Antimalarial Bioavailability and Disposition of Artesunate in Acute Falciparum Malaria

ABSTRACT The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated Plasmodium falciparum malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimalarial agent in patients with acute malaria was 61% (95% confidence interval [CI], 52 to 70%). The absorption and elimination of oral artesunate were rapid, with a mean elimination half-life of antimalarial activity of 43 min (95% CI, 33 to 53 min). Following oral administration to patients with acute falciparum malaria, peak antimalarial activity in plasma and the area under the plasma concentration-time curve were approximately double those during convalescence and the apparent volume of distribution and clearance were approximately half those during convalescence (P ≤ 0.005). Acute malaria is associated with a significant reduction in the clearance of artesunate-associated antimalarial activity.

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PHARMACOKINETICS OF EN0XAPARIN AFTER SINGLE SUBCUTANEOUS ADMINISTRATION OF INCREASING DOSES (20 UP TO 80 MG) TO HEALTHY VOLUNTEERS

10.1055/s-0038-1643216 ◽

1987 ◽

Author(s):

L Bara ◽

Y Le Roux ◽

M Woler ◽

F Chauliac ◽

A Frydman ◽

...

Keyword(s):

Subcutaneous Administration ◽

Apparent Volume ◽

Volume Of Distribution ◽

Thrombin Time ◽

Mean Values ◽

Elimination Half ◽

Heparin Plasma ◽

The Mean ◽

The One ◽

Apparent Volume Of Distribution

The pharmacokinetics of enoxaparin (E) was randomly studied in 12 healthy male volunteers. Each dose (20-40-60 and 80 mg) was injected via subcutaneous (sc) route with a one-week wash out period. Anti-Xa and anti-IIa activities (ACT), calcium thrombin time (CTT) and Heptest were measured over a 36 hour period. E and the IV th International Heparin Standard were both used as internal standards.The anti IIa and CTT effects were only measurable when the injected dose was higher than 40 mg. The maximum anti-Xa and anti-IIa ACT were obtained 3 to 4 hours after the dose. As anti-IIa ACT is lower than anti-Xa ACT (anti-Xa/anti-IIa ACT ration I .6 to 2), the complete pharmacokinetic description of E was only based on anti-Xa data. Thus, the mean values of the maximal anti-Xa ACT (A max) were respectively: 1.58 ± 0.35 pg/ml; 3.83 ± 0.98 jig/ml, 5.38 ± 0.75 ug/ml and 7.44 ± 1.4 pg/ml for the four doses (20-40-60 and 80 mg). The resorption of E after sc injection was strictly linear whereas the relationships between A max or AUC in the one hand and dose in the other hand were A (anti Xa) Max = 0.0954 (dose) - 0,2083 r = 0.9146/p < 0.001; n = 48) and AUC (0 - 36 h) = 0.9117 (dose) - 7.59 (r = 0.9133/p < 0.001; n = 48). The mean residence time of E was close to 6 h (5.83 ± 0.86 h for D = 40 mg; 6.19 ± 0.74 h for D = 60 mg and 6.44 ± 0.76 h for 80 mg) indicating that around 50% of the total anti Xa ACT is induced in a 6 hour interval. The apparent volume of distribution V is close to 61 (6.59 1 ±1.33 1 for D = 60 mg) and the total Dody clearance is equal to 1.25 1/h, indicating the rate of depolymerisation of enoxaparin is lower than that of heparin. Plasma elimination half-life of anti-Xa ACT is equal to 4.36 ± 1.07 h (D = 40 mg) whereas that of anti-IIa ACT is shorter, fi) = 2.1 h). These results indicate that enoxaparin exhibits i) a differential anti-Xa/anti-IIa ACT profile, ii) a linear relationship between dose and anti-Xa/anti-IIa ACT and iii) a kinetic profile which is significantly different from that of standard heparin.

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Pharmacokinetics and Ex Vivo Pharmacodynamic Antimalarial Activity of Dihydroartemisinin-Piperaquine in Patients with Uncomplicated Falciparum Malaria in Vietnam

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01717-08 ◽

2009 ◽

Vol 53 (8) ◽

pp. 3534-3537 ◽

Cited By ~ 29

Author(s):

Dao Van Hoang Nguyen ◽

Quoc Phuc Nguyen ◽

Ngoa Dang Nguyen ◽

Thuy Thi Thanh Le ◽

The Duy Nguyen ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Body Weight ◽

Healthy Subjects ◽

Antimalarial Activity ◽

Ex Vivo ◽

Apparent Volume ◽

Volume Of Distribution ◽

Oral Clearance ◽

The Mean ◽

Apparent Volume Of Distribution

ABSTRACT Compared to healthy subjects, malaria patients show a reduction in the mean oral clearance (1.19 versus 5.87 liters/h/kg of body weight) and apparent volume of distribution (1.47 versus 8.02 liters/kg) of dihydroartemisinin in Vietnamese patients following treatment with dihydroartemisinin-piperaquine (Artekin) for uncomplicated Plasmodium falciparum. Dihydroartemisinin is responsible for most of the ex vivo antimalarial activity of dihydroartemisinin-piperaquine.

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Safety, toleration, and pharmacokinetics of intravenous azithromycin.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.11.2577 ◽

1996 ◽

Vol 40 (11) ◽

pp. 2577-2581 ◽

Cited By ~ 48

Author(s):

D R Luke ◽

G Foulds ◽

S F Cohen ◽

B Levy

Keyword(s):

Half Life ◽

Active Drug ◽

Slow Release ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Concentration Time ◽

Elimination Half ◽

The Mean ◽

Male Subjects

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.

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Resin Haemoperfusion in Levomepromazine Poisoning: Evaluation of Effect on Plasma Drug and Metabolite Levels

Human Toxicology ◽

10.1177/096032718400300604 ◽

1984 ◽

Vol 3 (6) ◽

pp. 497-503 ◽

Cited By ~ 6

Author(s):

P.-A. Hals ◽

D. Jacobsen

Keyword(s):

Blood Flow ◽

Plasma Levels ◽

Apparent Volume ◽

Volume Of Distribution ◽

The Body ◽

Metabolic Clearance ◽

Plasma Drug ◽

The Mean ◽

Apparent Volume Of Distribution

1 Plasma levels of levomepromazine and two of its major metabolites N-desmethyl-levomepromazine and levomepromazine sulphoxide were studied in two poisoned patients treated with resin haemoperfusion at a constant blood flow of 200 ml/min. 2 The mean haemoperfusion clearance of levomepromazine, N-desmethyl-levomepromazine and levomepromazine sulphoxide was 114, 123 and 151 ml/min, respectively, in patient no. 1, and 153, 148 and 184 ml/min, respectively, in patient no. 2. Patient no. 2 had also ingested amitriptyline, and the mean haemoperfusion clearance of amitriptyline and its metabolite nortriptyline was 183 and 183 ml/min respectively. 3 Haemoperfusion did not seem to alter the elimination profile of levomepromazine or the two metabolites in either patient. 4 We conclude that haemoperfusion is of little value in removing levomepromazine, N-desmethyl-levomepromazine or levomepromazine sulphoxide from the body. This is probably due to the large apparent volume of distribution and the high intrinsic hepatic metabolic clearance of these compounds.

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A Semimechanistic Pharmacokinetic-Enzyme Turnover Model for Rifampin Autoinduction in Adult Tuberculosis Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05792-11 ◽

2012 ◽

Vol 56 (4) ◽

pp. 2091-2098 ◽

Cited By ~ 49

Author(s):

Wynand Smythe ◽

Akash Khandelwal ◽

Corinne Merle ◽

Roxana Rustomjee ◽

Martin Gninafon ◽

...

Keyword(s):

Steady State ◽

Hiv Infection ◽

Selection Procedure ◽

Apparent Volume ◽

Volume Of Distribution ◽

Oral Clearance ◽

Time Curve ◽

Turnover Model ◽

Enzyme Turnover ◽

Apparent Volume Of Distribution

ABSTRACTThe currently recommended doses of rifampin are believed to be at the lower end of the dose-response curve. Rifampin induces its own metabolism, although the effect of dose on the extent of autoinduction is not known. This study aimed to investigate rifampin autoinduction using a semimechanistic pharmacokinetic-enzyme turnover model. Four different structural basic models were explored to assess whether different scaling methods affected the final covariate selection procedure. Covariates were selected by using a linearized approach. The final model included the allometric scaling of oral clearance and apparent volume of distribution. Although HIV infection was associated with a 30% increase in the apparent volume of distribution, simulations demonstrated that the effect of HIV on rifampin exposure was slight. Model-based simulations showed close-to-maximum induction achieved after 450-mg daily dosing, since negligible increases in oral clearance were observed following the 600-mg/day regimen. Thus, dosing above 600 mg/day is unlikely to result in higher magnitudes of autoinduction. In a typical 55-kg male without HIV infection, the oral clearance, which was 7.76 liters · h−1at the first dose, increased 1.82- and 1.85-fold at steady state after daily dosing with 450 and 600 mg, respectively. Corresponding reductions of 41 and 42%, respectively, in the area under the concentration-versus-time curve from 0 to 24 h were estimated. The turnover of the inducible process was estimated to have a half-life of approximately 8 days in a typical patient. Assuming 5 half-lives to steady state, this corresponds to a duration of approximately 40 days to reach the induced state for rifampin autoinduction.

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Individualization of Theophylline Dosage in Adults with Bronchial Asthma

Drug Intelligence & Clinical Pharmacy ◽

10.1177/106002808602000917 ◽

1986 ◽

Vol 20 (9) ◽

pp. 704-707 ◽

Cited By ~ 7

Author(s):

Maria J. Otero ◽

Miguel Barrueco ◽

Eduardo L. Marino ◽

Francisco Gomez ◽

Alfonso Dominguez-Gil

Keyword(s):

Elderly Patients ◽

Bronchial Asthma ◽

Total Body Clearance ◽

Apparent Volume ◽

Volume Of Distribution ◽

Dosage Regimens ◽

Elimination Half ◽

Total Body ◽

Apparent Volume Of Distribution ◽

Body Clearance

The influence of age on the disposition of theophylline was studied in 95 adult patients (nonsmokers) with bronchial asthma requiring oral theophylline therapy: 17 patients age ≥39 years, 50 patients age 40–59 years, and 28 patients < 60 years. A decrease was observed in total body clearance together with an increase in the elimination half-life of theophylline parallel to the advance in age of the patients. The apparent volume of distribution of theophylline was similar in the three groups of patients. According to the results obtained, recommendations are made regarding the dosage regimens of theophylline in elderly patients.

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Phase I Study To Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00464-18 ◽

2018 ◽

Vol 62 (8) ◽

Cited By ~ 9

Author(s):

Eric Wenzler ◽

Susan C. Bleasdale ◽

Monica Sikka ◽

Kristen L. Bunnell ◽

Matthew Finnemeyer ◽

...

Keyword(s):

Phase I ◽

Healthy Adult ◽

Apparent Volume ◽

Volume Of Distribution ◽

Open Label ◽

Time Curve ◽

Elimination Half ◽

Apparent Clearance ◽

Dosing Regimens ◽

Repeated Dosing

ABSTRACTThe pharmacokinetics (PK), safety, and tolerability of two repeated dosing regimens of oral fosfomycin tromethamine were evaluated in 18 healthy adult subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses, or vice versa, in a phase I, randomized, open-label, two-period-crossover study. Serial blood (n= 11) and urine (n= 4 collection intervals) samples were collected before and up to 24 h after dosing on days 1 and 5, along with predose concentrations on days 3 and 7. PK parameters were similar between days 1 and 5 within and between dosing regimens. The mean (± standard deviation [SD]) PK parameters for fosfomycin in plasma on day 5 during the respective QOD and QD dosing regimens were as follows: maximum concentration of drug in serum (Cmax) = 24.4 ± 6.2 versus 23.8 ± 5.6 μg/ml, time toCmax(Tmax) = 2.2 ± 0.7 versus 2.0 ± 0.4 h, apparent volume of distribution (V/F) = 141 ± 67.9 versus 147 ± 67.6 liters, apparent clearance (CL/F) = 21.4 ± 8.0 versus 20.4 ± 5.3 liters/h, renal clearance (CLR) = 7.5 ± 4.1 versus 7.3 ± 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0–24) = 151.6 ± 35.6 versus 156.6 ± 42.5 μg · h/ml, and elimination half-life (t1/2) = 4.5 ± 1.1 versus 5.0 ± 1.7 h. Urine concentrations peaked at approximately 600 μg/ml through the 0- to 8-h urine collection intervals but displayed significant interindividual variability. Roughly 35 to 40% of the 3-g dose was excreted in the urine by 24 h postdose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower with the QD regimen than with the QOD regimen (61% versus 77%;P< 0.0001). Further studies to establish the clinical benefit/risk ratio for repeated dosing regimens of oral fosfomycin tromethamine are warranted. (This trial is registered at ClinicalTrials.gov under registration no. NCT02570074.)

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Pharmacokinetics of Marbofloxacin Following Oral Administration in Piperine, Quercetin Alone and Both in Combination Pretreated Broiler Chickens

Indian Journal of Animal Research ◽

10.18805/ijar.b-4300 ◽

2021 ◽

Author(s):

H.B. Patel ◽

U.D. Patel ◽

C.M. Modi ◽

V.C. Ladumor ◽

C.N. Makwana ◽

...

Keyword(s):

Oral Administration ◽

Broiler Chickens ◽

High Performance ◽

Apparent Volume ◽

Volume Of Distribution ◽

Metabolizing Enzymes ◽

Single Oral Administration ◽

Elimination Half ◽

Combined Pretreatment ◽

Apparent Volume Of Distribution

Background: Various antibacterial drugs are substrates for drug metabolizing enzymes. They suffer from reduced bioavailability after oral administration in chickens. Herbal bio-enhancers increased the absorption of co-administered drugs. Hence, present study was planned to explore the bio-enhancing effect of piperine and quercetin pretreatment on pharmacokinetics of marbofloxacin after oral administration in broiler chickens.Methods: The pharmacokinetics of marbofloxacin was investigated following single dose (5 mg/kg) oral administration in piperine, quercetin alone and both in combination pretreated (10 mg/kg each, oral, 3 days) broiler chickens. The concentrations of marbofloxacin in plasma samples were analyzed by high performance liquid chromatography.Result: Following single oral administration of marbofloxacin, elimination half-lives (t1/2β) were 6.23 ± 1.01, 5.69 ± 0.39 and 7.71 ± 0.59 h in piperine, quercetin and both in combination pretreated chickens, respectively. The elimination half-life (t1/2β), apparent volume of distribution (Vd(area)/F) and mean residence time (MRT) were significantly (p less than 0.05) higher in combination pretreated chickens as compared to piperine and quercetin alone groups. Piperine and quercetin combined pretreatment has improved the pharmacokinetics profile of marbofloxacin after oral administration in broiler chickens. Findings of the study are expedient for the development of protocol for use of bio-enhancers with antibiotics in broiler chickens.

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The Pharmacokinetics of Buserelin after Intramuscular Administration in Pigs and Cows

10.21203/rs.3.rs-900328/v1 ◽

2021 ◽

Author(s):

Zhengrong Gao ◽

Yu Liu ◽

Yuxin Yang ◽

Yuying Cao ◽

Jicheng Qiu ◽

...

Keyword(s):

Area Under The Curve ◽

Apparent Volume ◽

Ultra Performance Liquid Chromatography ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Elimination Half ◽

Liquid Chromatography Tandem Mass ◽

Stability Method ◽

Apparent Volume Of Distribution

Abstract Background: Buserelin is a LHRH agonist used for the treatment of hormone-dependent diseases in males and females. However, the pharmacokinetics of buserelin in pigs and cows are not clearly understood. This study was designed to develop a sensitive method to determine the concentration of buserelin and to investigate the pharmacokinetic parameters after intramuscular (i.m.) administration in pigs and cows. Results: A sensitive and rapid stability method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed. The pharmacokinetic parameters of buserelin after i.m. administration were studies in five pigs and five cows at a single dose of 1 mg per pig and 3 mg per cow. The plasma kinetics were analyzed by WinNonlin 8.1.0 software using a non-compartmental model. The mean concentration area under the curve (AUC0-t) was 25.02 ± 6.93 h·ng/mL for pigs and 5.63 ±1.86 h·ng/mL for cows. The maximum plasma concentration (Cmax) and time to reach the maximum concentration (tmax) were 10.99 ± 2.04 ng/mL and 0.57 ± 0.18 h for pigs and 2.68 ± 0.36 ng/mL and 1.05 ±0.27 h for cows, respectively. The apparent volume of distribution (Vz) in pigs and cows was 80.49 ± 43.88 L and 839.88 ± 174.77 L, respectively. The elimination half-time (t1/2λz), and clearance (CL) were 1.29 ± 0.40 h and 41.15 ± 11.18 L/h for pigs and 1.13 ± 0.3 h and 545.04 ± 166.40 L/h for cows, respectively. No adverse effects were observed in any of the animals. Conclusion: This study extends previous studies describing the pharmacokinetics of buserelin following i.m. administration in pigs and cows. Further studies investigating other factors were needed to establish therapeutic protocol in pigs and cows and to extrapolate these parameters to others economic animals.

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Pharmacokinetics of Dirithromycin in Patients with Mild or Moderate Cirrhosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.7.1556 ◽

1999 ◽

Vol 43 (7) ◽

pp. 1556-1559 ◽

Cited By ~ 6

Author(s):

Teresita Mazzei ◽

Calogero Surrenti ◽

Andrea Novelli ◽

Maria Rosa Biagini ◽

Stefania Fallani ◽

...

Keyword(s):

Healthy Volunteers ◽

Volume Of Distribution ◽

Time Curve ◽

Class A ◽

Elimination Half ◽

Class B ◽

Child's Classification ◽

Cirrhotic Patients ◽

The Mean ◽

Limited Basis

ABSTRACT The pharmacokinetics of dirithromycin were determined over a 72-h period following oral administration of a single 500-mg dose to 8 healthy volunteers and to 16 cirrhotic patients (8 patients with class A cirrhosis and 8 patients with class B cirrhosis according to Pugh’s & Child’s classification). Drug levels in plasma and urine were determined by microbiological assay. The mean maximum concentrations of drug in serum obtained 3 to 4 h after administration were 0.29 ± 0.22 mg/liter in volunteers and 0.48 ± 0.21 and 0.52 ± 0.38 mg/liter in patients with class A and class B cirrhosis, respectively. The elimination half-life (t 1/2β) was 23.3 ± 7.6 h in healthy subjects and 35.2 ± 11.8 h and 39.5 ± 11.0 h in patients with class A and class B cirrhosis, respectively. The mean area under the concentration-time curve (AUC) and t 1/2β were significantly higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced (P < 0.01). The time to the maximum concentration of drug in serum and the volume of distribution values appeared to be similar in all groups, and the mean recovery in urine at 72 h ranged from 3.7 to 5.7%, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, an increase in the t 1/2β or AUC, which is also observed with other semisynthetic macrolides (e.g., azithromycin), does seem to be not clinically relevant if one takes into account both the high therapeutic indices of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.

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