scholarly journals Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Cholic Acid (MT921) after a Subcutaneous Injection in the Submental Area to Humans

2021 ◽  
Vol 14 (8) ◽  
pp. 830
Author(s):  
Hyewon Chung ◽  
Jin-Woo Park ◽  
Dai-Hyun Kim ◽  
Soo-Hong Seo ◽  
Kyoung-Ah Kim ◽  
...  
Keyword(s):  
Cholic Acid ◽  
Deoxycholic Acid ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Systemic Exposure ◽  
Blood Lipid ◽  
Pharmacokinetic Analysis ◽  
Post Dose ◽  
Before And After

This study aimed to explore pharmacokinetics, pharmacodynamics, and safety/tolerability of MT921, an injectable cholic acid, after a single subcutaneous administration to healthy volunteers. A randomized, double-blinded, placebo-controlled, single dose-ascending phase 1 study enrolled 24 subjects who were assigned to three groups (60 mg, 120 mg, and 150 mg) of MT921. Blood samples were obtained for a 24-h period before and after injecting MT921 to the submental fat area. Plasma concentrations of cholic acid and deoxycholic acid were determined for pharmacokinetic analysis. Levels of free fatty acid, triglyceride, and total cholesterol were measured for pharmacodynamic analysis. Safety and tolerability were assessed until 21 days post-dose. While systemic exposure to cholic acid tended to increase as the MT921 dose increased, pharmacokinetic profiles of deoxycholic acid were similar among dose groups without showing significant changes. Pharmacodynamic profiles were comparable when measured at baseline and post-dose. The most frequent adverse events were injection site pain and edema. All adverse drug reactions resolved without treatment. MT921 appeared to be well-tolerated after an injection to the submental area at a dose up to 150 mg. Systemic exposure to cholic acid increased as the dose increased. Blood lipid profiles and deoxycholic acid levels were not affected by MT921 treatment.

scholarly journals Pharmacokinetic analysis of an extended-pulsed fidaxomicin regimen for the treatment of Clostridioides (Clostridium) difficile infection in patients aged 60 years and older in the EXTEND randomized controlled trial

2020 ◽  
Vol 75 (4) ◽  
pp. 1014-1018
Author(s):  
Benoit Guery ◽  
Areti Georgopali ◽  
Andreas Karas ◽  
Gbenga Kazeem ◽  
Ingrid Michon ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Analysis ◽  
Plasma Samples ◽  
Post Dose ◽  
Recommended Treatment ◽  
Clostridioides Difficile ◽  
Stool Samples

Abstract Background Fidaxomicin is a recommended treatment for Clostridioides difficile infection (CDI) and reduces CDI recurrence incidence versus vancomycin. An extended-pulsed fidaxomicin (EPFX) regimen further reduces recurrence frequency. However, the pharmacokinetic profile of fidaxomicin in an EPFX regimen is unknown. Objectives To evaluate plasma and stool concentrations of fidaxomicin and its metabolite, OP-1118, after EPFX administration for CDI. Methods In the Phase 3b/4 EXTEND trial, patients aged ≥60 years with toxin-confirmed CDI were randomized to receive EPFX (oral fidaxomicin twice daily, Days 1–5; once daily on alternate days, Days 7–25). Fidaxomicin and OP-1118 concentrations were determined using post-dose plasma samples obtained on Days 5 ± 1, 12 ± 1 and 25/26, and post-dose stool samples obtained on Days 5 ± 1, 12 ± 1 and 26 ± 1. Results Plasma samples from 14 patients were included in the pharmacokinetic analysis; 12 of these patients provided stool samples. Median (range) plasma concentrations of fidaxomicin on Day 5 ± 1 and Day 25/26 were 0.0252 (0.0038–0.1220) mg/L and 0.0069 (0–0.0887) mg/L, respectively, and those of OP-1118 were 0.0648 (0.0142–0.3250) mg/L and 0.0206 (0–0.3720) mg/L, respectively. Median (range) stool concentrations of fidaxomicin and OP-1118 on Day 26 ± 1 were 272.5 (0–524) mg/kg and 280.5 (0–1120) mg/kg, respectively. Conclusions EPFX treatment maintained fidaxomicin stool concentrations above the C. difficile MIC90 until Day 26 ± 1. Systemic exposure to fidaxomicin and OP-1118 was low throughout and there was no evidence of accumulation in plasma or stool during treatment.

Potentiation of Mivacurium Blockade by Low Dose of Pancuronium

2003 ◽  
Vol 98 (5) ◽  
pp. 1057-1062 ◽  
Author(s):  
Cyrus Motamed ◽  
Riad Menad ◽  
Robert Farinotti ◽  
Krassen Kirov ◽  
Xavier Combes ◽  
...  
Keyword(s):  
Acetylcholine Receptors ◽  
Low Dose ◽  
Cholinesterase Activity ◽  
Plasma Concentrations ◽  
Orotracheal Intubation ◽  
Plasma Cholinesterase ◽  
Neuromuscular Blocking ◽  
Pharmacokinetic Analysis ◽  
Plasma Cholinesterase Activity ◽  
Before And After

Background Mivacurium is potentiated by pancuronium to a much greater extent than other relaxants. In a previous investigation we suggested that this potentiation could be due to the ability of pancuronium to inhibit plasma cholinesterase activity, but we did not measure plasma concentrations of mivacurium. In the current study we performed a pharmacokinetic analysis by measuring the plasma concentration of mivacurium when preceded by administration of a low dose of pancuronium. Methods After induction of general anesthesia with propofol and fentanyl and orotracheal intubation, 10 patients (pancuronium-mivacurium group) received 15 microg/kg pancuronium followed 3 min later by 0.1 mg/kg mivacurium, whereas 10 other patients (mivacurium group) received saline followed by 0.13 mg/kg mivacurium 3 min later. Plasma cholinesterase activity was measured before and 3 and 30 min after pancuronium dosing in the pancuronium-mivacurium group and was measured before and after administration of saline in the mivacurium group. Arterial plasma concentrations of mivacurium and its metabolites were measured at 0.5, 1, 1.5, 2, 4, 10, 20, and 30 min after injection. Neuromuscular blockade was assessed by mechanomyography. Results Plasma cholinesterase activity decreased by 26% in the pancuronium-mivacurium group 3 min after injection of pancuronium (P < 0.01) and returned to baseline values 30 min later; however, no significant variation was observed in the mivacurium group. The clearances of the two most active isomers (Cis-Trans and Trans-Trans) were lower in the pancuronium-mivacurium group (17.6 +/- 5.1, 14.7 +/- 5.3 ml. min-1. kg-1, respectively) than in the mivacurium group (32.4 +/- 20.2, 24.8 +/- 13.5 ml. min-1. kg-1; P < 0.05). Conclusions A subparalyzing dose of pancuronium decreased plasma cholinesterase activity and the clearance of the two most active isomers of mivacurium. Pancuronium potentiates mivacurium more than other neuromuscular blocking agents because, in addition to its occupancy of postsynaptic acetylcholine receptors, it slows down the hydrolysis of mivacurium.

scholarly journals 1335. Safety and Pharmacokinetic Profile of PC786, a Novel Inhibitor of Respiratory Syncytial Virus L-protein Polymerase, in a Single and Multiple-Ascending Dose Study in Healthy Volunteer and Mild Asthmatics

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S407-S408
Author(s):  
Lindsey Cass ◽  
Amanda Davis ◽  
Alison Murray ◽  
Kathy Woodward ◽  
Kazuhiro Ito ◽  
...  
Keyword(s):  
Half Life ◽  
Board Member ◽  
Phase 1 ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Preclinical Studies ◽  
Laboratory Findings ◽  
L Protein ◽  
Syncytial Virus

Abstract Background RSV is the most common cause of bronchiolitis in infants and is responsible for severe respiratory infections in the elderly and immunocompromised populations. RSV replicates in the columnar epithelial cells of the proximal and distal airways which are accessible to inhaled therapies. PC786 is a potent non-nucleoside RSV L-protein polymerase inhibitor designed for inhaled delivery. In preclinical studies, PC786 exhibits prolonged lung tissue residence with minimal systemic exposure, thus limiting the potential for adverse systemic effects. Methods A phase 1 study was conducted to evaluate the safety and pharmacokinetics of PC786 delivered in a suspension formulation by nebulizer (PARI LC SPRINT® device). Healthy volunteers (HVs) received placebo or PC786 as single ascending doses (0.5–20 mg, Cohort (C) 1), 5 mg BD for 7 days (C2), or 10 mg BD for 7 days (C3). Mild asthmatics received a single dose of PC786 5 mg or placebo (C4). PC786 PK was measured in plasma and in nasal mucosal lining fluid (MLF) collected using a synthetic absorptive matrix. Results PC786 was well tolerated, with no significant adverse clinical nor laboratory findings. Following single inhaled doses PC786 appeared rapidly in the plasma; mean plasma Cmax of 190, 571, 1,760, and 3,270 pg/mL, for the 0.5, 2, 8, and 20 mg doses, respectively, were measured on average at 0.68 to 0.93 hours (Tmax) post-inhalation. Following administration of 5 mg BD (C2) the extent of accumulation was approximately 2-fold. The geometric mean apparent terminal half-life measured following 10 mg BD (C3) was 97 hours. The ratio of MLF:plasma concentrations ranged from 6,347 (+2 hours) to 1,050 (+24h). Conclusion PC786 was well tolerated by HVs and asthmatics. The compound showed a rapid Tmax, suggesting rapid exposure of the respiratory epithelium. The PC786 concentrations in MLF exceed the IC90 for RSV, but circulating plasma concentrations were low. The MLF:plasma measured in this study was consistent with lung:plasma ratios measured in preclinical studies. The long plasma half-life is consistent with slow absorption from the lung being the dominant process controlling systemic kinetic behavior. The long t½ and 2-fold accumulation ratio observed on repeat dosing supports once daily dosing in subsequent studies. Disclosures L. Cass, Pulmocide Ltd.: Employee and Shareholder, Salary. A. Davis, Pulmocide Ltd.: Employee and Shareholder, Salary. A. Murray, Pulmocide Ltd.: Employee and Shareholder, Salary. K. Woodward, Pulmocide Ltd.: Consultant, Consulting fee. K. Ito, Pulmocide Ltd.: Employee and Shareholder, Salary. P. Strong, Pulmocide Ltd.: Board Member, Employee and Shareholder, Salary. G. Rapeport, Pulmocide Ltd.: Board Member, Employee and Shareholder, Salary.

Outcomes of the miltuximab first in human trial and proposed study design for a phase I trial 89Zr/177Lu theranostic trial.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 261-261 ◽  
Author(s):  
Douglas Campbell ◽  
Dhanusha Sabanathan ◽  
Howard Gurney ◽  
David Gillatt ◽  
Marko Trifunovic ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Phase 1 ◽  
Standard Of Care ◽  
The Body ◽  
Whole Body ◽  
Chimeric Antibody ◽  
Pharmacokinetic Data ◽  
Post Dose ◽  
Before And After

261 Background: Miltuximab is a chimeric antibody targeting Glypican-1 which is overexpressed in prostate cancer. Miltuximab has shown promising safety and efficacy in radioimmunotherapy models of prostate cancer. Methods: Metastatic patients (prostate, pancreatic and bladder) were dosed with unlabelled Miltuximabfollowed by the infusion of 1 mg/250MBq 67Ga-Miltuximab. Patients underwent whole body gamma and SPECT/CT scans up to 144 hours post-infusion. Standard of care imaging was performed at least 14 days before and after participation. Safety was evaluated by an external monitoring committee. Total organ exposure was determined by dosimetry of whole-body gamma scans. Antibody pharmacokinetics were also determined. Results: 12 patients were enrolled into the trial. Miltuximabwas well tolerated and did not elicit any drug-related adverse reactions. Liver and spleen uptake of 67Ga-Miltuximabwas observed from 30 min to 72 hours post dose. Pre-infusion of unlabelled Miltuximab resulted in reduced liver accumulation and increased distribution in the rest of the body. Miltuximab targeting to sites of active progressive disease was observed in certain prostate cancer patients who had failed enzalutamide treatment. Dosimetry analysis combined with antibody pharmacokinetic data was used to establish safe dose limits for a Phase 1 study. Conclusions: This study is the first in human for Miltuximaband demonstrates its potential for further clinical evaluation as a theranostic in prostate cancers and formed the basis for a Phase I imaging and therapy study planned for 2019. This study will use 89Zr-labelled Miltuximab to screen eligible patients and confirm tumour localisation, followed by treatment with 177Lu-labelled Miltuximab. Clinical trial information: ACTRN12616000787482.

A phase I, dose-escalation study of ADG106, a fully human anti-CD137 agonistic antibody, in subjects with advanced solid tumors or relapsed/refractory non-Hodgkin lymphoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3105-3105 ◽  
Author(s):  
Li Zhang ◽  
Hongyun Zhao ◽  
Yuxiang Ma ◽  
Xin Zheng ◽  
Ji Jiang ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Systemic Exposure ◽  
Pharmacokinetic Analysis ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma ◽  
Expansion Cohort ◽  
Dose Levels

3105 Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody, targeting a unique epitope of CD137 with novel mechanism of actions for CD137 agonism, CD137 ligand antagonism and potent cross-linking via FcgRIIb. This phase 1 study was conducted to assess its safety, tolerability, pharmacokinetic (PK) profile, immunogenicity and preliminary efficacy. Methods: Eligible patients with age 18 to 75, ECOG ≤1, measurable lesion received intravenous infusion of ADG106 every 3 weeks for a maximum of 24 months. Accelerated titration was applied in 0.1mg/kg dose level and traditional Fibonacci 3+3 method was applied in 0.5, 1.5, 3.0, 5.0 and 10.0 mg/kg dose levels. A dose-expansion cohort will be started for dose levels that have been proved tolerable and with evidence of clinical or biological activity. Results: Data cutoff at Jan 17 2020, 15 patients [5 adenoid cystic carcinoma (ACC), 5 non-small cell lung cancer (NSCLC), 3 nasopharyngeal carcinoma, 1 malignant pleural mesothelioma and 1 follicular lymphoma] were enrolled and received treatment: 0.1mg/kg (n = 1), 0.5mg/kg (n = 3), 1.5mg/kg (n = 5), 3mg/kg (n = 3), and 5mg/kg (n = 3). Of these 15 patients, 6 with ongoing treatment, 9 discontinued (8 progression disease, 1 lack of clinical benefit). Medium treatment duration was 2 cycles (range 2-8). No dose limiting toxicities were observed. Seven (47%) patients experienced treatment-related AEs (TRAEs): rash (13%), pruritus (13%), nausea (7%), pyrexia (7%), hemoptysis (7%), mouth ulceration (7%), vomiting (7%), chest discomfort (7%), LDH increased (7%). All TRAEs were grade 1, no grade ≥3 occurred. One serious adverse event (anemia, not related) was observed. Pharmacokinetic analysis of ADG106 showed a half-life ranging from 5~10 days, with dose-dependent increase of systemic exposure. Treatment induced anti-drug antibodies were developed in 3 (20%) patients. No objective response was observed among the 14 evaluated patients. Disease control rate was 57% (8 stable disease), tumor shrinkage was observed in 3 (21%) patients (2 ACC, 1 NSCLC). Conclusions: ADG106 is safe and tolerable at doses up to 5 mg/kg in solid tumors and non-Hodgkin lymphoma. The dose expansion cohorts have started at selected doses. Clinical trial information: NCT03802955 .

Saturable pharmacokinetics and paclitaxel pharmacodynamics in children with solid tumors.

1994 ◽  
Vol 12 (3) ◽  
pp. 532-538 ◽  
Author(s):  
D S Sonnichsen ◽  
C A Hurwitz ◽  
C B Pratt ◽  
J J Shuster ◽  
M V Relling
Keyword(s):  
Solid Tumors ◽  
High Performance ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Compartment Model ◽  
Data Sets ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Time Curve ◽  
Elimination Clearance

PURPOSE Our aim was to evaluate the pharmacokinetics and pharmacodynamics of paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) in children, and to determine whether paclitaxel exhibited saturable pharmacokinetics. PATIENTS AND METHODS We evaluated the pharmacokinetics and pharmacodynamics of paclitaxel (200 to 420 mg/m2) administered as a 24-hour intravenous (i.v.) infusion in a phase 1 study of 30 pediatric patients (age, 2.3 to 22.8 years) with refractory solid tumors. Fourteen serial blood samples were obtained during and up to 48 hours after the infusion, and paclitaxel concentrations were measured by a high-performance liquid chromatography-UV (HPLC-UV) method. Four pharmacokinetic models were compared for their ability to describe the patients' data. RESULTS Paclitaxel disposition was not consistent with a first-order, two-compartment pharmacokinetic model. Rather, the majority of data sets were best described by a two-compartment model that incorporated both saturable tissue distribution and saturable elimination; a smaller number of patient data sets were best described by models that incorporated either saturable distribution or saturable elimination. Clearance was dose-dependent, with a median clearance at the lower dosages (< 400 mg/m2) of 161 mL/min/m2, and at the highest dosages (> 400 mg/m2) of 123 mL/min/m2 (P = .044). The duration that paclitaxel plasma concentrations exceeded 0.1 mumol/L was highly variable (range, 26 to 71 hours). There was a trend toward higher median area under the concentration-versus-time curve (AUC) in those children with musculoskeletal (72 mumol/L.h; P = .054) or neurologic toxicity (54 mumol/L.h; P = .062) versus those without toxicity (30 mumol/L.h). Toxicity was not significantly correlated with dosage. CONCLUSION We conclude that paclitaxel distribution and elimination are saturable, and that estimates of paclitaxel systemic exposure correlate better with toxicity than does dosage.

scholarly journals Plasma Concentrations of Boswellic Acids in Fasting Healthy Humans Supplemented with a Water-Soluble Boswellia Extract (78% AKBA) vs. Reference Boswellia Extract (30% AKBA) (P06-005-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Barbara Davis ◽  
Krishanu Sengupta ◽  
Venkata Krishnaraju Alluri ◽  
Trimurtulu Golakoti
Keyword(s):  
Plasma Concentrations ◽  
Water Soluble ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Oral Ingestion ◽  
Post Dose ◽  
Geometric Means ◽  
Funding Sources ◽  
Healthy Humans

Abstract Objectives A randomized, open label, balanced, two-way crossover study compared the oral bioavailability and pharmacokinetic profiles of two Boswellia products standardized to 3-O-acetyl-11-Keto-β-boswellic acid (AKBA). Methods Twenty-two fasted male participants completed the study. They received a single oral-dose of water-soluble Boswellia extract 78% (LI51202F1) or the standard Boswellia extract 30% (5-Loxin) at 30 mg AKBA equivalent with 240 mL water on 2 separate occasions 12 days apart. Plasma AKBA and KBA were analyzed using a LC-MS/MS in pre- (0 hr) and post-dose (00.50, 01.00, 01.50, 02.00, 02.50, 03.00, 04.00, 08.00, 12.00 and 24.00 hrs) blood samples. Pharmacokinetic analysis was performed using WinNonlin® version 7.0 (Pharsight corporation, USA). Results Comparative analysis of the pharmacokinetic parameters showed LI51202F1 had higher (111.11%) Cmax for AKBA vs. 5-Loxin. The bioavailability indicated by Geometric means of AUC0-t and AUC0-∞ were 25.49% and 16.13% higher in LI51202F1 than 5-Loxin. Conclusions The present study demonstrates that oral ingestion of water soluble and standard Boswellia extracts resulted in similar bioavailability. Interestingly, the water-soluble version exhibited higher Cmax and AUC values, which could be attributed to the improved solubility of LI51202F1. Funding Sources Laila Nutraceuticals.

scholarly journals Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

2016 ◽  
Vol 60 (3) ◽  
pp. 1830-1833 ◽  
Author(s):  
R. Brigg Turner ◽  
Aaron Cumpston ◽  
Michael Sweet ◽  
Frank Briggs ◽  
Douglas Slain ◽  
...  
Keyword(s):  
Body Weight ◽  
Single Dose ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Ideal Body Weight ◽  
Normal Weight ◽  
Controlled Study ◽  
Pharmacokinetic Analysis ◽  
Obese Patients ◽  
Time Curve

The current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normal-weight patients were enrolled, with mean body mass indexes of 45.0 and 22.5 kg/m2, respectively. Systemic clearance was substantially higher in the obese than normal-weight patients (mean, 19.4 ± 5.3 versus 14.3 ± 5.4 liters/h;P= 0.047). Area under the concentration-time curve was lower in the obese patients (15.2 ± 2.9 versus 24.0 ± 9.4 mg · h/liter;P= 0.011), as was maximum concentration (5.8 ± 0.9 versus 8.2 ± 1.3 mg/liter;P= 0.031). Utilization of IBW for dose calculation of i.v. acyclovir in obese patients leads to lower systemic exposure than dosing by TBW in normal-weight patients. While not directly evaluated in this study, utilization of an adjusted body weight for dose determination appears to more closely approximate the exposure seen in normal-weight patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01714180.)

scholarly journals Safety and Population Pharmacokinetic Analysis of Intravenous Acetaminophen in Neonates, Infants, Children, and Adolescents With Pain or Fever

2011 ◽  
Vol 16 (4) ◽  
pp. 246-261 ◽  
Author(s):  
Athena F. Zuppa ◽  
Gregory B. Hammer ◽  
Jeffrey S. Barrett ◽  
Brian F. Kenney ◽  
Nastya Kassir ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Age Groups ◽  
Rectal Administration ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Intravenous Acetaminophen

OBJECTIVES The administration of acetaminophen via the oral and rectal routes may be contraindicated in specific clinical settings. Intravenous administration provides an alternative route for fever reduction and analgesia. This phase 1 study of intravenous acetaminophen (Ofirmev, Cadence Pharmaceuticals, Inc., San Diego, CA) in inpatient pediatric patients with pain or fever requiring intravenous therapy was designed to assess the safety and pharmacokinetics of repeated doses over 48 hours. METHODS Neonates (full-term to 28 days) received either 12.5 mg/kg every 6 hours or 15 mg/kg every 8 hours. Infants (29 days to &lt;2 years), children (2 to &lt;12 years) and adolescents (≥12 years) received either 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours. Both noncompartmental and population nonlinear mixed-effects modeling approaches were used. Urinary metabolite data were analyzed, and safety and tolerability were assessed. RESULTS Pharmacokinetic parameters of acetaminophen were estimated using a two-compartment disposition model with weight allometrically expressed on clearances and central and peripheral volumes of distribution (Vds). Postnatal age, with a maturation function, was a significant covariate on clearance. Total systemic normalized clearance was 18.4 L/hr per 70 kg, with a plateau reached at approximately 2 years. Total central and peripheral Vds of acetaminophen were 16 and 59.5 L/70 kg, respectively. The drug was well tolerated based on the incidence of adverse events. The primary and minor pathways of elimination were acetaminophen glucuronidation, sulfation, and glutathione conjugate metabolites across all age groups. CONCLUSIONS Intravenous acetaminophen in infants, children, and adolescents was well tolerated and achieved plasma concentrations similar to those achieved with labeled 15 mg/kg body weight doses by oral or rectal administration.

The comparative arthropathy of fluoroquinolones in dogs

1999 ◽  
Vol 18 (6) ◽  
pp. 392-399 ◽  
Author(s):  
T Takizawa ◽  
K Hashimoto ◽  
T Minami ◽  
S Yamashita ◽  
K Owen
Keyword(s):  
Histopathological Examination ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Outer Wall ◽  
Joint Toxicity ◽  
Blister Formation ◽  
Joint Surfaces ◽  
Fluoroquinolone Antibiotics

1 Fluoroquinolone antibiotics are generally only prescribed to paediatric patients on compassionate grounds. This is because they are known to cause lesions in the cartilage of the major diarthroidal joints in immature experimental animals. As dogs are considered to be the most sensitive species, a series of studies was performed to compare the potential for grepafloxacin (a new fluoroquinolone) to cause arthropathy to that of ofloxacin and ciprofloxacin in juvenile (month old) beagles. 2 Grepafloxacin was administered once daily to male juvenile dogs at dosages of up to 100 mg/kg/day (intravenously), 60 mg/kg/day (orally) or 30 mg/kg/ day (subcutaneously) for 1 week. Blister formation was observed on the surface of the joints in one of the three animals treated with grepafloxacin intravenously at 100 mg/kg/day. No abnormalities were observed at lower dosages or when grepafloxacin was administered orally or subcutaneously, regardless of dose. In animals treated with ofloxacin or ciprofloxacin at dosages of 10-30 mg/kg/day, blister formation or erosion was observed on the surface of joints regardless of dose or route of administration. 3 Histopathological examination of the joint surfaces of affected animals revealed the loss of cartilaginous matrix and chondrocytes, cavitation within the intermediate zone of cartilage accompanied by cartilage fibrillation or chondrocyte clustering, or loss of the surface layer which covers the cavitation (or loss of outer wall of the cavity). These findings were not present in the absence of grossly observed lesions. 4 Absorption following oral administration of grepa-floxacin was low. Examination of plasma concentrations of drug following intravenous administration showed that joint toxicity was seen with ofloxacin and ciprofloxacin at maximum concentrations as low as 3.80 and 4.24 mg/l, respectively, while plasma levels of grepafloxacin of up to 11.95 mg/l failed to cause such lesions. When the concentration of grepafloxacin was 18.69 mg/l a single joint lesion was seen. Following subcutaneous administration of grepafloxacin, systemic exposure (area under the curve) of approximately 1.5 times that seen in man was not associated with joint lesions. However, lesions were noted for ofloxacin and ciprofloxacin treated animals at exposures equal to or below those seen in man. Therefore grepafloxacin appeared to have a relatively low potential for joint toxicity; this was not due to lack of penetration into the synovial fluid.

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