scholarly journals Pharmacokinetics of Chloroquine and Monodesethylchloroquine in Pregnancy

2010 ◽  
Vol 54 (3) ◽  
pp. 1186-1192 ◽  
Author(s):  
Harin A. Karunajeewa ◽  
Sam Salman ◽  
Ivo Mueller ◽  
Francisca Baiwog ◽  
Servina Gomorrai ◽  
...  
Keyword(s):  
High Performance ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Presumptive Treatment ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Elimination Half ◽  
Intermittent Presumptive Treatment ◽  
Papua New Guinean ◽  
In Pregnancy

ABSTRACT In order to determine the pharmacokinetic disposition of chloroquine (CQ) and its active metabolite, desethylchloroquine (DECQ), when administered as intermittent presumptive treatment in pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were administered three daily doses of 450 mg CQ (8.5 mg/kg of body weight/day) in addition to a single dose of sulfadoxine-pyrimethamine. For all women, blood was taken at baseline; at 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h posttreatment; and at 7, 10, 14, 28, and 42 days posttreatment. Plasma was subsequently assayed for CQ and DECQ by high-performance liquid chromatography, and population pharmacokinetic modeling was performed. Pregnant subjects had significantly lower area under the plasma concentration-time curve for both CQ (35,750 versus 47,892 μg·h/liter, P < 0.001) and DECQ (23,073 versus 41,584 μg·h/liter, P < 0.001), reflecting significant differences in elimination half-lives and in volumes of distribution and clearances relative to bioavailability. Reduced plasma concentrations of both CQ and DECQ could compromise both curative efficacy and posttreatment prophylactic properties in pregnant patients. Higher IPTp CQ doses may be desirable but could increase the risk of adverse hemodynamic effects.

scholarly journals Pharmacokinetic Properties of Sulfadoxine-Pyrimethamine in Pregnant Women

2009 ◽  
Vol 53 (10) ◽  
pp. 4368-4376 ◽  
Author(s):  
Harin A. Karunajeewa ◽  
Sam Salman ◽  
Ivo Mueller ◽  
Francisca Baiwog ◽  
Servina Gomorrai ◽  
...  
Keyword(s):  
High Performance ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Third Trimester ◽  
Presumptive Treatment ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Pharmacokinetic Properties ◽  
Intermittent Presumptive Treatment ◽  
Papua New Guinean

ABSTRACT To determine the pharmacokinetic disposition of sulfadoxine (SDOX) and pyrimethamine (PYR) when administered as intermittent presumptive treatment during pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were given a single dose of 1,500 mg of SDOX plus 75 mg of pyrimethamine PYR. Blood was taken at baseline and 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h and at 7, 10, 14, 28, and 42 days posttreatment in all women. Plasma samples were assayed for SDOX, N-acetylsulfadoxine (NASDOX), and PYR by high-performance liquid chromatography. Population pharmacokinetic modeling was performed using NONMEM v6.2.0. Separate user-defined mamillary models were fitted to SDOX/NASDOX and PYR. When the covariate pregnancy was applied to clearance, there was a significant improvement in the base model for both treatments. Pregnancy was associated with a significantly lower area under the concentration-time curve from 0 to ∞ for SDOX (22,315 versus 33,284 mg·h/liter), NASDOX (801 versus 1,590 mg·h/liter), and PYR (72,115 versus 106,065 μg·h/liter; P < 0.001 in each case). Because lower plasma concentrations of SDOX and PYR could compromise both curative efficacy and posttreatment prophylaxis in pregnant patients, IPTp regimens incorporating higher mg/kg doses than those recommended for nonpregnant patients should be considered.

scholarly journals Pharmacokinetic Properties of Azithromycin in Pregnancy

2009 ◽  
Vol 54 (1) ◽  
pp. 360-366 ◽  
Author(s):  
Sam Salman ◽  
Stephen J. Rogerson ◽  
Kay Kose ◽  
Susan Griffin ◽  
Servina Gomorai ◽  
...  
Keyword(s):  
High Performance ◽  
Antimalarial Activity ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Central Compartment ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Pharmacokinetic Properties ◽  
In Pregnancy

ABSTRACT Azithromycin (AZI) is an azalide antibiotic with antimalarial activity that is considered safe in pregnancy. To assess its pharmacokinetic properties when administered as intermittent preventive treatment in pregnancy (IPTp), two 2-g doses were given 24 h apart to 31 pregnant and 29 age-matched nonpregnant Papua New Guinean women. All subjects also received single-dose sulfadoxine-pyrimethamine (SP) (1,500 mg or 75 mg) or chloroquine (450-mg base daily for 3 days). Blood samples were taken at 0, 1, 2, 3, 6, 12, 24, 32, 40, 48, and 72 h and on days 4, 5, 7, 10, and 14 for AZI assay by ultra-high-performance liquid chromatography-tandem mass spectrometry. The treatments were well tolerated. Using population pharmacokinetic modeling, a three-compartment model with zero-order followed by first-order absorption and no lag time provided the best fit. The areas under the plasma concentration-time curve (AUC0-∞) (28.7 and 31.8 mg·h liter−1 for pregnant and nonpregnant subjects, respectively) were consistent with the results of previous studies, but the estimated terminal elimination half-lives (78 and 77 h, respectively) were generally longer. The only significant relationship for a range of potential covariates, including malarial parasitemia, was with pregnancy, which accounted for an 86% increase in the volume of distribution of the central compartment relative to bioavailability without a significant change in the AUC0-∞. These data suggest that AZI can be combined with compounds with longer half-lives, such as SP, in combination IPTp without the need for dose adjustment.

scholarly journals Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide.

1997 ◽  
Vol 41 (12) ◽  
pp. 2670-2679 ◽  
Author(s):  
C A Peloquin ◽  
G S Jaresko ◽  
C L Yong ◽  
A C Keung ◽  
A E Bulpitt ◽  
...  
Keyword(s):  
Expectation Maximization ◽  
High Performance ◽  
Posteriori Probability ◽  
Maximum A Posteriori ◽  
Population Pharmacokinetic ◽  
A Posteriori ◽  
Population Pharmacokinetic Modeling ◽  
A Posteriori Probability ◽  
Modeling Methods ◽  
Elimination Half

Isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) are the most important drugs for the treatment of tuberculosis (TB). The pharmacokinetics of all three drugs in the plasma of 24 healthy males were studied as part of a randomized cross-over phase I study of two dosage forms. Subjects ingested single doses of INH at 250 mg, RIF at 600 mg, and PZA at 1,500 mg. Plasma was collected for 36 h and was assayed by high-performance liquid chromatography. The data were analyzed by noncompartmental, iterative two-stage maximum a posteriori probability Bayesian (IT2B) and nonparametric expectation maximization (NPEM) population modeling methods. Fast and slow acetylators of INH had median peak concentrations in plasma (C[max]) of 2.44 and 3.64 microg/ml, respectively, both of which occurred at 1.0 h postdose (time of maximum concentrations of drugs in plasma [T(max)]), with median elimination half-lives (t1/2) of 1.2 and 3.3 h, respectively (by the NPEM method). RIF produced a median C(max) of 11.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 3.4 h. PZA produced a median C(max) of 28.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 10.0 h. The pharmacokinetic behaviors of INH, RIF, and PZA were well described by the three methods used. These models can serve as benchmarks for comparison with models for other populations, such as patients with TB or TB with AIDS.

scholarly journals Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Bruna G. S. Torres ◽  
Victória E. Helfer ◽  
Priscila M. Bernardes ◽  
Alexandre José Macedo ◽  
Elisabet I. Nielsen ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Tissue Concentration ◽  
Plasma Concentrations ◽  
Central Compartment ◽  
Population Pharmacokinetic ◽  
Plasma Exposure ◽  
Time Curve ◽  
Content Type ◽  
Population Pharmacokinetic Modeling ◽  
Free Interstitial

ABSTRACT Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 ± 12.1 μg · h/ml and 13.3 ± 3.5 μg · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor = 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CLlung) was added to the model for these animals (CLlung = 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.

scholarly journals Influences of tolfenamic acid and flunixin meglumine on the disposition kinetics of levofloxacin in sheep

2020 ◽  
Vol 68 (1) ◽  
pp. 65-70 ◽  
Author(s):  
Duygu Durna Corum ◽  
Orhan Corum ◽  
Ramazan Yildiz ◽  
Hatice Eser Faki ◽  
Merve Ider ◽  
...  
Keyword(s):  
Half Life ◽  
High Performance ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Tolfenamic Acid ◽  
Time Curve ◽  
Inflammatory Conditions ◽  
Flunixin Meglumine ◽  
Model Following ◽  
Elimination Half

AbstractThe pharmacokinetics of levofloxacin (4 mg/kg), administered both alone and in combination with tolfenamic acid (2 mg/kg) and flunixin meglumine (2.2 mg/kg), was established after intravenous administration in sheep. Plasma levofloxacin concentrations were assayed by high-performance liquid chromatography and analysed according to the two-compartment open model. Following the administration of levofloxacin alone, the mean distribution half-life, elimination half-life, total clearance, volume of distribution at steady state and area under the plasma concentration–time curve were 0.20 h, 1.82 h, 0.39 L/h/kg, 0.96 L/kg and 10.40 h × µg/mL, respectively. Tolfenamic acid and flunixin meglumine caused a slow elimination and increased plasma concentrations of levofloxacin in combination administration. Levofloxacin, with an alteration in the dosage regimen, can be used effectively with tolfenamic acid and flunixin meglumine for the therapy of infections and inflammatory conditions in sheep.

Pharmacokinetics and bioequivalence of etoposide following intravenous administration of etoposide phosphate and etoposide in patients with solid tumors.

1995 ◽  
Vol 13 (11) ◽  
pp. 2835-2841 ◽  
Author(s):  
S Kaul ◽  
L N Igwemezie ◽  
D J Stewart ◽  
S Z Fields ◽  
M Kosty ◽  
...  
Keyword(s):  
Confidence Interval ◽  
High Performance ◽  
Plasma Concentrations ◽  
Systemic Circulation ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Etoposide Phosphate ◽  
Elimination Half ◽  
Constant Rate

PURPOSE To assess the pharmacokinetics and bioequivalence of etoposide following intravenous (i.v.) administration of etoposide phosphate (Etopophos; Bristol-Myers Squibb, Princeton, NJ), a prodrug of etoposide, and VePesid (Bristol-Myers Squibb). PATIENTS AND METHODS Forty-nine solid tumor patients were randomized to receive Etopophos or VePesid on day 1 of a day-1,3,5 schedule of treatment. The alternate drug was given on day 3 and repeated on day 5. The dose, 150 mg/m2 of etoposide equivalent, was administered by constant rate infusion over 3.5 hours. The plasma concentrations of etoposide phosphate and etoposide were determined using validated high-performance liquid chromatography (HPLC) assays. Pharmacokinetic parameters were calculated by a noncompartmental method. Etopophos was considered to be bioequivalent to VePesid if the 90% confidence limits for the differences in mean maximum concentration (Cmax) and AUCinf of etoposide were contained within 80% to 125% for the long-transformed data. RESULTS Forty-one patients were assessable for pharmacokinetics and bioequivalence assessment. Following i.v. administration, etoposide phosphate was rapidly and extensively converted to etoposide in systemic circulation, resulting in insufficient data to estimate its pharmacokinetics. The mean bioavailability of etoposide from Etopophos, relative to VePesid, was 103% (90% confidence interval, 99% to 106%) based on Cmax, and 107% (90 confidence interval, 105% to 110%) based on area under the concentration versus time curve from zero to infinity (AUCinf) values. Mean terminal elimination half-life (t1/2), steady-state volume of distribution (Vss), and total systemic clearance (CL) values of etoposide were approximately 7 hours, 7 L/m2, and 17 mL/min/m2 after Etopophos and VePesid treatments, respectively. The main toxicity observed was myelosuppression, characterized by leukopenia and neutropenia. CONCLUSION With respect to plasma levels of etoposide, i.v. Etopophos is bioequivalent to i.v. VePesid.

scholarly journals Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

2012 ◽  
Vol 56 (10) ◽  
pp. 5076-5081 ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
J. Gordon Still ◽  
Kay Clark ◽  
Prabhavathi Fernandes
Keyword(s):  
Steady State ◽  
High Performance ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Drug Concentrations ◽  
The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

scholarly journals Pharmacokinetics of Doxycycline in Adults with Cystic Fibrosis

2011 ◽  
Vol 56 (1) ◽  
pp. 70-74 ◽  
Author(s):  
Paul M. Beringer ◽  
Heather Owens ◽  
Albert Nguyen ◽  
Debbie Benitez ◽  
Adupa Rao ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Oral Administration ◽  
Maximum Concentration ◽  
Airway Remodeling ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Time Curve ◽  
Elimination Half ◽  
Dose Oral

ABSTRACTCystic fibrosis (CF) is characterized by a chronic neutrophilic inflammatory response resulting in airway remodeling and progressive loss of lung function. Doxycycline is a tetracycline antibiotic that inhibits matrix metalloproteinase 9, a protease known to be associated with the severity of lung disease in CF. The pharmacokinetics of doxycycline was investigated during the course of a clinical trial to evaluate the short-term efficacy and safety in adults with CF. Plasma samples were obtained from 14 patients following a single intravenous dose and after 2 and 4 weeks of oral administration of doses ranging from 40 to 200 mg daily. The data were analyzed using noncompartmental and compartmental pharmacokinetics. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to infinity (AUC0-∞) values ranged from 1.0 to 3.16 mg/liter and 15.2 to 47.8 mg/liter × h, respectively, following single intravenous doses of 40 to 200 mg.Cmaxand time to maximum concentration of drug in serum (Tmax) values following multiple-dose oral administration ranged from 1.15 to 3.04 mg/liter and 1.50 to 2.33 h, respectively, on day 14 and 1.48 to 3.57 mg/liter and 1.00 to 2.17 on day 28. Predose sputum/plasma concentration ratios on days 14 and 28 ranged from 0.33 to 1.1 (mean, 0.71 ± 0.33), indicating moderate pulmonary penetration. A 2-compartment model best described the combined intravenous and oral data. Absorption was slow and delayed (absorption rate constant [Ka], 0.414 h−1; lag time, 0.484 h) but complete (bioavailability [F], 1.16). The distribution and elimination half-lives were 0.557 and 18.1 h, respectively. Based on these data, the plasma concentrations at the highest dose, 200 mg/day, are in the range reported to produce anti-inflammatory effectsin vivoand should be evaluated in clinical trials.

Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis

2021 ◽  
Author(s):  
Antonin Praet ◽  
Laurent Bourguignon ◽  
Florence Vetele ◽  
Valentine Breant ◽  
Charlotte Genestet ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dose Adjustment ◽  
Total Body Weight ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Two Compartment Model ◽  
Total Body

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC 24 /MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC 24 /MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

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