Pharmacokinetics and tolerance of a new penem antibiotic, FCE 22101, in healthy volunteers after a single intravenous dose

ABSTRACTHospitalized patients with severe influenza are at significant risk for morbidity and mortality. MHAA4549A is a human monoclonal immunoglobulin (Ig) G1 antibody that binds to a highly conserved stalk region of the influenza A virus hemagglutinin protein and neutralizes all tested seasonal human influenza A virus strains. Two phase 1 trials examined the safety, tolerability, and pharmacokinetics of MHAA4549A in healthy volunteers. Both single ascending-dose trials were randomized, double blinded, and placebo controlled. Trial 1 randomized 21 healthy adults into four cohorts receiving a single intravenous dose of 1.5, 5, 15, or 45 mg/kg MHAA4549A or placebo. Trial 2 randomized 14 healthy adults into two cohorts receiving a single intravenous fixed dose of 8,400 mg or 10,800 mg of MHAA4549A or placebo. Subjects were followed for 120 days after dosing. No subject was discontinued in either trial, and no serious adverse events were reported. The most common adverse event in both studies was mild headache (trial 1, 4/16 subjects receiving MHAA4549A and 1/5 receiving placebo; trial 2, 4/8 subjects receiving MHAA4549A and 2/6 receiving placebo). MHAA4549A produced no relevant time- or dose-related changes in laboratory values or vital signs compared to those with placebo. No subjects developed an antitherapeutic antibody response following MHAA4549A administration. MHAA4549A showed linear serum pharmacokinetics, with a mean half-life of 22.5 to 23.7 days. MHAA4549A is safe and well tolerated in healthy volunteers up to a single intravenous dose of 10,800 mg and demonstrates linear serum pharmacokinetics consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (These trials have been registered at ClinicalTrials.gov under registration no. NCT01877785 and NCT02284607).

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Cytopathology of Cardiac Tissue from Daunomycin-Treated Mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100066802 ◽

1971 ◽

Vol 29 ◽

pp. 550-551

Author(s):

Robert H. Liss ◽

Frances A. Cotton

Keyword(s):

Cardiac Tissue ◽

Cardiac Toxicity ◽

Drug Distribution ◽

Personal Communication ◽

Intravenous Dose ◽

Single Intravenous Dose ◽

Physiologic Saline ◽

Histopathologic Changes ◽

Distribution Studies ◽

Lung And Kidney

Daunomycin, an antibiotic used in the clinical management of acute leukemia, produces a delayed, lethal cardiac toxicity. The lethality is dose and schedule dependent; histopathologic changes induced by the drug have been described in heart, lung, and kidney from hamsters in both single and multiple dose studies. Mice given a single intravenous dose of daunomycin (10 mg/kg) die 6-7 days later. Drug distribution studies indicate that the rodents excrete most of a single dose of the drug as daunomycin and metabolite within 48 hours after dosage (M. A. Asbell, personal communication).Myocardium from the ventricles of 6 moribund BDF1 mice which had received a single intravenous dose of daunomycin (10 mg/kg), and from controls dosed with physiologic saline, was fixed in glutaraldehyde and prepared for electron microscopy.

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A Single Intravenous Dose of E3112 in Japanese Healthy Adult Male Participants

Case Medical Research ◽

10.31525/ct1-nct03922633 ◽

2019 ◽

Author(s):

Keyword(s):

Adult Male ◽

Healthy Adult ◽

Intravenous Dose ◽

Single Intravenous Dose ◽

Healthy Adult Male

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Effect of polyaspartic acid on pharmacokinetics of gentamicin after single intravenous dose in the dog.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.5.1237 ◽

1996 ◽

Vol 40 (5) ◽

pp. 1237-1241 ◽

Cited By ~ 8

Author(s):

T Whittem ◽

K Parton ◽

K Turner

Keyword(s):

Aspartic Acid ◽

Elimination Rate ◽

Volume Of Distribution ◽

Intravenous Dose ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Peripheral Compartment ◽

Single Intravenous Dose ◽

Polyaspartic Acid ◽

Peripheral Tissues

The effects of poly-L-aspartic acid on the pharmacokinetics of gentamicin were examined by using a randomized crossover trial design with the dog. When analyzed according to a three-compartment open model, poly-L-aspartic acid reduced some first-order rate equation constants (A3, lambda 1, and lambda 3), the deep peripheral compartment exit microconstant (k31), the elimination rate constant (k(el)), and the area under the concentration-time curve from 0 to 480 h (AUC0-480) (0.21-, 0.60-, 0.26-, 0.27-, 0.72-, and 0.76-fold, respectively; P < 0.05) but increased the volume of distribution at steady state (Vss), the volume of distribution calculated by the area method (V(area)), the apparent volume of the peripheral compartment (Vp), and all mean time parameters. These results suggested that poly-L-aspartic acid increased the distribution of gentamicin to or binding within the deep peripheral compartment and that poly-L-aspartic acid may have delayed gentamicin transit through the peripheral tissues. In contrast, poly-L-aspartic acid did not alter pharmacokinetic parameters relevant to the central or shallow peripheral compartments to a clinically significant extent. Although gentamicin's pharmacokinetic parameters of relevance to therapeutic drug monitoring were not directly altered, this study has provided pharmacokinetic evidence that poly-L-aspartic acid alters the peripheral distribution of gentamicin. This pharmacokinetic interaction occurred after a single intravenous dose of each drug. Therefore, this interaction should be investigated further, before polyaspartic acid can be considered for use as a clinical nephroprotectant.

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Letters to the Editor

PEDIATRICS ◽

10.1542/peds.68.4.601 ◽

1981 ◽

Vol 68 (4) ◽

pp. 601-602

Author(s):

M. Spino ◽

J. J. Thiessen ◽

A. Isles ◽

H. Levison ◽

S. M. MacLeod

Keyword(s):

Clinical Application ◽

Drug Concentration ◽

Apparent Volume ◽

Volume Of Distribution ◽

Intravenous Dose ◽

Single Intravenous Dose ◽

Letters To The Editor ◽

Potential Clinical Application ◽

Apparent Volume Of Distribution

We found the report by Feldman et al1 interesting with potential clinical application. However, we would like to point out an error in their determination of the apparent volume of distribution (V) and comment on both their methodology and results. They state that V was calculated by dividing the dose of the drug by the extrapolated y intercept for drug concentration at time 0. This method is correct for a drug which exhibits monoexponential elimination following a single intravenous dose.

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A double-blind trial of a single intravenous dose of metronidazole as prophylaxis against wound infection following appendicectomy

British Journal of Surgery ◽

10.1002/bjs.1800660617 ◽

1979 ◽

Vol 66 (6) ◽

pp. 428-429 ◽

Cited By ~ 36

Author(s):

M. J. Greenall ◽

A. Bakran ◽

I. R. Pickford ◽

J. A. Bradley ◽

A. Halsall ◽

...

Keyword(s):

Wound Infection ◽

Intravenous Dose ◽

Double Blind Trial ◽

Single Intravenous Dose ◽

Double Blind ◽

Blind Trial

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Pharmacokinetics of Intermittent Intravenous Cefazolin and Tobramycin in Patients Treated with Automated Peritoneal Dialysis

Journal of the American Society of Nephrology ◽

10.1681/asn.v1171310 ◽

2000 ◽

Vol 11 (7) ◽

pp. 1310-1316

Author(s):

HAROLD J. MANLEY ◽

GEORGE R. BAILIE ◽

REGINALD FRYE ◽

LORRAINE D. HESS ◽

M. DONALD MCGOLDRICK

Keyword(s):

Peritoneal Dialysis ◽

Intravenous Administration ◽

Intraperitoneal Administration ◽

Intravenous Dose ◽

Urine Samples ◽

Pharmacokinetic Parameters ◽

Single Intravenous Dose ◽

Automated Peritoneal Dialysis ◽

Minimum Inhibitory Concentrations ◽

Monoexponential Model

Abstract. There is increasing use of intermittent dosing of antibiotics to treat peritoneal dialysis (PD)-related peritonitis. The disposition of intravenous cefazolin and tobramycin was studied in automated PD (APD) patients. Ten patients were recruited and received a single intravenous dose of cefazolin (15 mg/kg) and tobramycin (0.6 mg/kg). Blood and dialysate samples were collected at the beginning, middle, and end of dwells 1 to 3 (on cycler), and at the end of dwells 4 to 5 (off cycler) for a 24-h period. Baseline and 24-h urine samples were collected. Pharmacokinetic parameters were calculated using a monoexponential model. Cefazolin and tobramycin half-lives were markedly different on cycler than off cycler (cefazolin on cycler : 10.67 ± 4.66 h ; cefazolin off cycler : 23.09 ± 5.6 h ; P = 0.001 ; tobramycin on cycler : 14.27 ± 4.53 h ; tobramycin off cycler : 68.5 ± 26.47 h ; P < 0.001). Mean serum and dialysate concentrations were above minimum inhibitory concentrations of susceptible organisms throughout the 24-h period for both drugs with intravenous administration. A model was developed to examine serum and dialysate concentrations after intermittent intraperitoneal administration of 15 mg/kg cefazolin and 0.6 mg/kg tobramycin. Model-predicted intraperitoneal cefazolin provides adequate serum and dialysate concentrations for 24 h. Intermittent intraperitoneal tobramycin doses must be 1.5 mg/kg for one exchange during the first day and then given as 0.5 mg/kg thereafter. It is concluded that the current empiric dosing recommendations for PD-related peritonitis may be adequate for cefazolin (15 to 20 mg/kg) ; however, tobramycin doses must be changed to 1.5 mg/kg intraperitoneally on day 1, then to 0.5 mg/kg intraperitoneally thereafter in APD patients.

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