scholarly journals Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

2009 ◽  
Vol 53 (9) ◽  
pp. 3837-3846 ◽  
Author(s):  
Joel Tarning ◽  
Rose McGready ◽  
Niklas Lindegardh ◽  
Elizabeth A. Ashley ◽  
Mupawjay Pimanpanarak ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Pregnant Women ◽  
Population Pharmacokinetics ◽  
Plasma Concentrations ◽  
Plasmodium Falciparum Malaria ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Increased Risk ◽  
Pharmacokinetic Properties

ABSTRACT Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.

scholarly journals Pharmacodynamics and pharmacokinetics of dermatan sulfate in humans

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1577-1582
Author(s):  
F Dol ◽  
G Houin ◽  
M Rostin ◽  
JL Montastruc ◽  
D Dupouy ◽  
...  
Keyword(s):  
Dermatan Sulfate ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Intravenous Injections ◽  
Routes Of Administration ◽  
Chromogenic Assay ◽  
Interindividual Variations ◽  
Pharmacokinetic Properties ◽  
Hemorrhagic Risk

Dermatan sulfate (DS), a catalyst of the thrombin-heparin cofactor II interaction, has antithrombotic activity and is devoid of significant hemorrhagic risk in several animal models. We investigated the pharmacodynamic and pharmacokinetic properties of DS in humans. DS was injected in single bolus intravenous injections of four increasing doses (0.5, 1, 1.5, 2 mg/kg) to six healthy volunteers. The resulting anticoagulant activities were assessed by the activated partial thromboplastin time (APTT) and the thrombin clotting time (TCT). There were dose-dependent prolongations of the APTT and TCT, and the anticoagulant activities disappeared in less than three hours. The pharmacokinetic parameters were calculated from the plasma concentrations of DS measured with a new chromogenic assay. The volume of distribution was approximately 1.8 times greater than the theoretical plasma volume and was independent of dose. In contrast, the clearance decreased with dose and the terminal half-life ranged from 0.45 +/- 0.08 hours at 0.5 mg/kg to 0.72 +/- 0.11 hours (mean +/- SD) at 2 mg/kg. The bioavailabilities of subcutaneous (SC) and intramuscular (IM) administration relative to those of intravenous administration were determined in 12 other volunteers. The respective bioavailabilities were 24.7% +/- 12.9% and 12.4% +/- 9.2% for SC and IM administration. There was no detectable change in the APTT and the TCT when the volunteers were injected with 1.5 mg/kg SC or IM. In addition, the pharmacokinetic parameters derived from plasma concentrations of DS showed considerable interindividual variations by the two later routes of administration. Peak concentrations were noted 2.7 +/- 1.3 hours after SC injection and 4.3 +/- 4.9 hours after IM injection. The average peak concentrations were 0.7 +/- 0.3 and 0.4 +/- 0.2 mg/L after SC and IM injections, respectively. The half-lives of DS were 7.9 +/- 6.5 hours (SC) and 6.3 +/- 7.4 hours (IM). No adverse reaction to DS was recorded during this study.

scholarly journals Population Pharmacokinetics of Piperaquine after Two Different Treatment Regimens with Dihydroartemisinin-Piperaquine in Patients with Plasmodium falciparum Malaria in Thailand

2008 ◽  
Vol 52 (3) ◽  
pp. 1052-1061 ◽  
Author(s):  
J. Tarning ◽  
E. A. Ashley ◽  
N. Lindegardh ◽  
K. Stepniewska ◽  
L. Phaiphun ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Body Weight ◽  
Population Pharmacokinetics ◽  
Plasma Concentrations ◽  
Plasmodium Falciparum Malaria ◽  
Time Curve ◽  
Treatment Regimens ◽  
Elimination Half ◽  
Adults And Children ◽  
Random Variability

ABSTRACT The population pharmacokinetics of piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria treated with two different dosage regimens of dihydroartemisinin-piperaquine were characterized. Piperaquine pharmacokinetics in 98 Burmese and Karen patients aged 3 to 55 years were described by a two-compartment disposition model with first-order absorption and interindividual random variability on all parameters and were similar with the three- and four-dose regimens. Children had a lower body weight-normalized oral clearance than adults, resulting in longer terminal elimination half-lives and higher total exposure to piperaquine (area under the concentration-time curve from 0 to 63 days [AUCday 0-63]). However, children had lower plasma concentrations in the therapeutically relevant posttreatment prophylactic period (AUCday 3-20) because of smaller body weight-normalized central volumes of distribution and shorter distribution half-lives. Our data lend further support to a simplified once-daily treatment regimen to improve treatment adherence and efficacy and indicate that weight-adjusted piperaquine doses in children may need to be higher than in adults.

Population Pharmacokinetics of Enoxaparin in Children at Risk for Symptomatic Thromboembolism.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1071-1071
Author(s):  
Mirjam Nadine Trame ◽  
Lesley Mitchell ◽  
Christoph Male ◽  
Jeffrey S. Barrett ◽  
Georg Hempel ◽  
...  
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Maintenance Dose ◽  
Factor Xa ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Safety And Efficacy ◽  
Off Label ◽  
Final Population

Abstract Abstract 1071 Poster Board I-93 Introduction: Enoxaparin, a low-molecular-weight-heparin (LMWH), is used off-label in children to prevent symptomatic thromboembolism when acute anticoagulation or secondary prevention is required due to venous thrombosis or stroke. This investigation was conducted because of concerns of altered pharmacokinetics and a lack of safety and efficacy data when used in children. Patients and Methods: Data of 126 children and adolescents with a median age of 5.9 years receiving enoxaparin either as a once or twice daily dosing regimen were analyzed. Children < 12 months of age received a starting dose of 1.5 mg/kg followed by a maintenance dose of 1.3 mg/kg. Children > 12 months of age were started on 1 mg/kg followed by a maintenance dose of 1 mg/kg. Blood samples were drawn after patients reached steady-state on their maintenance dose at baseline prior to the next dose, and at 2, 4, 8 and 12 hours after administration. The median enoxaparin concentration in our population resulted in a median anti-factor Xa activity of 0.4 U/ml (range 0 – 1 U/ml anti-factor Xa). By means of population pharmacokinetics using nonlinear mixed-effects modelling (NONMEM) plasma concentration-time data were analyzed. Several covariates such as age, body weight and body surface area were tested on their effects on the pharmacokinetic parameters. Results: Using a two-compartment model the enoxaparin kinetics were described sufficiently. By using body weight and age as covariates for clearance (CL) and central volume of distribution (V1) the best results were obtained. The final population estimates of enoxaparin resulted to be: CL 7.11 ml h-1 kg-1 ± 14.3%, V1 7.31 ml kg-1 ± 33.5%, intercompartimental clearance (Q) 194 ml h-1 ± 24.7%, peripheral volume of distribution (V2) 45.1 l ± 52.5% and absorption rate (ka) 0.0799 h-1 ± 21.7% (estimates ± standard errors). Interindividual variability (IIV) was found to be 75.6% for CL and 78.4% for Q, respectively. Figure 1 shows the predicted activity time-course versus the measured activities for a representative patient. The model is capable of describing all aging and dosing groups of our childhood population (neonates, infants to adolescents). Conclusion: The high IIV in CL and Q in our population underlines the need for monitoring the activity and individualizing the dose. Further population pharmacokinetic/-dynamic investigations should be conducted to predict target enoxaparin levels or other new antithrombotic drugs for more safety and efficacy during antithrombotic therapy when used in children. Disclosures: Off Label Use: Enoxaparin (LMWH) is used off-label in children to prevent symptomatic thromboembolism..

scholarly journals Population Pharmacokinetics of Artemether, Dihydroartemisinin, and Lumefantrine in Rwandese Pregnant Women Treated for UncomplicatedPlasmodium falciparumMalaria

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Jesmin Lohy Das ◽  
Stephen Rulisa ◽  
Peter J. de Vries ◽  
Petra F. Mens ◽  
Nadine Kaligirwa ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Population Pharmacokinetics ◽  
Plasma Concentrations ◽  
Target Attainment ◽  
Time Curve ◽  
Content Type ◽  
Mixed Effects Modeling ◽  
Increased Risk ◽  
Dose Combination ◽  
Median Area

ABSTRACTThe artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients. However, the effect of pregnancy-related changes on exposure is unclear, and pregnancy has been associated with decreased efficacy in previous studies. This study aimed to characterize the population pharmacokinetics of artemether, its active metabolite dihydroartemisinin, and lumefantrine in 22 Rwandese pregnant women in their second (n= 11) or third (n= 11) trimester with uncomplicatedPlasmodium falciparummalaria. These patients were enrolled from Rwamagana district hospital and received the standard fixed oral dose combination of 80 mg of artemether and 480 mg of lumefantrine twice daily for 3 days. Venous plasma concentrations were quantified for all three analytes using liquid chromatography coupled with tandem mass spectroscopy, and data were analyzed using nonlinear mixed-effects modeling. Lumefantrine pharmacokinetics was described by a flexible but highly variable absorption, with a mean absorption time of 4.04 h, followed by a biphasic disposition model. The median area under the concentration-time curve from 0 h to infinity (AUC0–∞) for lumefantrine was 641 h · mg/liter. Model-based simulations indicated that 11.7% of the study population did not attain the target day 7 plasma concentration (280 ng/ml), a threshold associated with increased risk of recrudescence. The pharmacokinetics of artemether was time dependent, and the autoinduction of its clearance was described using an enzyme turnover model. The turnover half-life was predicted to be 30.4 h. The typical oral clearance, which started at 467 liters/h, increased 1.43-fold at the end of treatment. Simulations suggested that lumefantrine pharmacokinetic target attainment appeared to be reassuring in Rwandese pregnant women, particularly compared to target attainment in Southeast Asia. Larger cohorts will be required to confirm this finding.

scholarly journals Pharmacodynamics and pharmacokinetics of dermatan sulfate in humans

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1577-1582 ◽  
Author(s):  
F Dol ◽  
G Houin ◽  
M Rostin ◽  
JL Montastruc ◽  
D Dupouy ◽  
...  
Keyword(s):  
Dermatan Sulfate ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Intravenous Injections ◽  
Routes Of Administration ◽  
Chromogenic Assay ◽  
Interindividual Variations ◽  
Pharmacokinetic Properties ◽  
Hemorrhagic Risk

Abstract Dermatan sulfate (DS), a catalyst of the thrombin-heparin cofactor II interaction, has antithrombotic activity and is devoid of significant hemorrhagic risk in several animal models. We investigated the pharmacodynamic and pharmacokinetic properties of DS in humans. DS was injected in single bolus intravenous injections of four increasing doses (0.5, 1, 1.5, 2 mg/kg) to six healthy volunteers. The resulting anticoagulant activities were assessed by the activated partial thromboplastin time (APTT) and the thrombin clotting time (TCT). There were dose-dependent prolongations of the APTT and TCT, and the anticoagulant activities disappeared in less than three hours. The pharmacokinetic parameters were calculated from the plasma concentrations of DS measured with a new chromogenic assay. The volume of distribution was approximately 1.8 times greater than the theoretical plasma volume and was independent of dose. In contrast, the clearance decreased with dose and the terminal half-life ranged from 0.45 +/- 0.08 hours at 0.5 mg/kg to 0.72 +/- 0.11 hours (mean +/- SD) at 2 mg/kg. The bioavailabilities of subcutaneous (SC) and intramuscular (IM) administration relative to those of intravenous administration were determined in 12 other volunteers. The respective bioavailabilities were 24.7% +/- 12.9% and 12.4% +/- 9.2% for SC and IM administration. There was no detectable change in the APTT and the TCT when the volunteers were injected with 1.5 mg/kg SC or IM. In addition, the pharmacokinetic parameters derived from plasma concentrations of DS showed considerable interindividual variations by the two later routes of administration. Peak concentrations were noted 2.7 +/- 1.3 hours after SC injection and 4.3 +/- 4.9 hours after IM injection. The average peak concentrations were 0.7 +/- 0.3 and 0.4 +/- 0.2 mg/L after SC and IM injections, respectively. The half-lives of DS were 7.9 +/- 6.5 hours (SC) and 6.3 +/- 7.4 hours (IM). No adverse reaction to DS was recorded during this study.

scholarly journals Lumefantrine and Desbutyl-Lumefantrine Population Pharmacokinetic-Pharmacodynamic Relationships in Pregnant Women with Uncomplicated Plasmodium falciparum Malaria on the Thailand-Myanmar Border

2015 ◽  
Vol 59 (10) ◽  
pp. 6375-6384 ◽  
Author(s):  
Frank Kloprogge ◽  
Rose McGready ◽  
Warunee Hanpithakpong ◽  
Daniel Blessborn ◽  
Nicholas P. J. Day ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Treatment Outcomes ◽  
Falciparum Malaria ◽  
Plasma Concentrations ◽  
Plasmodium Falciparum Malaria ◽  
Population Pharmacokinetic ◽  
Time To Event ◽  
Combined Model ◽  
Therapeutic Outcomes ◽  
Cure Rates

ABSTRACTArtemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-lumefantrine correlate better with treatment outcomes than those of lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary lumefantrine and desbutyl-lumefantrine plasma samples from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-lumefantrine concentrations, implemented in anEmaxmodel, both predicted treatment outcomes, but lumefantrine provided better predictive power. A combined model including both lumefantrine and desbutyl-lumefantrine did not improve the model further. Simulations suggested that cure rates in pregnant women with falciparum malaria could be increased by prolonging the treatment course. (These trials were registered at controlled-trials.com [ISRCTN 86353884].)

scholarly journals A Population Pharmacokinetic Approach to Describe Cephalexin Disposition in Adult and Aged Dogs

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Ana Paula Prados ◽  
Paula Schaiquevich ◽  
Verónica Kreil ◽  
Agustina Monfrinotti ◽  
Pamela Quaine ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Elimination Rate ◽  
Compartment Model ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Mixed Breed ◽  
Pharmacokinetic Approach

This study was conducted in order to characterize the pharmacokinetics of orally administered cephalexin to healthy adult and aged dogs, using a population pharmacokinetic approach. Two hundred and eighty-six cephalexin plasma concentrations obtained from previous pharmacokinetic studies were used. Sex, age, pharmaceutical formulation, and breed were evaluated as covariates. A one-compartment model with an absorption lag-time (Tlag) best described the data. The final model included age (adult; aged) on apparent volume of distribution (Vd/F), apparent elimination rate (ke/F), and Tlag; sex (female; male) on ke/F, and breed (Beagle; mixed-breed) on Vd/F. Addition of the covariates to the model explained 78% of the interindividal variability (IIV) in Vd/F, 36% in ke/F, and 24% in Tlag, respectively. Formulation did not affect the variability of any of the pharmacokinetic parameters. Tlag was longer, whereas Vd/F and ke/F were lower in aged compared to adult animals; in female aged dogs ke/F was lower than in male aged dogs; however, the differences were of low magnitude. Different disposition of cephalexin may be expected in aged dogs.

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