scholarly journals Pharmacokinetic Comparison of Two Piperaquine-Containing Artemisinin Combination Therapies in Papua New Guinean Children with Uncomplicated Malaria

2012 ◽  
Vol 56 (6) ◽  
pp. 3288-3297 ◽  
Author(s):  
Sam Salman ◽  
Madhu Page-Sharp ◽  
Kevin T. Batty ◽  
Kaye Kose ◽  
Susan Griffin ◽  
...  
Keyword(s):  
Body Weight ◽  
Liquid Chromatography ◽  
Uncomplicated Malaria ◽  
High Performance ◽  
World Health ◽  
Published Data ◽  
Combination Therapies ◽  
Time Curve ◽  
Papua New Guinean ◽  
Artemisinin Combination Therapies

ABSTRACTPharmacokinetic differences between piperaquine (PQ) base and PQ tetraphosphate were investigated in 34 Papua New Guinean children aged 5 to 10 years treated for uncomplicated malaria with artemisinin-PQ (ART-PQ) base or dihydroartemisinin-PQ (DHA-PQ) tetraphosphate. Twelve children received ART-PQ base (two daily doses of 3 mg of ART and 18 mg of PQ base as granules/kg of body weight) as recommended by the manufacturer, with regular clinical assessment and blood sampling over 56 days. PQ concentrations in plasma samples collected from 22 children of similar ages with malaria in a previously published pharmacokinetic study of DHA-PQ tetraphosphate (three daily doses of 2.5 mg of ART and 20 mg of PQ tetraphosphate as tablets/kg of body weight) were available for comparison. The disposition of ART was also assessed in the 12 children who received ART-PQ base. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and ART was assayed using liquid chromatography-mass spectrometry. Multicompartment pharmacokinetic models for PQ and ART were developed using a population-based approach. ART-PQ base was well tolerated, and initial fever abatement and parasite clearance were prompt. There were no differences between the two treatments in the values for the PQ area under the concentration-time curve from time zero to infinity (AUC0–∞), with medians of 49,451 (n= 12) and 44,556 (n= 22) μg · h/liter for ART-PQ base and DHA-PQ tetraphosphate, respectively. Recurrent parasitemia was associated with lower PQ exposure. Using a two-compartment ART model, the median AUC0–∞was 1,652 μg · h/liter. There was evidence of autoinduction of ART metabolism (relative bioavailability for the second dose, 0.27). These and previously published data suggest that a 3-day ART-PQ base regimen should be further evaluated, in line with World Health Organization recommendations for all artemisinin combination therapies.

scholarly journals Population Pharmacokinetics of Artemether, Lumefantrine, and Their Respective Metabolites in Papua New Guinean Children with Uncomplicated Malaria

2011 ◽  
Vol 55 (11) ◽  
pp. 5306-5313 ◽  
Author(s):  
Sam Salman ◽  
Madhu Page-Sharp ◽  
Susan Griffin ◽  
Kaye Kose ◽  
Peter M. Siba ◽  
...  
Keyword(s):  
Liquid Chromatography ◽  
Uncomplicated Malaria ◽  
Antimalarial Activity ◽  
Parent Drug ◽  
Published Data ◽  
Active Metabolites ◽  
Time Curve ◽  
Limit Of Quantitation ◽  
Papua New Guinean

ABSTRACTThere are sparse published data relating to the pharmacokinetic properties of artemether, lumefantrine, and their active metabolites in children, especially desbutyl-lumefantrine. We studied 13 Papua New Guinean children aged 5 to 10 years with uncomplicated malaria who received the six recommended doses of artemether (1.7 mg/kg of body weight) plus lumefantrine (10 mg/kg), given with fat over 3 days. Intensive blood sampling was carried out over 42 days. Plasma artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine were assayed using liquid chromatography-mass spectrometry or high-performance liquid chromatography. Multicompartmental pharmacokinetic models for a drug plus its metabolite were developed using a population approach that included plasma artemether and dihydroartemisinin concentrations below the limit of quantitation. Although artemether bioavailability was variable and its clearance increased by 67.8% with each dose, the median areas under the plasma concentration-time curve from 0 h to infinity (AUC0-∞s) for artemether and dihydroartemisinin (3,063 and 2,839 μg·h/liter, respectively) were similar to those reported previously in adults with malaria. For lumefantrine, the median AUC0–∞(459,980 μg·h/liter) was also similar to that in adults with malaria. These data support the higher dose recommended for children weighing 15 to 35 kg (35% higher than that for a 50-kg adult) but question the recommendation for a lower dose in children weighing 12.5 to 15 kg. The median desbutyl-lumefantrine/lumefantrine ratio in the children in our study was 1.13%, within the range reported for adults and higher at later time points because of the longer desbutyl-lumefantrine terminal elimination half-life. A combined desbutyl-lumefantrine and lumefantrine AUC0–∞weighted onin vitroantimalarial activity was inversely associated with recurrent parasitemia, suggesting that both the parent drug and the metabolite contribute to the treatment outcome of artemether-lumefantrine.

scholarly journals Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

2015 ◽  
Vol 59 (7) ◽  
pp. 4260-4271 ◽  
Author(s):  
John M. Benjamin ◽  
Brioni R. Moore ◽  
Sam Salman ◽  
Madhu Page-Sharp ◽  
Somoyang Tawat ◽  
...  
Keyword(s):  
Liquid Chromatography ◽  
Racial Differences ◽  
High Performance ◽  
Drug Disposition ◽  
Population Based ◽  
Obstetric Outcomes ◽  
Time Curve ◽  
Content Type ◽  
Papua New Guinean

ABSTRACTThe tolerability, safety, and disposition of dihydroartemisinin (DHA) and piperaquine (PQ) were assessed in 32 pregnant (second/third trimester) and 33 nonpregnant Papua New Guinean women randomized to adult treatment courses of DHA-PQ (three daily doses) or sulfadoxine-pyrimethamine (SP)-PQ (three daily PQ doses, single dose of SP). All dose adminstrations were observed, and subjects fasted for 2 h postdose. Plasma PQ was assayed by using high-performance liquid chromatography, and DHA was assessed by using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models were developed using a population-based approach. Both regimens were well tolerated. There was an expected increase in the rate-corrected electrocardiographic QT interval which was independent of pregnancy and treatment. Two pregnant and two nonpregnant women hadPlasmodium falciparumparasitemia which cleared within 48 h, and no other subject became slide positive for malaria during 42 days of follow-up. Of 30 pregnant women followed to delivery, 27 (90%) delivered healthy babies and 3 (10%) had stillbirths; these obstetric outcomes are consistent with those in the general population. The area under the plasma PQ concentration-time curve (AUC0–∞) was lower in the pregnant patients (median [interquartile range], 23,721 μg · h/liter [21,481 to 27,951 μg · h/liter] versus 35,644 μg · h/liter [29,546 to 39,541 μg · h/liter];P< 0.001) in association with a greater clearance relative to bioavailability (73.5 liters/h [69.4 to 78.4] versus 53.8 liters/h [49.7 to 58.2];P< 0.001), but pregnancy did not influence the pharmacokinetics of DHA. The apparent pharmacokinetic differences between the present study and results from other studies of women with uncomplicated malaria that showed no effect of pregnancy on the AUC0–∞of PQ and greater bioavailability may reflect differences in postdose fat intake, proportions of women with malaria, and/or racial differences in drug disposition.

scholarly journals Effect of Coadministered Fat on the Tolerability, Safety, and Pharmacokinetic Properties of Dihydroartemisinin-Piperaquine in Papua New Guinean Children with Uncomplicated Malaria

2014 ◽  
Vol 58 (10) ◽  
pp. 5784-5794 ◽  
Author(s):  
B. R. Moore ◽  
J. M. Benjamin ◽  
S. Salman ◽  
S. Griffin ◽  
E. Ginny ◽  
...  
Keyword(s):  
Liquid Chromatography ◽  
High Performance ◽  
Clinical Laboratory ◽  
Parasite Clearance ◽  
Population Based ◽  
Laboratory Assessment ◽  
Time Curve ◽  
Group A ◽  
Group B ◽  
Papua New Guinean

ABSTRACTCoadministration of dihydroartemisinin-piperaquine (DHA-PQ) with fat may improve bioavailability and antimalarial efficacy, but it might also increase toxicity. There have been no studies of these potential effects in the pediatric age group. The tolerability, safety, efficacy, and pharmacokinetics of DHA-PQ administered with or without 8.5 g fat were investigated in 30 Papua New Guinean children aged 5 to 10 years diagnosed with uncomplicated falciparum malaria. Three daily 2.5:11.5-mg-base/kg doses were given with water (n= 14, group A) or milk (n= 16, group B), with regular clinical/laboratory assessment and blood sampling over 42 days. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and DHA was assayed using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models for PQ and DHA were developed using a population-based approach. DHA-PQ was generally well tolerated, and initial fever and parasite clearance were prompt. There were no differences in the areas under the concentration-time curve (AUC0–∞) for PQ (median, 41,906 versus 36,752 μg · h/liter in groups A and B, respectively;P= 0.24) or DHA (4,047 versus 4,190 μg · h/liter;P= 0.67). There were also no significant between-group differences in prolongation of the corrected electrocardiographic QT interval (QTc) initially during follow-up, but the QTctended to be higher in group B children at 24 h (mean ± standard deviation [SD], 15 ± 10 versus 6 ± 15 ms0.5in group A,P= 0.067) and 168 h (10 ± 18 versus 1 ± 23 ms0.5,P= 0.24) when plasma PQ concentrations were relatively low. A small amount of fat does not change the bioavailability of DHA-PQ in children, but a delayed persistent effect on ventricular repolarization cannot be excluded.

scholarly journals Pharmacokinetics of Artemether-Lumefantrine and Artesunate-Amodiaquine in Children in Kampala, Uganda

2009 ◽  
Vol 54 (1) ◽  
pp. 52-59 ◽  
Author(s):  
Julia Mwesigwa ◽  
Sunil Parikh ◽  
Bryan McGee ◽  
Polina German ◽  
Troy Drysdale ◽  
...  
Keyword(s):  
Uncomplicated Malaria ◽  
Active Metabolite ◽  
Geometric Mean ◽  
World Health ◽  
Published Data ◽  
Time Curve ◽  
Artemisinin Derivatives ◽  
Dosing Strategies ◽  
Drug Regimens ◽  
Health Organization

ABSTRACT The World Health Organization recommends the use of artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria. The two most widely adopted ACT regimens are artemether (AR)-lumefantrine (LR) (the combination is abbreviated AL) and amodiaquine (AQ)-artesunate (AS). Pharmacokinetic (PK) data informing the optimum dosing of these drug regimens is limited, especially in children. We evaluated PK parameters in Ugandan children aged 5 to 13 years with uncomplicated malaria treated with AL (n = 20) or AQ-AS (n = 21), with intensive venous sampling occurring at 0, 2, 4, 8, 24, and 120 h following administration of the last dose of 3-day regimens of AL (twice daily) or AQ-AS (once daily). AS achieved an estimated maximum concentration in plasma (C max) of 51 ng/ml and an area under the concentration-time curve from time zero to infinity (AUC0-∞) of 113 ng·h/ml; and its active metabolite, dihydroartemisinin (DHA), achieved a geometric mean C max of 473 ng/ml and an AUC0-∞ of 1,404 ng·h/ml. AR-DHA exhibited a C max of 34/119 ng/ml and an AUC0-∞ of 168/382 ng·h/ml, respectively. For LR, C max and AUC0-∞ were 6,757 ng/ml and 210 μg·h/ml, respectively. For AQ and its active metabolite, desethylamodiaquine (DEAQ), the C maxs were 5.2 ng/ml and 235 ng/ml, respectively, and the AUC0-∞s were 39.3 ng·h/ml and 148 μg·h/ml, respectively. Comparison of the findings of the present study to previously published data for adults suggests that the level of exposure to LR is lower in children than in adults and that the level of AQ-DEAQ exposure is similar in children and adults. For the artemisinin derivatives, differences between children and adults were variable and drug specific. The PK results generated for children must be considered to optimize the dosing strategies for these widely utilized ACT regimens.

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 Artemisinin Combination Therapies for Treatment of Uncomplicated Malaria in Uganda

2006 ◽  
Vol 1 (1) ◽  
pp. e7 ◽  
Author(s):  
Hasifa Bukirwa ◽  
Adoke Yeka ◽  
Moses R Kamya ◽  
Ambrose Talisuna ◽  
Kristin Banek ◽  
...  
Keyword(s):  
Uncomplicated Malaria ◽  
Combination Therapies ◽  
Artemisinin Combination Therapies

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 STUDY OF THE INFLUENCE OF LOW-INTENSITY INFRARED LASER RADIATION ON CONCENTRATION OF DICLOFENAC SODIUM IN RATS’ PLASMA BY THE METHOD OF HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY

2016 ◽  
Author(s):  
L. V. Brun ◽  
V. I. Makolinets
Keyword(s):  
Body Weight ◽  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Laser Radiation ◽  
Drug Administration ◽  
High Performance ◽  
Diclofenac Sodium ◽  
Infrared Laser ◽  
Male Rats ◽  
Low Intensity

The aim of this study is to determine the influence of low-intensity infrared laser radiation (LIIRLR) on concentrationof diclofenac sodium in the experiment on rats by the method of high-performance liquid chromatography. For study conduct, a total of 15 male rats with body weight of 250–300 g were used. Experimental animals were subdivided into 3 groups. Animals of group 1 received diclofenac sodium per os at the dose of ED50 (8 mg/kg of animal body weight). Animals of group 2 received diclofenac sodium per os (8 mg/kg) and in 15 min were exposed to LIIRLR. Animals of group 3 were exposed to LIIRLR and in 15 min received diclofenac sodium per os at the dose of 8 mg/kg. Animals were sacrificed in 60 min after drug administration. For extraction of diclofenac sodium from rat plasma samples, we used a method of solid-phase extraction, which had been modified due to microoncentrationsof the active substance. In the result of the studies conducted, it has been determined that therapy regimen with the following sequence is the most efficient in the animals studied: exposure of LIIRLR and administration per os of diclofenac sodium in15 min. The results obtained indicate to the fact that concomitant use of LIIRLR potentiates diclofenac sodium. Itwill allow to decrease the dose, influence on its entry and duration of its action in the organism, as well as to decreasethe frequency of drug administration.

scholarly journals Decreasing half-life of dieldrin in egg yolk following a single oral administration of aldrin to laying hens

2001 ◽  
Vol 49 (4) ◽  
pp. 465-472
Author(s):  
N. Furusawa
Keyword(s):  
Body Weight ◽  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Single Dose ◽  
Half Life ◽  
High Performance ◽  
Laying Hens ◽  
Egg Yolk ◽  
Single Oral Administration ◽  
Low Levels

Laying hens were treated orally with a single dose of aldrin (AD) 1 mg/kg body weight. Concentrations (μg/g) of AD or its epoxide (= dieldrin, DD) in the yolk of eggs laid for 21 days after AD treatment were determined by normalphase high-performance liquid chromatography. The limits of determination were 0.02 μg/g for AD and 0.03 μg/g for DD, respectively. After AD treatment, although the low levels of AD (mean 0.02–0.03 μg/g) were observed only during a three-day period (from 4th to 6th days), DD (mean 0.15 μg/g) was found already on the 2nd day, indicating that the epoxidation of AD to DD in the hen’s body is rapid. The highest level of DD (mean 0.40 μg/g) was detected on the 6th day, and then DD levels decreased slowly and were detected up to the 21st day. In this decreasing phase, the half-life of DD in the yolk was estimated to be 25.6 days with a 95% confidence interval from 22.7 to 29.4 days.

scholarly journals Pharmacokinetics of sparfloxacin and interaction with cisapride and sucralfate.

1997 ◽  
Vol 41 (8) ◽  
pp. 1668-1672 ◽  
Author(s):  
J A Zix ◽  
H F Geerdes-Fenge ◽  
M Rau ◽  
J Vöckler ◽  
K Borner ◽  
...  
Keyword(s):  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Peak Concentration ◽  
High Performance ◽  
Random Order ◽  
Pharmacokinetic Parameters ◽  
Qtc Interval ◽  
Urinary Recovery ◽  
Time Curve ◽  
Concentration Time

In an open, randomized, triple crossover study, the effects of cisapride and sucralfate on the pharmacokinetics of sparfloxacin were assessed. Fifteen healthy volunteers received 400 mg of sparfloxacin as a single oral dose on day 0. In a random order, concomitant doses of 10 mg of cisapride three times daily from day -2 to day 2 and 1 g of sucralfate four times daily from day -2 to day 0 were administered. Sparfloxacin concentrations were measured by bioassay and high-performance liquid chromatography. Pharmacokinetic parameters for sparfloxacin alone were as follows (mean +/- standard deviation): maximum concentration of drug in serum (C(max)), 1.27 +/- 0.39 microg/ml; time to C(max) (T(max)), 4.1 +/- 1.9 h; area under the concentration-time curve (AUC), 35.0 +/- 9.7 microg x h/ml; mean residence time, 28.5 +/- 5.7 h; half-life (t1/2), 20 +/- 4 h; urinary recovery (UR x f), 11.0% +/- 2.7%; and metabolite-sparfloxacin ratio in urine, 2.6. For the cisapride group there was a significant decrease in the sparfloxacin T(max) (1.9 +/- 2.1 h) and a significant increase in C(max) (1.74 +/- 0.73 microg/ml). The QTc interval for patients receiving sparfloxacin and cisapride was prolonged by 7.7% compared to the QTc interval during medication-free periods. Significant differences in the values for the group receiving sucralfate compared to the values for the group receiving sparfloxacin alone were found: C(max), 0.77 +/- 0.31 microg/ml; AUC, 18.6 +/- 5.8 microg x h/ml; t1/2, 26 +/- 10 h; and UR x f, 5.8 +/- 1.8%. Concomitant adminstration of cisapride accelerates the absorption and increases the peak concentration of sparfloxacin without having a significant effect on the extent of bioavailability. Coadministration of sucralfate leads to a 44% decrease in the bioavailability of sparfloxacin.

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