) in black-bone silky fowl following a single intravenous or intramuscular injection of ceftiofur sodium.Methods: Ceftiofur sodium was intravenously and intramuscularly given to six healthy black-bone silky fowl at the dose of 10 mg/kg body weight. A derivatization method was used to quantify the concentrations of ceftiofur and its active metabolites (expressed as desfuroylceftiofur acetamide) in plasma samples. A non-compartmental method was used to calculate the pharmacokinetics parameters. Results: The terminal half-life (t1/2lz) was calculated as 3.19±0.28 and 3.36±0.17 h following intravenous and intramuscular injections, respectively. After intravenous treatment, the total body clearance (Cl) and volume of distribution at steady state (VSS) were determined as 73.79±5.83 ml/h/kg and 318.65±30.06 ml/kg, respectively. After intramuscular injection, the peak concentration (Cmax; 22.55±0.89 ìg/ml) was observed at 1.67±0.26 h and the absorption half-life (t1/2ka) and absolute bioavailability (F) were calculated as 0.40±0.13 h and 93.03%±7.07%, respectively. The current results demonstrated the rapid and complete absorption, however, poor distribution and rapid elimination of ceftiofur and its active metabolites in black-bone silky fowl.

Pharmacokinetics of thiamphenicol in Japanese quails (Coturnix japonica) after single intravenous and oral administrations.

Thiamphenicol (TP) pharmacokinetics were studied in Japanese quails (Coturnix japonica) following a single intravenous (IV) and oral (PO) administration at 30mg/kg BW. Concentrations of TP were determined with HPLC and were analyzed by a noncompartmental method. After IV injection, elimination half-life (t1/2λz ), total body clearance (Cltot ) volume of distribution at steady state (Vdss ), and mean residence time (MRT) of TP were 3.83hr, 0.19L/hr/kg, 0.84L/kg, and 4.37hr, respectively. After oral administration of TP, the peak plasma concentration (Cmax ) was 19.81μg/ml and was obtained at 2.00hr (tmax ) postadministration. Elimination half-life (t1/2λz ) and mean absorption time (MAT) were 4.01hr and 1.56hr, respectively. The systemic bioavailability following oral administration of TP was 78.10%. TP therapy with an oral dosage of 30mg/kg BW is suggested for a beneficial clinical effect in quails.

Pharmacokinetics and bioavailability of tildipirosin following intravenous and subcutaneous administration in sheep.

Tildipirosin is a semi-synthetic macrolide antibiotic commonly used in cattle and swine to treat bacterial pneumonia. The objective of this study was to investigate the pharmacokinetic profile of tildipirosin after a single intravenous (i.v.) and subcutaneous (s.c.) administration in healthy lambs. Eighteen lambs were randomly divided into three groups (n=6 each). Lambs received a single s.c. dose of tildipirosin at 4 and 6mg/kg b.w. in group 1 and 2, respectively. Lambs in group 3 received a single i.v. dose of tildipirosin at 4mg/kg b.w. Blood samples were collected at 0, 0.5, 0.75, 1.5, 2, 3, 4, 6, 8, 10, 24, 36, 48hr, and every 24hr to day 21, and thereafter at day 28 posttildipirosin administration. The plasma concentrations of tildipirosin were determined using high-performance liquid chromatography with tandem mass spectrometry detection (LC⁄MS⁄MS). All lambs appeared to tolerate both the intravenous and subcutaneous injection of tildipirosin. Following i.v. administration, the elimination half-life (T1/2 ), mean residence time (MRT), volume of distribution (Vd/F), and total body clearance (Cl/F) were 119.6±9.0hr, 281.9±25.7hr, 521.1±107.2 L, and 2.9±0.5L/hr, respectively. No significant differences in Cmax (657.0±142.8 and 754.6±227.1ng/ml), Tmax (1.21±0.38 and 1.35±0.44hr), T1/2 (144±17.5, 156.5±33.4hr), and MRT (262.0±30.2 and 250.6±54.5hr) were found in tildipirosin after s.c. dosing at 4 and 6mg/kg b.w., respectively. The absolute bioavailability (F) of tildipirosin was 71.5% and 75.3% after s.c. administration of 4 and 6mg/kg b.w., respectively. In conclusion, tildipirosin was rapidly absorbed and slowly eliminated after a single s.c. administration in healthy lambs. Tildipirosin could be used for the treatment and prevention of respiratory bacterial infections in sheep. However, further in vitro and in vivo studies to determine the efficacy and safety are warranted. To our knowledge, this is the first study to determine the tildipirosin pharmacokinetic parameters in sheep plasma.