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Rivaroxaban has been investigated in the EINSTEIN‐Jr program for the treatment of acute venous thromboembolism (VTE) in children aged 0 to 18 years and in the UNIVERSE program for thromboprophylaxis in children aged 2 to 8 years with congenital heart disease after Fontan‐procedure. Physiologically‐based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) modeling were used throughout the pediatric development of rivaroxaban according to the learn‐and‐confirm paradigm. The development strategy was to match pediatric drug exposures to adult exposure proven to be safe and efficacious. In this analysis, a refined pediatric PopPK model for rivaroxaban based on integrated EINSTEIN‐Jr data and interim PK data from part A of the UNIVERSE phase III study was developed and the influence of potential covariates and intrinsic factors on rivaroxaban exposure was assessed. The model adequately described the observed pediatric PK data. PK parameters and exposure metrics estimated by the PopPK model were compared to the predictions from a previously published pediatric PBPK model for rivaroxaban. Ninety‐one percent of the individual post hoc clearance estimates were found within the 5th to 95th percentile of the PBPK model predictions. In patients below 2 years of age, however, clearance was underpredicted by the PBPK model. The iterative and integrative use of PBPK and PopPK modeling and simulation played a major role in the establishment of the bodyweight‐adjusted rivaroxaban dosing regimen that was ultimately confirmed to be a safe and efficacious dosing regimen for children aged 0 to 18 years with acute VTE in the EINSTEIN‐Jr phase III study.

A population pharmacokinetic model was developed using data from healthy subjects and patients with moderate‐to‐severe asthma receiving intravenous or subcutaneous dupilumab doses. A total of nine phase I to phase III studies were pooled (202 healthy subjects and 1912 patients with asthma including 68 adolescents) in the model development. The best model was a two‐compartment model with parallel linear and nonlinear Michaelis–Menten elimination with first order absorption. The PK parameter estimates were distribution volume of central compartment 2.76 L, linear elimination rate 0.0418 1/day, and subcutaneous bioavailability 60.9%. Pharmacokinetics (PK) properties of dupilumab in patients with asthma were determined to be comparable to those of healthy subjects and patients with atopic dermatitis. Only body weight exerts a notable effect explaining between‐subject variability in dupilumab PK, but dose adjustment for weight is not warranted based on results from clinical studies. There is no PK difference between adolescent and adult patients with asthma after correction for body weight.

Aims RO5459072, a cathepsin‐S inhibitor, Biopharmaceutics Classification System class 2 and P‐glycoprotein substrate, exhibited complex, nonlinear pharmacokinetics (PK) while fasted that seemed to impact both the absorption and the disposition phases. When given with food, all nonlinearities disappeared. Physiologically based PK (PBPK) modelling attributed those nonlinearities to dose‐dependent solubilisation and colonic absorption. The objective of this population PK analysis was to complement the PBPK analysis. Methods PK profiles in 39 healthy volunteers after first oral dosing (1–600 mg) while fasted or fed in single and multiple ascending dose studies were analysed using population compartmental modelling. Results The PK of RO5459072 while fed was characterized by a 1‐compartmental PK model with linear absorption and elimination. The nonlinearities while fasted were captured using dose dependent bioavailability and 2 sequential first‐order absorption phases: one following drug administration and one occurring 11 hours later and only for doses >10 mg. The bioavailability in the first absorption phase increased between 1 and 10 mg and then decreased with dose, in agreement with in vitro dissolution and solubility studies. The remaining fraction of doses to be absorbed by the second absorption phase was found to have a bioavailability similar to that in the first absorption phase. Conclusion The population PK model supported that dissolution‐ and solubility‐limited absorption from the proximal and distal intestine alone explains the nonlinear PK of RO5459072 in fasted state and the linear PK in fed state. This work, together with the PBPK analysis, raised our confidence in the understanding of this complex PK.

The aim of this study was to investigate the pharmacokinetic properties of mosapride after intravenous and oral administration to beagle dogs. To obtain the advanced pharmacokinetic parameters of mosapride, both noncompartmental analysis and pharmacokinetic modeling were performed. Twenty beagle dogs were randomly sorted into intravenous (1 mg single administration of mosapride) and oral (5 mg once a day administration of mosapride) groups. Blood samples were collected according to the reported schedule for pharmacokinetics. The plasma concentration of mosapride was analyzed using liquid chromatography-tandem mass spectrometry. According to the pharmacokinetic analysis, the absorption rate of mosapride was 3.14 ± 1.14 hr-1 and oral bioavailability of mosapride was approximately 1%. The one-compartment model well described the pharmacokinetics of mosapride after both intravenous and oral administration to dogs. These findings will help facilitate the determination of the optimal dose regimen of mosapride for dogs with gastrointestinal disorder.

BACKGROUND The shutter-speed model dynamic contrast-enhanced (SSM-DCE) MRI pharmacokinetic analysis adds a metabolic dimension to DCE-MRI. This is of particular interest in cancers, since abnormal metabolic activity might happen. PURPOSE To develop a DCE-MRI SSM analysis framework for glioblastoma multiforme (GBM) cases considering the heterogeneous tissue found in GBM. STUDY TYPE Prospective. SUBJECTS Ten GBM patients. FIELD STRENGTH/SEQUENCE 3T MRI with DCE-MRI. ASSESSMENTS The corrected Akaike information criterion (AICc ) was used to automatically separate DCE-MRI data into proper SSM versions based on the contrast agent (CA) extravasation in each pixel. The supra-intensive parameters, including the vascular water efflux rate constant (kbo ), the cellular efflux rate constant (kio ), and the CA vascular efflux rate constant (kpe ), together with intravascular and extravascular-extracellular water mole fractions (pb and po , respectively) were determined. Further error analyses were also performed to eliminate unreliable estimations on kio and kbo . STATISTICAL TESTS Student's t-test. RESULTS For tumor pixels of all subjects, 88% show lower AICc with SSM than with the Tofts model. Compared to normal-appearing white matter (NAWM), tumor tissue showed significantly larger pb (0.045 vs. 0.011, P

Paracetamol is a widely used, non-opioid analgesic and antipyretic drug. Scientific evidence suggests that it is an effective pain treatment in equine medicine. However, there is very little published information about the pharmacokinetics of the drug in the horse. The aim of the research was to determine the pharmacokinetics of paracetamol in equine plasma and urine to inform treatment of Thoroughbred racehorses. In this multi-dose study, paracetamol was administered orally at 20 mg/kg to six Thoroughbred horses. Pre- and post-administration urine and plasma samples were collected and analysed using a quantitative liquid chromatography–tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic analysis of urine and plasma paracetamol clearance profiles was carried out, which enabled the calculation of possible screening limits (SL) that can regulate for a detection time of 120 h. Additionally, an estimation of orthocetamol concentration levels in urine was carried out to investigate any underlying relationship between the para- and ortho-isomers as both were suspected to contribute to basal levels, possibly due to environmental feed sources. Open Research

Magnetic resonance imaging of hyperpolarized pyruvate provides a new imaging biomarker for cancer metabolism, based on the dynamic in vivo conversion of hyperpolarized pyruvate to lactate. Methods for quantification of signal evolution need to be robust and reproducible across a range of experimental conditions. Pharmacokinetic analysis of dynamic spectroscopic imaging data from hyperpolarized pyruvate and its metabolites generally assumes that signal arises from ideal rectangular slice excitation profiles. In this study, we examined whether this assumption could lead to bias in kinetic analysis of hyperpolarized pyruvate and if so, whether such a bias can be corrected. A Bloch-McConnell simulator was used to generate synthetic data using a known set of “ground truth” pharmacokinetic parameter values. Signal evolution was then analyzed using analysis software that either assumed a uniform slice profile, or incorporated information about the slice profile into the analysis. To correct for slice profile effects, the expected slice profile was subdivided into multiple sub-slices in order to account for variable excitation angles along the slice dimension. An ensemble of sub-slices was then used to fit the measured signal evolution. A mismatch between slice profiles used for data acquisition and those assumed during kinetic analysis was identified as a source of quantification bias. Results indicate that imperfect slice profiles preferentially increase detected lactate signal, leading to an overestimation of the apparent metabolic exchange rate. The slice profile correction algorithm was tested in simulation, in phantom measurements, and applied to data acquired from a patient with prostate cancer. The results demonstrated that slice profile induced biases can be minimized by accounting for the slice profile during pharmacokinetic analysis. This algorithm can be used to correct data from either single or multi-slice acquisitions.

This prospective observational study analyzed the pharmacokinetics of busulfan in Japanese children and evaluated the predicting accuracy of previous pediatric PPK models of busulfan. This study enrolled five patients (aged 2-12 years, BW 14-48 kg) receiving a busulfan-based conditioning regimen for hematopoietic stem cell transplantation at our hospital between January 2017 and December 2018. All patients received a 2-hour intravenous busulfan infusion four times daily for a total of 16 doses. After the infusions, 51 plasma samples were collected with the plasma busulfan concentration measured by liquid chromatography-tandem mass spectrometry. PPK model fitting was analyzed using the (%MPE) and the (%MAPE). Limited sampling strategies for estimating busulfan AUC were also evaluated. High interpatient variability was observed in the PK parameters. The most suitable PPK model that reflected our data was McCune's two-compartment model (%MPE -8.7, %MAPE 19.3). A combination sampling method using the busulfan concentration at 2 and 6 hours after the start of the first busulfan dose was found to be able to estimate AUC4 day . These results provide useful information on busulfan therapeutic drug monitoring in the Japanese pediatric population.

The pharmacokinetic properties of vitacoxib have not been established completely; current dosage recommendations are based on clinical experiences. The primary objective of this study was to describe plasma concentrations and characterize the pharmacokinetics of vitacoxib formulation following oral administrations in horses. Also, the effect of the state of stomach contents on the absorption of vitacoxib was investigated in fed/fasted horses. Blood samples were collected prior to and at various times up to 72 hr post-administration. Drug concentrations were measured using ultra high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using Non-Compartmental Analysis Model 200 in WinNonlin™ software. No complications resulting from the vitacoxib administration were noted. All procedures were tolerated well by the horses throughout the study. Cmax was 17.5 ± 9.36 ng/ml (fasted) and 9.47 ± 3.53 ng/ml (fed) following oral administrations. AUClast was 173.7 ± 137.9 ng hr/ml (fasted) and 113.2 ± 70.8 ng h/ml (fed). No significant differences in pharmacokinetic parameters were noted and the results from the pharmacokinetic analysis were similar between the studies, regardless of precision of dosage and fasted and fed conditions. The study extends previous studies describing the pharmacokinetics of vitacoxib following p.o. administration to the horses. Further studies investigating the pharmacokinetics/pharmacodynamics of vitacoxib are necessary to establish adequate therapeutic protocols (optimal dosage and frequency of administration) in horses.

In llama crias (tekes), Escherichia coli and Staphylococcus aureus are major pathogens, and marbofloxacin could be a suitable choice. The objectives of this study were (a) to evaluate the serum pharmacokinetics of marbofloxacin (5 mg/kg) after intravenous administration in tekes and simulate a multidose regimen; (b) to emulate pharmacokinetic profiles after single dose and steady-state conditions by Monte Carlo simulation (c) to determine the MIC of regional strains of Escherichia coli and Staphylococcus aureus; (d) to perform a PK/PD analysis by Monte Carlo simulation. Pharmacokinetics of marbofloxacin was evaluated in six animals at 3, 10, 24, 50, and 80 days after birth. Marbofloxacin were determined by HPLC. A steady-state multi-dose simulation was carried out, and concentration-time profiles were generated by Monte Carlo simulation. MIC of marbofloxacin against regional E. coli and S. aureus strains were also determined. Finally, a PK/PD analysis was conducted by Monte Carlo simulation. After pharmacokinetic analysis, clearance showed a trend to increase (0.14 and 0.18 L kg-1 hr-1 ), and AUC (36.74 and 15.21 μg hr-1 ml-1 ) and Vss (3.06 and 3.37 L/kg) trended to decrease at 3 and 80 days-old, respectively, showing accumulation ~50% in animals with 3 days. All strains tested of E. coli (MIC90 = 0.06 μg/ml) and S. aureus (MIC90 = 0.25 μg/ml) were susceptible to marbofloxacin. PK/PD analysis suggests that the therapeutic regimen of marbofloxacin could be effective for infections caused by E. coli strains in animals between 3 and 80 days, with a CFR for Cmax /MIC > 10 of 100% and for AUC24 /MIC > 125 of 99.99%; and for infections produced by S. aureus in animals between 3 and 24 days old, with a CFR for Cmax /MIC > 10 of 93.08% and for AUC24 /MIC > 60 of 97.01%, but a higher dose should be used in older animals, because PK/PD endpoints were not met.

Massive metformin overdose can cause metabolic acidosis with hyperlactatemia. A 55-year-old female presented 5h post multi-drug overdose, including 132 g extended-release metformin. Continuous venovenous haemodiafiltration (CVVHDF) and noradrenaline were commenced due to metabolic acidosis (pH 7.0, lactate 17 mmol/L) and shock. Despite 3 hours of CVVHDF, her acidosis worsened (pH 6.83, lactate 24 mmol/L). Intermittent haemodialysis(IHD) improved acidosis (pH 7.13, lactate 26 mmol/l), but again worsened (pH 6.91, lactate 30 mmol/L) with CVVHDF recommencement. IHD (12 h), CVVHDF (26 h) and vasopressor support for 7 days resulted in survival. Measured metformin concentrations were extremely high with a peak of 292 μg/ml at 8 h post-ingestion. IHD, but not CVVHDF in this case was associated with improvement in metabolic acidosis and hyperlactatemia. Pharmacokinetic analysis of metformin concentrations found a reduced apparent oral clearance (CL/F) of 8.2 L/h and a half-life of approximately 30 h. During IHD, the CL/F increased to 22.2 L/h with an approximate half-life of 10 h. The impact of prolonged oral absorption from a pharmacobezoar and re-distribution of metformin from peripheral sites (including erythrocytes) on the pharmacokinetic profile cannot be determined from the data available.

The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population-specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI). Rivaroxaban PK were adequately described by a one-compartment disposition model with a first-order absorption rate constant. Significant effects of CrCL, use of comedications, and study population on CL/F, age, weight, and gender on V/F, and dose on F were identified. CrCL had a modest influence on exposure, whereas age and BMI had a minor influence. The model was suitable to predict rivaroxaban exposure in patient subgroups of special interest.

This study describes the pharmacokinetics of intravenously administered (i.v.) fentanyl citrate, and its primary metabolite norfentanyl in Holstein calves. Eight calves (58.6 ± 2.2 kg), aged 3-4 weeks, were administered fentanyl citrate at a single dose of 5.0 μg/kg i.v. Blood samples were collected from 0 to 24 hr. Plasma (nor)fentanyl concentrations were determined using liquid chromatography with mass spectrometry and a lower limit of quantification (LLOQ) of 0.03 ng/ml. To explore the effect of analytical performance on fentanyl parameter estimation, the noncompartmental pharmacokinetic analysis was then repeated with a hypothetical LLOQ value of 0.05 ng/ml. Terminal elimination half-life was estimated at 12.7 and 3.6 hr for fentanyl and norfentanyl, respectively. For fentanyl, systemic clearance was estimated at 2.0 L hr-1 kg-1 , volume of distribution at steady-state was 24.8 L/kg and extraction ratio was 0.42. At a hypothetical LLOQ of 0.05 ng/ml fentanyl half-life, volume of distribution at steady-state and clearance were, respectively, of 3.0 hr, 8.8 L/kg and 3.4 L kg-1 hr-1 . Fentanyl citrate administered i.v. at 5.0 μg/kg can reach levels associated with analgesia in other species. Pharmacokinetic parameters should be interpreted with respect to LLOQ, as lower limits can influence estimated parameters, such as elimination half-life or systemic clearance and have significant impact on dosage regimen selection in clinical practice.

Aims Intravenous tocilizumab is currently dosed on body weight, although a weak correlation between body weight and clearance has been described. The aim of the study was to assess the current dosing strategy and provide a scientific rational for dosing using a modelling and simulation approach. Methods Serum concentrations and covariates were obtained from intravenous tocilizumab treated subjects at a dose of 4, 6 or 8 mg every 28 days. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling. The final model was used to simulate tocilizumab exposure to assess a dosing strategy based on body weight or fixed dosing, using as target a cumulative area under the curve at 24 weeks of treatment above 100 × 103 μg h ml-1 . Results A one-compartment disposition model with parallel linear and nonlinear elimination best described the concentration-time data. The typical population mean values for clearance, apparent volume of distribution, maximum elimination rate and Michaelis-Menten constant were 0.0104 l h-1 , 4.83 l, 0.239 mg h-1 and 4.22 μg ml-1 , respectively. Interindividual variability was included for clearance (17.0%) and volume of distribution (30.8%). Significant covariates for clearance were patient body weight and C-reactive protein serum levels. An estimated exponent for body weight of 0.360 confirms the weak relationship with tocilizumab clearance. Simulations demonstrate that patients with lower weights are at risk of underdosing if the weight-based dosing approach is used. However, fixed-dosing provides a more consistent drug exposure regardless of weight category. Conclusions Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight-based dosing approach.

PURPOSE To explore the effects of noise and error on kinetic analyses of tumor metabolism using hyperpolarized [1-13 C] pyruvate. METHODS Numerical simulations were performed to systematically investigate the effects of noise, the number of unknowns, and error in kinetic parameter estimates on kinetic analysis of the apparent rate of chemical conversion from hyperpolarized pyruvate to lactate (kPL ). A pharmacokinetic model with two physical and two chemical pools of hyperpolarized spins was used to generate and analyze the synthetic data. RESULTS The reproducibility of kPL estimates worsened quickly when peak signal-to-noise ratio for hyperpolarized pyruvate was below approximately 20. The accuracy of kPL estimates was most sensitive to errors in high excitation angles, the vascular blood volume fraction (vb ), and the rate of pyruvate extravasation (kve ), and was least sensitive to errors in the T1 of pyruvate. When vb and/or kve were fit as additional unknowns, the accuracy of kPL estimates suffered, and when the vascular input function of pyruvate was also fit, the reproducibility of kPL estimates worsened. CONCLUSIONS The accuracy and precision of kPL estimates improve substantially for peak signal-to-noise ratio above approximately 20. Accurate estimates of perfusion parameters (combinations of vb , kve , and the pyruvate vascular input function) and transmit calibration at high excitation angles have the greatest effect on the accuracy of kinetic analyses. Magn Reson Med 79:3239-3248, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The nonsteroidal anti-inflammatory drug (NSAID) diclofenac is highly toxic to Gyps vultures, and its recent widespread use in South Asia caused catastrophic declines in at least 3 scavenging raptors. The manufacture of veterinary formulations of diclofenac has since been banned across the region with mixed success. However, at least 12 other NSAIDs are available for veterinary use in South Asia. Aceclofenac is one of these compounds, and it is known to metabolize into diclofenac in some mammal species. The metabolic pathway of aceclofenac in cattle, the primary food of vultures in South Asia, is unknown. We gave 6 cattle the recommended dose of aceclofenac (2 mg/kg), collected blood thereafter at intervals for up to 12 h, and used liquid chromatography with mass spectrometry in a pharmacokinetic analysis of aceclofenac and diclofenac in the plasma. Nearly all the aceclofenac administered to the cattle was very rapidly metabolized into diclofenac. At 2 h, half the aceclofenac had been converted into diclofenac, and at 12 h four-fifths of the aceclofenac had been converted into diclofenac. Therefore, administering aceclofenac to livestock poses the same risk to vultures as administering diclofenac to livestock. This, coupled with the risk that aceclofenac may replace diclofenac in the veterinary market, points to the need for an immediate ban on all aceclofenac formulations that can be used to treat livestock. Without such a ban, the recovery of vultures across South Asia will not be successful.

Aims One barrier contributing to the lack of pharmacokinetic (PK) data in paediatric populations is the need for serial sampling. Analysis of clinically obtained specimens and data may overcome this barrier. To add evidence for the feasibility of this approach, we sought to determine PK parameters for fentanyl in children after cardiac surgery using specimens and data generated in the course of clinical care, without collecting additional blood samples. Methods We measured fentanyl concentrations in plasma from leftover clinically-obtained specimens in 130 paediatric cardiac surgery patients and successfully generated a PK dataset using drug dosing data extracted from electronic medical records. Using a population PK approach, we estimated PK parameters for this population, assessed model goodness-of-fit and internal model validation, and performed subset data analyses. Through simulation studies, we compared predicted fentanyl concentrations using model-driven weight-adjusted per kg vs. fixed per kg fentanyl dosing. Results Fentanyl clearance for a 6.4 kg child, the median weight in our cohort, is 5.7 l h–1 (2.2–9.2 l h–1), similar to values found in prior formal PK studies. Model assessment and subset analyses indicated the model adequately fit the data. Of the covariates studied, only weight significantly impacted fentanyl kinetics, but substantial inter-individual variability remained. In simulation studies, model-driven weight-adjusted per kg fentanyl dosing led to more consistent therapeutic fentanyl concentrations than fixed per kg dosing. Conclusions We show here that population PK modelling using sparse remnant samples and electronic medical records data provides a powerful tool for assessment of drug kinetics and generation of individualized dosing regimens.

Aims Sifalimumab, a human immunoglobulin (Ig) G1 monoclonal antibody against INF-alpha, is being studied as a treatment for systemic lupus erythematosus (SLE). This analysis characterized population pharmacokinetics (PK) of sifalimumab following repeat fixed dose and evaluated the utility of fixed dosing vs. body weight normalized dosing in SLE patients. Methods PK data were collected in a phase IIb study where 298 patients received multiple intravenous doses (200–1200 mg) of sifalimumab every 4 weeks for 52 weeks. A population pharmacokinetic model was developed using 3961 quantifiable serum concentrations and the impact of patient demographics, clinical indices and biomarkers on pharmacokinetic parameters was evaluated. The appropriateness of the final model was evaluated using visual predictive check and bootstrap. Results A two compartment model with first order elimination adequately described sifalimumab serum PK. The estimated typical clearance (CL) and central volume of distribution (V1) were 184 ml day–1 and 2.82 l with 24% and 16% between-subject variability (BSV), respectively. Body weight, dose, 21 INF gene signature baseline and concomitant steroid use were identified as statistically significant covariates for CL and V1 and accounted for

$PROBLEM MLN9708 ORAL AND IV BASE MODEL /additive error model ;------------------------- ; UNITS ; Time – h ; Dose – mg ; Cp – ng ml−1 = μg l−1 ; Clearances – l h−1 ; Volumes – l ;------------------------- ;C 3 compartment model with administration into either oral or the central compartment $DATA NM_061813_race.csv IGNORE=@ BLANKOK $INPUT COMMENT SID = DROP ID STDY SUB AMT NAMT TIME UN DV MDV CMT RTE RACE AGE HT BWT BSAC SEX SRCR CRCL ALT AST ALBUMIN BILIRUBIN DOSECAT = DROP $SUBROUTINES ADVAN12;TRANS4 $PK V0 =(BSAC/1.90)**THETA(9) IF (V0.LE.0) V0 = 0.1 CL = THETA(1)*EXP(ETA(1)) ; CL clearance V2 = THETA(2)*EXP(ETA(2)) ; V2 central volume Q3 = THETA(3)*EXP(ETA(3)) ; Q3 intercompartmental clearance (central and periph 1) V3 = THETA(4)*EXP(ETA(4)) ; V3 peripheral 1 volume Q4 = THETA(5)*EXP(ETA(5)) ; Q4 intercompartmental clearance (central and periph 2) V4 = (THETA(6)*V0)*EXP(ETA(6)); V4 peripheral 2 volume KA = THETA(7)*EXP(ETA(7)) ; KA absorption rate constant F1 = THETA(8)*EXP(ETA(8)) ; F1 Bioavailability S2 = V2/1000 ; Relationship: K = CL/V2 K23 = Q3/V2 K32 = Q3/V3 K24 = Q4/V2 K42 = Q4/V4 $ERROR IPRED = 0 IF(F.GT.0) IPRED = LOG(F) Y = IPRED+ERR(1) $THETA (0.01 3) ; Theta (1) is CL clearance (0.01 110) ; Theta (2) is V2 central volume (0.01 13) ; Theta (3) is Q3 intercompartmental clearance (central and periph 1) (0.01 590) ; Theta (4) is V3 peripheral 1 volume (0.01 22) ; Theta (5) is Q4 intercompartmental clearance (central and periph 2) (0.01 135) ; Theta (6) is V4 peripheral 2 volume (0.01 1) ; Theta (7) is KA absorption rate constant (0.01 0.5 1) ; Theta (8) is F1 Bioavailability (0.01,1) ; THETA(9) $OMEGA 0.34 ;FIXED ; ETA(1) applies to CL clearance 0.62 ;FIXED ; ETA(2) applies to V2 central volume 0 FIXED ; ETA(3) applies to Q3 intercompartmental clearance (central and periph 1) 0 FIXED ; ETA(4) applies to V3 peripheral 1 volume 0 FIXED ; ETA(5) applies to Q4 intercompartmental clearance (central and periph 2) 0.64 ;FIXED ; ETA(6) applies to V4 peripheral 2 volume 0.4 ;FIXED ; ETA(7) applies to KA absorption rate constant 0.16 ;FIXED ; ETA(8) applies to F1 bioavailability $SIGMA 0.61 ; EPS(1) $ESTIMATION METHOD = 1 PRINT = 5 MAX = 9999 NOABORT NSIG = 3 SIGL = 8 POSTHOC INTER MSFO = msfo.outputfile $COVA $TABLE ID STDY SUB AMT NAMT TIME UN MDV RTE RACE SEX AGE BWT BSAC SRCR CRCL ALT AST ALBUMIN BILIRUBIN CWRES IPRED KA CL V2 V3 Q3 Q4 V4 F1 ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7 ETA8 NOPRINT FILE =./BSA_V4.tab

Aims The standard dose of ceftaroline fosamil for patients with normal renal function is 600 mg diluted in 250 ml by 60 min intravenous infusion every 12 h. This two part phase I trial (NCT01577589) assessed safety and local tolerability of multiple ceftaroline fosamil 50 ml and 250 ml infusions, and pharmacokinetics following single administrations of each infusion volume. Methods Part A was a placebo-controlled, double-blind, multiple dose crossover study. Twenty-four healthy subjects were randomized to simultaneous, bilateral ceftaroline fosamil 600 mg and placebo infusions in each arm (50 ml then 250 ml or vice versa) every 12 h for 72 h, with a ≥ 4.5 day washout. Local tolerability was evaluated by the Visual Infusion Phlebitis scale, with scores ≥2 considered infusion site reactions (ISRs). Part B was an open label crossover study. Ten subjects were randomized to single 50 ml and 250 ml ceftaroline fosamil 600 mg infusions on days 1 and 3 (washout on day 2). Blood samples for pharmacokinetic analysis were taken over 24 h. Results In part A, four subjects (16.7%) experienced ISRs, all of which were associated with placebo infusions. No ISRs were reported for either ceftaroline fosamil 50 ml or 250 ml. Plasma pharmacokinetics (ceftaroline fosamil, active ceftaroline and an inactive metabolite) were similar following single 50 ml and 250 ml infusions in part B. Conclusions No new safety concerns were identified for ceftaroline fosamil 600 mg 50 ml compared with 250 ml. These findings suggest infusion volumes down to 50 ml may be used in patients with fluid intake restrictions.

The purpose of this study was to compare the pharmacokinetics of meloxicam in mature swine after intravenous (i.v.) and oral (p.o.) administration. Six mature sows (mean bodyweight ± standard deviation = 217.3 ± 65.68 kg) were administered an i.v. or p.o. dose of meloxicam at a target dose of 0.5 mg/kg in a cross-over design. Plasma samples collected up to 48 h postadministration were analyzed by high-pressure liquid chromatography and mass spectrometry (HPLC-MS) followed by noncompartmental pharmacokinetic analysis. Mean peak plasma concentration (CMAX ) after p.o. administration was 1070 ng/mL (645-1749 ng/mL). TMAX was recorded at 2.40 h (0.50-12.00 h) after p.o. administration. Half-life (T½ λz ) for i.v. and p.o. administration was 6.15 h (4.39-7.79 h) and 6.83 h (5.18-9.63 h), respectively. The bioavailability (F) for p.o. administration was 87% (39-351%). The results of this study suggest that meloxicam is well absorbed after oral administration.

Pharmacokinetic studies in the neonatal population are often limited by the small volume of blood that can be collected. The high sensitivity of (14) C-accelerator mass spectrometry (AMS) enables pharmacokinetic studies to be conducted with greatly reduced sample volumes. We demonstrated the utility of AMS in infants by studying the plasma pharmacokinetic behavior of nanogram doses of (14) C-ursodiol administered as a non-perturbing microdose or as a microtracer with therapeutic doses of non-labeled ursodiol in infants. Five non-cholestatic infants were administered 3 consecutive oral microdoses of (14) C-ursodiol: 8 ng (1.0 nCi), 26 ng (3.3 nCi), and 80 ng (10 nCi) 48 hours apart. Three additional infants with cholestasis were administered a single 80 ng (10.0 nCi) oral dose of (14) C-ursodiol together with a therapeutic dose of 40 mg/kg of non-labeled ursodiol. A pharmacokinetic model describing ursodiol concentrations was developed using nonlinear mixed-effects modeling. The pharmacokinetics of ursodiol in this pilot study were best described by a two-compartment model with first-order elimination. This study demonstrates the feasibility and utility of microdose and microtrace methodology in pediatric research.

SummaryBackground A phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads was performed in cirrhotic patients with hepatocellular carcinoma (HCC). Aim To estimate the maximum-tolerated dose (MTD) and to assess safety, efficacy, pharmacokinetics and quality of life. Methods Patients received a single TACE session with injection of 2 mL drug-eluting beads (DEBs; DC Bead 300–500 μm) loaded with idarubicin. The idarubicin dose was escalated according to a modified continuous reassessment method. MTD was defined as the dose level closest to that causing dose-limiting toxicity (DLT) in 20% of patients. Results Twenty-one patients were enrolled, including nine patients at 5 mg, six patients at 10 mg, and six patients at 15 mg. One patient at each dose level experienced DLT (acute myocardial infarction, hyperbilirubinaemia and elevated aspartate aminotransferase (AST) at 5-, 10- and 15-mg, respectively). The calculated MTD of idarubicin was 10 mg. The most frequent grade ≥3 adverse events were pain, elevated AST, elevated γ-glutamyltranspeptidase and thrombocytopenia. At 2 months, the objective response rate was 52% (complete response, 28%, and partial response, 24%) by modified Response Evaluation Criteria in Solid Tumours. The median time to progression was 12.1 months (95% CI 7.4 months – not reached); the median overall survival was 24.5 months (95% CI 14.7 months – not reached). Pharmacokinetic analysis demonstrated the ability of DEBs to release idarubicin slowly. Conclusions Using drug-eluting beads, the maximum-tolerated dose of idarubicin was 10 mg per TACE session. Encouraging responses and median time to progression were observed. Further clinical investigations are warranted (NCT01040559).

The plasma kinetic profile of moxidectin (MXD) in ewes during the last third of pregnancy was studied after the subcutaneous dose of 0.2 mg/kg of body weight (bw). Two groups of sheep (n = 7) that were equally balanced in body weight were used. Group I (control) was maintained unmated, while Group II (pregnant) was estrous-synchronized and mated with fertile rams. Both groups were maintained under similar conditions regarding management and feeding. When the ewes from Group II fulfilled 120 days of pregnancy, both groups were treated with a subcutaneous injection of 0.2 mg of MXD/kg bw. Blood samples were collected at different set times between 1 h and 40 days post-treatment. After plasma extraction and derivatization, the samples were analyzed using high-performance liquid chromatography with fluorescence detection. A noncompartmental pharmacokinetic analysis was performed, and the data were compared using Student's t-test. The mean pharmacokinetic parameters, including Cmax , Tmax , and the area under the concentration-time curve (AUC), were similar for both groups of sheep. The average of elimination half-life was significantly lower (P = 0.0023) in the pregnant (11.49 ± 2.2 days) vs. the control (17.89 ± 4.84 days) sheep. Similarly, the mean residence time (MRT) for the pregnant group (20.6 ± 3.8 days) was lower (P = 0.037) than that observed in the control group (27.4 ± 9.1 days). It is concluded that pregnancy produces a significant decrease in mean values of half-life of elimination of MXD, indicating that pregnancy can increase the rate of elimination of the drug reducing their permanence in the body.

This study reports the pharmacokinetics of buprenorphine in conscious rhesus macaques (Macaca mulatta) after intravenous (IV) and intramuscular (IM) administration. Four healthy, opioid-naïve, socially-housed, adult male macaques were used. Buprenorphine (0.03 mg/kg) was administered intravenously as a bolus or intramuscularly on separate occasions. Blood samples were collected prior to, and up to 24 h, post-administration. Serum buprenorphine concentrations were analyzed with liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic analysis was performed with commercially available software. Mean residence time in the IV study as compared to the IM study was 177 (159–189) minutes vs. 185 (174–214) minutes, respectively [median (range)]. In the IV study, concentration back extrapolated to time zero was found to be 33.0 (16.8–57.0) ng/mL [median (range)]. On the other hand, the maximum serum concentration found in the IM study was 11.8 (6.30–14.8) ng/mL [median (range)]. Rhesus macaques maintained concentrations greater than 0.10 ng/mL for over 24 h in the IV study and over 12 h in the IM study. Bioavailability was found to be 68.1 (59.3–71.2)% [median (range)]. No significant adverse effects were observed in the monkeys at the 0.03 mg/kg dose of buprenorphine during either study.

Patients undergoing hemodialysis (HD) are frequently elderly with poor performance status and usually cannot withstand chemotherapy because of its toxicities. We report a case of an elderly woman with chronic renal failure undergoing HD who was diagnosed with advanced non‐small cell lung cancer and treated with orally administered gefitinib. We analyzed the pharmacokinetic data of gefitinib in this patient and found that that gefitinib was safe under these conditions.

Standard dosing for individuals with hemophilia A is based on body weight such that 50 IU kg(-1) is defined as a 100% dose, or one attaining 1.00 IU mL(-1) factor VIII (FVIII) clotting activity. No guidelines exist, however, for individuals with hemophilia who are obese, body mass index (BMI) ≥ 30, who may actually be 'over'-treated based on higher in vivo recovery based on higher weight. Alternative treatment guidelines are needed for such patients. To determine FVIII pharmacokinetics we retrospectively collected data during ideal-body-weight dosing from six obese (BMI ≥ 30) hemophilia A patients cared for at the Hemophilia Center of Western PA, for prophylaxis or surgery. The pharmacokinetic data from six subjects undergoing ideal-body-weight dosing with recombinant FVIII indicate peak levels and half-life comparable to standard 50 IU kg(-1) dosing. The mean peak FVIII:C was 1.00 IU dL(-1) and the mean FVIII:C half-life was 10.14 h. IBW-dosing resulted in an average 48.9% reduction in factor use per patient over a 3-month period, for an annualized savings of $133,000 per patient. Ideal-body-weight dosing of recombinant FVIII in obese patients with hemophilia A results in comparable pharmacokinetics, including peak and half-life, with comparable hemostatic efficacy for prophylaxis and surgical treatment, at a significant reduction in factor use and cost. Future studies are needed to confirm these findings in individuals with other congenital bleeding disorders and in children.

This study investigated the effect of food on the plasma pharmacokinetics of bardoxolone methyl, an antioxidant inflammation modulator, at a 20mg dose, and the dose proportionality of bardoxolone methyl pharmacokinetics from 20 to 80mg. It was a single‐dose study conducted at a single center in 32 healthy volunteers aged 18–45 years using an amorphous spray‐dried dispersion formulation of bardoxolone methyl. In Part A, 16 subjects received single 20mg doses of bardoxolone methyl under fasting and non‐fasting conditions. In Part B, 16 subjects received a single 60 or 80mg dose of bardoxolone methyl and a matching placebo dose under fasting conditions.Blood samples for pharmacokinetic analysis were taken over 120hours following dose administration. Single dose administration of 20, 60, and 80mg bardoxolone methyl was safe and well‐tolerated in healthy volunteers. Total bardoxolone methyl exposure was unchanged in the presence of food. However, doses of bardoxolone methyl above 20mg appear to have a saturated dissolution or absorption process and are associated with less than proportional increases in drug exposure.

Keywords: dynamic contrast-enhanced MRI; abdominal aortic aneurysm; microvascularization; vessel wall imaging Purpose : To investigate the feasibility and reproducibility of dynamic contrast-enhanced MRI (DCE-MRI) to quantify abdominal aortic aneurysm (AAA) vessel wall enhancement dynamics which may reflect the amount of wall microvasculature. AAA vessel wall microvasculature has been linked with aneurysm progression and rupture. Materials and Methods : Thirty patients with AAA underwent DCE-MRI at 1.5 Tesla. Enhancement dynamics of the aneurysm wall were quantified in regions-of-interest (ROIs) in the vessel wall by calculating the transfer constant (Ktrans) using pharmacokinetic modeling and the area-under-gadolinium-curve (AUC). To assess reproducibility, 10 patients were imaged twice on different occasions. ROIs were drawn by two independent observers. The intraclass correlation coefficients (ICC) and coefficients of variation (CV) were determined to investigate intra-, interobserver, and interscan variability. Results : Twenty-eight analyzable MR examinations were included for pharmacokinetic analysis after excluding two examinations due to severe motion artifacts. Intra-, interobserver, and interscan variability for Ktrans were small (all ICC > 0.90, CV 0.88, CV

Purpose To assess inter- and intraobserver reproducibility of DCE-MRI measurements and possible differences between two directly adjacent slices. Materials and Methods DCE-MRI measurements of 30 patients with histologically proven rectal carcinoma were performed on a 1.5 Tesla (T) MR system during intravenous contrast agent application before and after neoadjuvant radiochemotherapy with two directly adjacent slices used for calculation per patient. Images were analyzed semiquantitatively (parameters TTP and MITR) and quantitatively using the Brix compartment model (parameters kep and A) by two different observers and at two different time points. The concordance correlation coefficient was calculated for every parameter in intra-/interobserver comparison and slice comparison. Results Median relative differences below 10% for all parameters and high values of the concordance correlation coefficient (CCC) were found for most pharmacokinetic parameters in inter-/intraobserver comparison and slice comparison, with the exception of the parameter A before therapy in intra-/ interobserver comparison (CCC: 0.315/0.452) and kep before therapy in intraobserver comparison (CCC: 0.362). Conclusion Our results indicate good inter- and intraobserver reproducibility for most pharmacokinetic parameters and for the two adjacent slices measured. However, as there were some parameters that demonstrated poor correlation, testing for reproducibility and a multiobserver approach might be considered whenever using pharmacokinetic parameters as biomarkers. J. Magn. Reson. Imaging 2014;40:715–722. © 2013 Wiley Periodicals, Inc.

The use of thimerosal preservative in childhood vaccines has been largely eliminated over the past decade in the United States because vaccines have been reformulated in single-dose vials that do not require preservative. An exception is the inactivated influenza vaccines, which are formulated in both multidose vials requiring preservative and preservative-free single-dose vials. As part of an ongoing evaluation by USFDA of the safety of biologics throughout their lifecycle, the infant body burden of mercury following scheduled exposures to thimerosal preservative in inactivated influenza vaccines in the United States was estimated and compared to the infant body burden of mercury following daily exposures to dietary methylmercury at the reference dose established by the USEPA. Body burdens were estimated using kinetic parameters derived from experiments conducted in infant monkeys that were exposed episodically to thimerosal or MeHg at identical doses. We found that the body burden of mercury (AUC) in infants (including low birth weight) over the first 4.5 years of life following yearly exposures to thimerosal was two orders of magnitude lower than that estimated for exposures to the lowest regulatory threshold for MeHg over the same time period. In addition, peak body burdens of mercury following episodic exposures to thimerosal in this worst-case analysis did not exceed the corresponding safe body burden of mercury from methylmercury at any time, even for low-birth-weight infants. Our pharmacokinetic analysis supports the acknowledged safety of thimerosal when used as a preservative at current levels in certain multidose infant vaccines in the United States.

A validated LCMS method was developed for the quantitative determination of caffeic acid phenethyl amide (CAPA) and caffeic acid phenethyl ester (CAPE) from rat plasma. Separation was achieved using a reverse-phase C12 HPLC column (150 × 2.00 mm, 4 µm) with gradient elution running water (A) and acetonitrile (B). Mass spectrometry was performed with electrospray ionization in negative mode. This method was used to determine the pharmacokinetic profiles of CAPA and CAPE in male Sprague–Dawley rats following intravenous bolus administration of 5, 10 and 20 mg/kg of CAPA and 20 mg/kg of CAPE. The pharmacokinetic analysis suggests the lack of dose proportionality in the dose range of 5–20 mg/kg of CAPA. Total clearance values for CAPA ranged from 45 to 156 mL/min and decreased with increasing dose of CAPA. The volume of distribution for CAPA ranged from 17,750 to 52,420 mL, decreasing with increasing dose. The elimination half-life for CAPA ranged from 243.1 to 295.8 min and no statistically significant differences were observed between dose groups in the range of 5–20 mg/kg (p > 0.05). The elimination half-life for CAPE was found to be 92.26 min. Copyright © 2013 John Wiley & Sons, Ltd.

Zhi Zhu Wan (ZZW), a classical Chinese medical formulae consisted of Atractylodes Rhizome and Fructus Citrus Immaturus, has been commonly used for treatment of gastrointestinal diseases. Hesperetin and naringenin are the main components of ZZW, and both can alleviate intestinal tract disorders. In this work, plasma pharmacokinetics and pharmacodynamics characteristics of ZZW after oral administration were investigated using a rapid and sensitive ultra performance liquid chromatography–tandem mass spectrometry method with an electrospray ionization source in positive ion mode. Biosamples were prepared using methanolic precipitation, and the separation of hesperetin and naringenin was achieved on a Waters ACQUITY HSS BEH (2.1 mm × 5 mm, 1.7 µm) column by linear gradient elution, and the total run time was only 3 min. Data were analyzed and estimated using WinNonlin Professional version 5.1. With pharmacokinetic analysis, the estimated pharmacokinetic parameters (i.e. Cmax, area under the concentration–time curve (AUC) and t1/2), were Cmax = 776.06 ng/mL, AUC = 9473 ng/mL·h, t1/2 = 5.26 h for hesperetin and Cmax = 2910.6 ng/mL, AUC = 40607.9 ng/mL·h, t1/2 = 4.69 h for naringenin, respectively. In the present study, we have also valuated and clarified the effect of ZZW on small intestinal movement. It was found that ZZW can accelerate intestinal motility in mice and may hold a promising treatment for intestinal diseases. Copyright © 2012 John Wiley & Sons, Ltd.

Objective To determine endogenous production of L-lactate and the clearance of exogenous sodium L-lactate (ExLC) in healthy adult horses. Design A sodium L-lactate solution (1 mmol/kg body weight qs to 500 mL final volume in 0.9% NaCl) was adminstered IV over 15 minutes. Blood samples for L-lactate concentration [LAC] measurement were collected immediately prior to infusion, at 5, 10, and 15 minutes during infusion and at 1 minute intervals for 15 minutes, at 30, 45, 60, 120, and 180 minutes postinfusion. Disposition modeling and pharmacokinetic analysis was performed using proprietary software. Setting University Teaching Hospital. Animals Six clinically healthy adult horses. Measurements and Main Results Median (range) baseline [LAC] was 0.43 (0.20–0.72) mmol/L for samples obtained every 3 hours over the 24 hours prior to ExLC and demonstrated variability primarily associated with horse. Median [LAC] immediately prior to ExLC was 0.43 (0.35–0.52) mmol/L. A 2-compartment model was used to specify the pharmacokinetic parameters. Median (range) ExLC was 1.05 (0.073–1.75) L·h−1·kg−1 and t1/2 β was 29.54 (20.8–38.6) min. Median lactate production based on basal [LAC] immediately prior to ExLC was was 0.49 (0.31–0.93) mmol·h−1·kg−1. Conclusions ExLC in healthy adult horses is greater than that of hyperlactemic human patients but similar to normolactemic-sick human patients examined using the same model, supporting development of species, and disease specific ExLC parameters.

Introduction: Model evaluation is an important issue in population pharmacokinetic analyses. The objectives were to evaluate the predictive performance of previously published pediatric population pharmacokinetic models for vancomycin in a new data set and to propose an optimal dose to obtain a vancomycin concentration target. Methods: External evaluation was conducted for all the published models of vancomycin in neonates and young infants with a new data set of 70 patients. Bias and accuracy were calculated. Advanced analyses were performed to evaluate the predictive performance of the best model. This population pharmacokinetic analysis was performed to simulate doses of vancomycin according to the appropriate target concentration. Results: All models gave almost the same results, except 2 that were not acceptable. Nevertheless, the model described by Oudin et al presented the best results with a bias and accuracy of 4.0% and 27.8%, respectively. Simulations showed that the maintenance dose should be adjusted more precisely to each neonate based on his or her weight and serum creatinine value. Conclusion: Simulations have allowed the authors to describe new dosage schedules, and a chart was created to help clinicians to adapt dosage of vancomycin. Because of pharmacokinetic variability, vancomycin still requires therapeutic drug monitoring.

Study Objective. To evaluate the extent of agreement between plasma gentamicin concentrations determined from samples collected by using implantable subcutaneous central venous catheters (ports) with the push-pull method and those collected by finger lancet punctures in children with febrile neutropenia. Design. Prospective, randomized study. Setting. University-affiliated, tertiary care hospital. Patients. Sixty-two children with cancer who had single- or double-lumen ports and who received gentamicin for treatment of febrile neutropenia between February 2008 and October 2009. Intervention. One blood sample was collected from the port by using the push-pull method at the same time one blood sample was collected by finger lancet puncture for determination of plasma gentamicin concentrations. Measurements and Main Results. Forty-four pairs of samples were available for assessment of agreement, and 43 were available for pharmacokinetic analysis. Agreement between plasma gentamicin concentrations determined from blood samples from ports and finger lancet punctures was assessed by the intraclass correlation coefficient (ICC), Bland-Altman analysis, and comparison of simulated dosage adjustments. Changes in port patency were monitored for 1 week after port sampling. Differences in simulated dosage adjustments calculated by using either the port or finger lancet puncture samples that differed by greater than 20% were considered clinically significant. Agreement between the 44 finger lancet puncture and port sample pairs was excellent (ICC 0.991, 95% confidence interval 0.984–0.995). Port plasma gentamicin concentrations were 4.7% lower than those concentrations determined in blood from finger lancet punctures. The observed limits of agreement ranged from −20.5% to 11%. Differences in dosage adjustments calculated by using port and finger lancet puncture plasma gentamicin concentrations were not clinically significant in 38 (88%) of 43 cases. No changes in port patency were observed in the week after port sampling. Conclusion. The push-pull method of blood sampling is a reliable and safe option for determining plasma gentamicin concentrations in children with ports.

Patients with highly hypoxic primary tumors show increased frequency of locoregional treatment failure and poor survival rates and may benefit from particularly aggressive treatment. The potential of gadolinium diethylene-triamine penta-acetic acid-based dynamic contrast-enhanced-MRI in assessing tumor hypoxia was investigated in this preclinical study. Xenografted tumors of eight human melanoma lines were subjected to dynamic contrast-enhanced-MRI and measurement of the fraction of radiobiologically hypoxic cells and the fraction of pimonidazole-positive hypoxic cells. Tumor images of K(trans) (the volume transfer constant of gadolinium diethylene-triamine penta-acetic acid) and v(e) (the fractional distribution volume of gadolinium diethylene-triamine penta-acetic acid) were produced by pharmacokinetic analysis of the dynamic contrast-enhanced-MRI data, and K(trans) and v(e) frequency distributions of the non-necrotic tumor tissue were established and related to the extent of hypoxia. Tumors showing high K(trans) values and high v(e) values had low fractions of hypoxic cells, whereas tumors showing both low K(trans) values and low v(e) values had high hypoxic fractions. K(trans) differentiated better between tumors with low and high hypoxic fractions than did v(e). This study supports the current attempts to establish dynamic contrast-enhanced-MRI as a method for assessing the extent of hypoxia in human tumors, and it provides guidelines for the clinical development of valid assays.

The population pharmacokinetic (PK) profile of oral clonidine was characterized in newborns with neonatal abstinence syndrome, and significant covariates affecting its PK parameters were identified. Plasma clonidine concentration data were obtained from a clinical trial in which 36 newborns, aged 1 to 25 days (postnatal age, PNA) and weighing 2.1 to 3.9 kg, were enrolled to take multiple oral doses of clonidine. The population PK model of clonidine was developed by NONMEM, and significant covariates were identified, followed by nonparametric bootstraps (2000 replicates) and simulation experiments. A 1-compartment open linear PK model was chosen to describe plasma concentrations of clonidine, and body weight and PNA were significant covariates for apparent clearance (CL/F) as follows: CL/F (L/h) = 15.2 × [body weight (kg)/70](0.75) × [PNA (day)(0.441)/(4.06(0.441) + PNA (day)(0.441))]. Furthermore, CL/F of clonidine increased rapidly with PNA during the first month of life after body weight was adjusted. Any optimal dosage regimen for clonidine in term neonates should be based on infant's age and body weight, and 1.5 µg/kg every 4 hours is proposed starting the second week of life based on the simulation results.

Purpose: To investigates the impact of nonrigid motion correction on pixel-wise pharmacokinetic analysis of free-breathing DCE-MRI in patients with solitary pulmonary nodules (SPNs). Misalignment of focal lesions due to respiratory motion in free-breathing dynamic contrast-enhanced MRI (DCE-MRI) precludes obtaining reliable time–intensity curves, which are crucial for pharmacokinetic analysis for tissue characterization. Materials and Methods: Single-slice 2D DCE-MRI was obtained in 15 patients. Misalignments of SPNs were corrected using nonrigid B-spline image registration. Pixel-wise pharmacokinetic parameters Ktrans, ve, and kep were estimated from both original and motion-corrected DCE-MRI by fitting the two-compartment pharmacokinetic model to the time–intensity curve obtained in each pixel. The “goodness-of-fit” was tested with χ2-test in pixel-by-pixel basis to evaluate the reliability of the parameters. The percentages of reliable pixels within the SPNs were compared between the original and motion-corrected DCE-MRI. In addition, the parameters obtained from benign and malignant SPNs were compared. Results: The percentage of reliable pixels in the motion-corrected DCE-MRI was significantly larger than the original DCE-MRI (P = 4 × 10−7). Both Ktrans and kep derived from the motion-corrected DCE-MRI showed significant differences between benign and malignant SPNs (P = 0.024, 0.015). Conclusion: The study demonstrated the impact of nonrigid motion correction technique on pixel-wise pharmacokinetic analysis of free-breathing DCE-MRI in SPNs. J. Magn. Reson. Imaging 2011;33:968–973. © 2011 Wiley-Liss, Inc.

The arterial input function is crucial in pharmacokinetic analysis of dynamic contrast-enhanced MRI data. Among other artifacts in arterial input function quantification, the blood inflow effect an ...

Methods for determination of albendazole (ALB), albendazole sulfoxide (SOX) and albendazole sulfone (SON) in turkey blood plasma, using high-performance liquid chromatography (HPLC) with fluorescence detection, were developed. Moreover, comparison of HPLC columns with ultra-performance liquid chromatography (UPLC) columns was performed. Albendazol was administered orally in 5-week-old birds (n = 18) at a dose of 25 mg/kg b.w. Accuracy and precision of the developed method were satisfactory and stability studies showed acceptable variation (below 15%) in ALB, SOX and SON concentrations when the samples were stored at -75°C for 15 days. UPLC(®) columns gave higher peaks from typical HPLC columns retaining high quality of analysis. Pharmacokinetic analysis indicated quick elimination of ALB from turkey blood plasma. The mean residence time of SON was at least two times longer than that of SOX and four times longer than that of ALB. The elimination half-lives for ALB, SOX and SON were 0.7 ± 0.27, 5.37 ± 6.03, 9.17 ± 5.12 h, respectively. The obtained results indicate that the described method allows for precise determination of albendazole and its metabolites in turkey plasma. Moreover, using UPLC columns in HPLC apparatus results in higher sensitivity as compared with the classical HPLC columns.

Zˇele, D., Tavcˇar-Kalcher, G., Kobal, S., Vengusˇt, G., Vengusˇt, A., Grabnar, I.Plasma pharmacokinetics of abamectin in fallow deer (Cervus damadama) following subcutaneous administration. J. vet. Pharmacol. Therap. 34,455–459.The pharmacokinetics of abamectin (ABM) following a single subcutaneousadministration of 200 lg⁄kg was evaluated in adult fallow deer by followingABM concentration in blood plasma. A nonlinear mixed effects modellingprocedure was used for pharmacokinetic analysis. The time course of ABMconcentration was described by a two-compartment model with first-orderabsorption. Abamectin absorption in fallow deer was rapid with a peak plasmaconcentration of 120.7 ± 33.2 ng⁄mL observed at 19.1 ± 7.7 h (mean ± SD).Half-lives of the distribution and terminal phase were 17.2 and 119.3 h,respectively. Typical apparent clearance of the bioavailable fraction (CL⁄F) was0.795 L⁄h and was independent of animal weight. Considering the obtainedpharmacokinetic parameters in our study, we may assume that effectiveparasite control in fallow deer is obtained using the usual recommended dose of200 lg⁄kg.(Paper received 26 July 2010; accepted for publication 31 October 2010)Diana Zˇele, Veterinary Faculty, University of Ljubljana, Gerbicˇeva 60, LjubljanaSI-1000, Slovenia. E-mail: diana.zele@vf.uni-lj.si

This article discusses the bioequivalence of Omnitrope (Sandoz's rhGH biosimilar) and Genotropin (reference rhGH product), assessed in the first 2 clinical phase 1 studies conducted during the development of Omnitrope. Both of these phase 1 studies were randomized, double-blind, crossover studies, each involving 24 healthy volunteers who underwent pituitary somatrope cell down-regulation using octreotide. Three different formulations of recombinant human growth hormone (rhGH) were compared: Omnitrope lyophilisate, Omnitrope liquid and Genotropin (lyophilized powder for injection). Both pharmacokinetics (area under the curve [AUC], C(max), t(max) and t(1/2)) and pharmacodynamics (serum levels of insulin-like growth factor 1, insulin-like growth factor binding protein-3 and non-esterified fatty acid) were assessed after a single subcutaneous injection of 5 mg rhGH. The 3 formulations had comparable pharmacokinetics and pharmacodynamics. All the 90% confidence intervals of the ratios of the least squares means for the pharmacokinetic and pharmacodynamic parameters AUC and C(max) were within the predefined FDA and EMEA acceptance range of 80%-125% for bioequivalence. In addition, a comparative population pharmacokinetic analysis further supports that Omnitrope lyophilisate, Omnitrope liquid and Genotropin can be regarded as equivalent in terms of pharmacokinetics. Therefore, Omnitrope lyophilisate was demonstrated to be bioequivalent to both Genotropin and the Omnitrope liquid formulation.

Fluorescence pharmacokinetic rates in tissues can provide additional specific and quantitative physiological and pathological information for evaluating organ function. This modality requires a highly sensitive diffuse fluorescence tomography (DFT) working in dynamic way to finally extract the pharmacokinetic rates from the measured pharmacokinetics-associated temporally varying boundary intensity, normally with the support of a priori anatomy. This paper is devoted to study pharmacokinetics of indocyanine green (ICG) in mouse liver based on synergistic dynamic-DFT and X-ray computer tomography (XCT): A highly sensitive dynamic DFT system of CT-scanning mode working with parallel 4 photomultiplier-tube photon-counting channels generates informative and instantaneous sampling datasets; An XCT system provides priori information of the target localization for improvement of the reconstruction quality; An analysis procedure extracts the pharmacokinetic rates from the reconstructed ICG concentration-time curves, using the Gauss-Newton scheme for fitting to a 2-compartment model. The uptake and excretion rates of ICG which were obtained in livers of 10 healthy mice in the in vivo experiments can be used to quantitatively evaluate liver function. The results can validate the effectiveness of both the imaging measurements system and pharmacokinetic analysis method.

Change in the pharmacokinetic disposition of an antifungal agent micafungin (MCFG) by 8-hour plasma exchange (PE) with 3200 mL replacement was examined in a stem cell transplant recipient. On pharmacokinetic analysis of the time course of the serum concentrations of MCFG, it was determined that PE shortened the elimination half-life of MCFG from 16.5 hours to 6.3 hours. Total clearance (CL(tot)) was increased from 0.366 L/h to 0.932 L/h by PE. PE-dependent clearance (CL(pe)) accounted for approximately two-thirds of CL(tot), and PE was found to contribute to the removal of nearly 40% of the total body store of MCFG. It was confirmed that a significant amount of MCFG was excluded into apheresed plasma waste. In addition, adsorption of MCFG onto plasma-separating membrane was strongly suggested, because the CL(pe) exceeded the rate of plasma apheresis and MCFG concentrations in apheresed plasma were lower than those in circulating blood collected at the same time. The marked elimination of MCFG during PE can be explained by its low volume of distribution and high affinity for serum proteins. Judging from these findings as well as those of other reports, MCFG can be considered one of the drugs most susceptible to removal by PE. Our findings suggest that an increment in the regular dose of MCFG would be required at the next administration after PE.

Summary On the basis of pharmacokinetic analysis of the results obtained in 230 sucking-pigs, the best combination partners for trimethoprim are sulfamethoxazole-sulfachloropyridazine SMZ/SCP-Na perorally and sulfamethoxazole parenterally. The half-life time in sucking pigs are: perorally SCP-Na = 3.01 hrs., SMZ = 8.83 hrs., SDI (sulfadimidine) = 21.55 hrs., SMZ/SCP-Na = 5.27 hrs.; parenterally SMZ = 3.06 hrs., SDO (sulfadoxine) = 10.46 hrs.; TMP total 3.41 hrs. On the basis of the data, in sucking pigs the composition of neither Trivetrin (TMP + SDO), nor Vetoprim 120 (TMP, SDI + STH) is the most favourable, since after the elimination of trimethoprim the residual level of sulfonamide existing for a longer period in the animal is so low that it does not reach the MIC value. It cannot thus be excluded that in some cases it favours the development of resistance of pathogens to sulfonamides. Zusammenfassung Untersuchungen uber die Pharmakokinetik von Sulfonamid-Trimethoprim-Kombination bei Saugferkeln Bei 230 Saugferkeln wurde gefunden, das bei peroraler Applikation die Kombination Trimethoprim-Sulfamethoxazol-Sulfachlorpyridazin am besten wirkt. Bei parenteraler Verabreichung erwies sich hingegen die Kombination Trimethoprim-Sulfamethoxazol als die gunstigste. Die Halbwertszeiten betragen bei peroraler Applikation: Sulfachlorpyridazin (SCP-Na) 3,01 h; Sulfamethoxazol (SMZ) 8,83 h, Sulfadimidin (SDI) 21,55 h, SMZ/SCP-Na 5,27 h. Bei parenteraler Applikation betragen die Halbwertszeiten: SMZ 3,06 h, Sulfadoxin (SDO) 10,46 h, Trimethoprim (TMP) 3,41 h. Da nach der Trimethoprim-Elimination die zuruckbleibenden Sulfonamidspiegel so niedrig sind, das sie den MIC-Wert (minimale inhibitorische Konzentration) nicht fur langere Zeit erreichen, kann weder die Kombination von Trivetrin (TMP + SDO) noch von Vetoprim (TMP, SDI + STH) als gunstig bezeichnet werden. Es kann somit nicht ausgeschlossen werden, das in gewissen Fallen die Resistenz von pathogenen Keimen gefordert wird. Resume Recherches sur la cynetique pharmacologique die sulfonamid-trimethoprim-combinaisons chez des porcelets Chez 230 porcelets trimethoprim-sulfamethoxazole-sulfachloropyridazine represente la meilleure combinaison orale. Chez une application parenterale la combinaison trimethoprim-sulfamethoxazole est la meilleure. Les temps moyens d'efficacite ont ete les suivants par application orale: sulfachloropyridazine (SCP-Na) 3,01 h; sulfamethoxazole (SMZ) 8,83 h; sulfadimidine (SDI) 21,55 h; SMZ/SCP-Na 5,27 h. Les temps furent les suivants avec une application parenterale: SMZ 3,06 h; sulfadoxine (SDO) 10,46 h; trimethoprim (TMP) 3,41 h. Etant donne que les taux de sulfonamide restants sont tres faibles apres l'elimination du trimethoprim et qu'ils n'atteignent pas plus longtemps la valeur MIC (concentration minimale d'inhibition), on ne peut pas donner comme favorable la combinaison Trivetrin (TMP + SDO) ou Vetoprim (TMP, SDI + STH). L'apparition d'une resistance de germes pathogenes n'est pas exclue dans certains cas. Resumen Datos sobre la cinetica farmacologica de combinaciones de sulfonamidotrimetoprima en lechones lactantes Sobre la base del analisis farmacocinetico de los resultados obtenidos en 230 lechones lactantes, la combinacion mejor es la de trimetoprima-sulfametazol-sulfacloropiridazina-Na (oral) y sulfametoxazol (parenteral). Los tiempos semivalor con aplicacion peroral son: sulfacloropiridazina (SCP-Na) 3,01 h, sulfametazol (SMZ) 8,83 h, sulfadimidina (SDI) 21,55 h, SMZ/SCP-Na 5,27 h. Con aplicacion parenteral, los tiempos semivalor importan: SMZ 3,06 h, sulfadoxina (SDO) 10,46 h, trimetoprima (TMP) 3,41 h. Puesto que despues de la eliminacion de TMP son tan bajos los niveles sulfonamidicos residuales que no alcanzan en bastante tiempo el valor CIM (concentracion inhibidora minima), no se pueden considerar favorables ni la combinacion de Trivetrina (TMP + SDO) ni la de Vetoprima (TMP, SDI + STH). Por lo tanto, no se puede excluir el que en algunos casos sea favorecido el desarrollo de resistencia de germenes patogenos a las sulfonamidas.

One of the most powerful features of the dynamic contrast-enhanced (DCE) MRI technique is its capability to quantitatively measure the physiological or pathophysiological environments assessed by the passage of contrast agent by means of model-based pharmacokinetic analysis. The widely used two-compartment pharmacokinetic model developed by Brix and colleges fits tumor data well in most cases, but fails to explain the biexponential arterial input function. In this work, this problem has been attacked from a theoretical point of view, showing that this problem can be solved by adopting a more realistic model assumption when simplifying the general solutions of the two-compartment pharmacokinetic equations. Pharmacokinetic parameters derived from our model were demonstrated to have comparative tissue specificity to Ktrans from Larsson's model, better than those from Brix's model and the empirical area-under-the-curve (AUC). Tissue-type classifier constructed with the arterial input function–decomposed kep-kpe pair from our model was also demonstrated to have superior performance than any other classifier based on DCE-MRI pharmacokinetic parameters or empirical AUC. The feature that this classifier has a near-zero false-negative rate makes it a highly desirable tool for clinical diagnostic and response assessment applications. Magn Reson Med 59:1448–1456, 2008. © 2008 Wiley-Liss, Inc.

The plasma kinetic profile of ivermectin during the last trimester of pregnancy was studied in ewes after a single subcutaneous administration of 0.2 mg/kg body weight (BW). Sheep were randomly distributed into two groups. Ewes in group 1 (control, n=6) were left unmated, whereas in group 2 (pregnant, n=6) ewes were estrus-synchronized and mated with rams. Both groups were housed under similar conditions of management and feeding. At 120 days of pregnancy, both groups were given a subcutaneous injection of 0.2 mg/kg BW of ivermectin. Blood samples were taken by jugular puncture according to a fixed protocol between 1 h and 40 days post-treatment. After plasma extraction and derivatization, samples were analyzed by high performance liquid chromatography with fluorescence detection. A computerized pharmacokinetic analysis was performed, and the data were compared by means of the Student t-test. The results showed that plasma concentrations of ivermectin remained longer in the pregnant than in the control group. The mean values of pharmacokinetic parameters C(max), t(max), and area under the concentration-time curve (AUC) were similar for both groups of sheep. The mean residence time (MRT) values for the pregnant group (8.8+/-1.4 days) were higher (P