| 1. |
- Blessborn, Daniel, et al.
(författare)
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Assay for screening for six antimalarial drugs and one metabolite using dried blood spot sampling, sequential extraction and ion-trap detection
- 2010
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Ingår i: Bioanalysis. - : Future Science Ltd. - 1757-6180 .- 1757-6199. ; 2:11, s. 1839-1847
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Tidskriftsartikel (refereegranskat)abstract
- Background: More parasites are becoming resistant to antimalarial drugs, and in many areas a change in first-line drug treatment is necessary. The aim of the developed assay is to help determine drug use in these areas and also to be a complement to interviewing patients, which will increase reliability of surveys.Results: This assay detects quinine, mefloquine, sulfadoxine, pyrimethamine, lumefantrine, chloroquine and its metabolite desethylchloroquine in a 100-mu l dried blood spot. Most of the drugs also have long half-lives that make them detectable at least 7 days after administration. The drugs are extracted from the dried blood spot with sequential extraction (due to the big differences in physicochemical properties), solid-phase extraction is used as sample clean-up and separation is performed with gradient-LC with MS ion-trap detection.Conclusion: Detection limits (S/N > 5:1) at 50 ng/ml or better were achieved for all drugs except lumefantrine (200 ng/ml), and thus can be used to determine patient compliance. A major advantage of using the ion-trap MS it that it will be possible to go back into the data and look for other drugs as needed.
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| 2. |
- Byakika-Kibwika, Pauline, et al.
(författare)
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Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults.
- 2012
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 67:5, s. 1217-23
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine after administration of a single dose of 80/480 mg of artemether/lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir.METHODS: A two-arm parallel study of 13 HIV-infected ART-naive adults and 16 HIV-infected adults stable on 400/100 mg of lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (ClinicalTrials.gov, NCT 00619944). Each participant received a single dose of 80/480 mg of artemether/lumefantrine under continuous cardiac function monitoring. Plasma concentrations of artemether, dihydroartemisinin and lumefantrine were measured.RESULTS: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly reduced artemether maximum concentration (C(max)) and area under the concentration-time curve (AUC) [median (range): 112 (20-362) versus 56 (17-236) ng/mL, P = 0.03; and 264 (92-1129) versus 151 (38-606) ng · h/mL, P < 0.01]. Dihydroartemisinin C(max) and AUC were not affected [66 (10-111) versus 73 (31-224) ng/mL, P = 0.55; and 213 (68-343) versus 175 (118-262) ng · h/mL P = 0.27]. Lumefantrine C(max) and AUC increased during co-administration [2532 (1071-5957) versus 7097 (2396-9462) ng/mL, P < 0.01; and 41,119 (12,850-125,200) versus 199,678 (71,205-251,015) ng · h/mL, P < 0.01].CONCLUSIONS: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly increases lumefantrine exposure, but decreases artemether exposure. Population pharmacokinetic and pharmacodynamic trials will be highly valuable in evaluating the clinical significance of this interaction and determining whether dosage modifications are indicated.
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| 3. |
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| 4. |
- Höglund, Richard, 1984, et al.
(författare)
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A population pharmacokinetic model of piperaquine in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Sudan.
- 2012
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Ingår i: Malaria journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Pregnancy is associated with an increased risk of developing a malaria infection and a higher risk of developing severe malaria. The pharmacokinetic properties of many anti-malarials are also altered during pregnancy, often resulting in a decreased drug exposure. Piperaquine is a promising anti-malarial partner drug used in a fixed-dose combination with dihydroartemisinin. The aim of this study was to investigate the population pharmacokinetics of piperaquine in pregnant and non-pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria. METHOD: Symptomatic patients received a standard dose regimen of the fixed dose oral piperaquine-dihydroartemisinin combination treatment. Densely sampled plasma aliquots were collected and analysed using a previously described LC-MS/MS method. Data from 12 pregnant and 12 non-pregnant women were analysed using nonlinear mixed-effects modelling. A Monte Carlo Mapped Power (MCMP) analysis was conducted based on a previously published study to evaluate the power of detecting covariates in this relatively small study. RESULTS: A three-compartment disposition model with a transit-absorption model described the observed data well. Body weight was added as an allometric function on all clearance and volume parameters. A statistically significant decrease in estimated terminal piperaquine half-life in pregnant compared with non-pregnant women was found, but there were no differences in post-hoc estimates of total piperaquine exposure. The MCMP analysis indicated a minimum of 13 pregnant and 13 non-pregnant women were required to identify pregnancy as a covariate on relevant pharmacokinetic parameters (80% power and p=0.05). Pregnancy was, therefore, evaluated as a categorical and continuous covariate (i.e. estimate gestational age) in a full covariate approach. Using this approach pregnancy was not associated with any major change in piperaquine elimination clearance. However, a trend of increasing elimination clearance with increasing gestational age could be seen. CONCLUSIONS: The population pharmacokinetic properties of piperaquine were well described by a three-compartment disposition model in pregnant and non-pregnant women with uncomplicated malaria. The modelling approach showed no major difference in piperaquine exposure between the two groups and data presented here do not warrant a dose adjustment in pregnancy in this vulnerable population.
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| 5. |
- Römsing, Susanne, et al.
(författare)
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Determination of tafenoquine in dried blood spots and plasma using LC and fluorescence detection
- 2011
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Ingår i: Bioanalysis. - 1757-6180 .- 1757-6199. ; 3:16, s. 1847-1853
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Tidskriftsartikel (refereegranskat)abstract
- Background: The growing problem of parasites developing resistance to the traditional antimalarial drugs makes the development of new effective and safe drugs crucial. Tafenoquine is a new promising antimalarial drug for prophylaxis and treatment.Results: A bioanalytical method for the determination of tafenoquine in 100 mu l of capillary blood applied onto sampling paper and in 100 mu l of plasma has been developed and validated. The Whatman 31 ET Chr paper was treated with 0.6 mol/l tartaric acid to improve the extraction recovery and solid-phase extraction was used for cleanup procedure of the blood samples. Plasma samples were precipitated with methanol. Tafenoquine and internal standard were separated on a Zorbax SB-CN column by reversed-phase LC and detected with fluorescence detection at 262 and 470 nm. The within- and between-day variations were below 10 and 14%, respectively, over the range 50-200 nmol/l for capillary blood on sampling paper and below 6 and 10% for plasma samples. The LLOQ of the method was 50 nmol/l.Conclusion: The developed method has adequate sensitivity and is highly suitable for clinical studies in dried blood spots and plasma.
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| 6. |
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| 7. |
- Tärning, Joel, 1977, et al.
(författare)
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Population pharmacokinetics of piperaquine after two different treatment regimens of dihydroartemisinin-piperaquine in patients with Plasmodium falciparum malaria in Thailand.
- 2008
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804. ; 52:3, s. 1052-61
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Tidskriftsartikel (refereegranskat)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 weightnormalized 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.
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