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Pharmacokinetics and pharmacodynamics of intravenous artesunate during severe malaria treatment in Ugandan adults.

ABSTRACT: Severe malaria is a medical emergency with high mortality. Prompt achievement of therapeutic concentrations of highly effective anti-malarial drugs reduces the risk of death. The aim of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous artesunate in Ugandan adults with severe malaria.Fourteen adults with severe falciparum malaria requiring parenteral therapy were treated with 2.4 mg/kg intravenous artesunate. Blood samples were collected after the initial dose and plasma concentrations of artesunate and dihydroartemisinin measured by solid-phase extraction and liquid chromatography-tandem mass spectrometry. The study was approved by the Makerere University Faculty of Medicine Research and Ethics Committee (Ref2010-015) and Uganda National Council of Science and Technology (HS605) and registered with ClinicalTrials.gov (NCT01122134).All study participants achieved prompt resolution of symptoms and complete parasite clearance with median (range) parasite clearance time of 17 (8-24) hours. Median (range) maximal artesunate concentration (Cmax) was 3260 (1020-164000) ng/mL, terminal elimination half-life (T1/2) was 0.25 (0.1-1.8)?hours and total artesunate exposure (AUC) was 727 (290-111256) ng·h/mL. Median (range) dihydroartemisinin Cmax was 3140 (1670-9530) ng/mL, with Tmax of 0.14 (0.6 - 6.07) hours and T1/2 of 1.31 (0.8-2.8) hours. Dihydroartemisinin AUC was 3492 (2183-6338) ng·h/mL. None of the participants reported adverse events.Plasma concentrations of artesunate and dihydroartemisinin were achieved rapidly with rapid and complete symptom resolution and parasite clearance with no adverse events.

SUBMITTER: Byakika-Kibwika P

PROVIDER: S-EPMC3489518 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Pharmacokinetics and pharmacodynamics of intravenous artesunate during severe malaria treatment in Ugandan adults.

Byakika-Kibwika Pauline P Lamorde Mohammed M Mayito Jonathan J Nabukeera Lillian L Mayanja-Kizza Harriet H Katabira Elly E Hanpithakpong Warunee W Obua Celestino C Pakker Nadine N Lindegardh Niklas N Tarning Joel J de Vries Peter J PJ Merry Concepta C

Malaria journal 20120427

<h4>Background</h4>Severe malaria is a medical emergency with high mortality. Prompt achievement of therapeutic concentrations of highly effective anti-malarial drugs reduces the risk of death. The aim of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous artesunate in Ugandan adults with severe malaria.<h4>Methods</h4>Fourteen adults with severe falciparum malaria requiring parenteral therapy were treated with 2.4 mg/kg intravenous artesunate. Blood samples were c ...[more]

PMID: 22540954

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Project description:BackgroundMalaria control largely depends on availability of highly efficacious drugs, however, over the years, has been threatened by emergence of drug resistance. It is, therefore, important to monitor the impact of recurrent anti-malarial treatment on the long-term efficacy of anti-malarial regimens, especially in sub-Saharan African countries with high malaria transmission. Evaluation of parasite clearance following treatment of severe malaria with intravenous artesunate among patients in Eastern Uganda, was performed, as a contribution to monitoring anti-malarial effectiveness.MethodsParasite clearance data obtained from a clinical trial whose objective was to evaluate the 42-day parasitological treatment outcomes and safety following treatment of severe malaria with intravenous artesunate plus artemisinin-based combination therapy among patients attending Tororo District Hospital in Eastern Uganda, were analysed. Serial blood smears were performed at 0, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 h, followed by 6-hourly blood smears post start of treatment until 6 h post the first negative blood smear when parasite clearance was achieved. Study endpoints were; parasite clearance half-life (the time required for parasitaemia to decrease by 50% based on the linear portion of the parasite clearance slope) and parasite clearance time (time required for complete clearance of initial parasitaemia).ResultsOne hundred and fifty participants with severe malaria were enrolled. All participants were treated with intravenous artesunate. All study participants tolerated artesunate well with rapid recovery from symptoms and ability to take oral mediation within 24 h. No immediate adverse events were recorded. The median (IQR) number of days to complete parasite clearance was of 2 (1-2). The median (IQR) time to clear 50% and 99% parasites was 4.8 (3.61-7.10) and 17.55 (14.66-20.66) h, respectively. The median estimated clearance rate constant per hour was 0.32. The median (IQR) slope half-life was 2.15 (1.64, 2.61) h.ConclusionParasite clearance following treatment with intravenous artesunate was rapid and adequate. This finding provides supportive evidence that resistance to artemisinins is unlikely to have emerged in this study area. Continuous monitoring of artemisinin effectiveness for malaria treatment should be established in high malaria transmission areas in sub-Saharan Africa where spread of resistance would be disastrous. Trial registration The study was registered with the Pan African Clinical Trial Registry (PACTR201110000321348). Registered 7th October 2011, http://www.pactr.org/ ).

Project description:BACKGROUND:The World Health Organization (WHO) recommends combinations of an artemisinin derivative plus an anti-malarial drug of longer half-life as treatment options for uncomplicated Plasmodium falciparum infections. In Africa, artesunate-mefloquine (ASMQ) is an infrequently used artemisinin-based combination therapy (ACT) because of perceived poor tolerance to mefloquine. However, the WHO has recommended reconsideration of the use of ASMQ in Africa. In this large clinical study, the pharmacokinetics (PK) of a fixed dose combination of ASMQ was investigated in an African paediatric population to support dosing recommendations used in Southeast Asia and South America. METHODS:Among the 472 paediatric patients aged 6-59 months from six African centres included in the large clinical trial, a subset of 50 Kenyan children underwent intensive sampling to develop AS, its metabolite dihydroartemisinin (DHA) and MQ PK models. The final MQ PK model was validated using sparse data collected in the remaining participants (NONMEM®). The doses were one or two tablets containing 25/55 mg AS/MQ administered once a day for 3 days according to patients' age. A sensitive LC-MS/MS method was used to quantify AS, DHA and MQ concentrations in plasma. An attempt was made to investigate the relationship between the absence/presence of malaria recrudescence and MQ area under the curve (AUC) using logistic regression. RESULTS:AS/DHA concentration-time profiles were best described using a one-compartment model for both compounds with irreversible AS conversion into DHA. AS/DHA PK were characterized by a significant degree of variability. Body weight affected DHA PK parameters. MQ PK was characterized by a two-compartment model and a large degree of variability. Allometric scaling of MQ clearances and volumes of distribution was used to depict the relationship between MQ PK and body weight. No association was found between the model predicted AUC and appearance of recrudescence. CONCLUSIONS:The population pharmacokinetic models developed for both AS/DHA and MQ showed a large variability in drug exposure in the investigated African paediatric population. The largest contributor to this variability was body weight, which is accommodated for by the ASMQ fixed dose combination (FDC) dosing recommendation. Besides body weight considerations, there is no indication that the dosage should be modified in children with malaria compared to adults. Trial registration Pan African Clinical Trials Registry PACTR201202000278282 registration date 2011/02/16.

Project description:BACKGROUND:Alternatives to treatment for malaria treatment of travellers are needed in the USA and in Europe for travellers who return with severe malaria infections. The objective of this study is to show the pharmacokinetic (PK) profile of intravenous artesunate (AS), which was manufactured under good manufacturing practice (GMP) conditions, in adults with uncomplicated falciparum malaria in Kenya. METHODS:The PK parameters of intravenous AS manufactured under current cGMP were evaluated after a single dose of drug at 2.4 mg/kg infused over 2 min in 28 adults with uncomplicated Plasmodium falciparum malaria. Plasma concentrations of AS and dihydroartemisinin (DHA) were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) methodology. Pharmacokinetic data were analysed with a compartmental analysis for AS and DHA. RESULTS:The results suggest there were no drug-related adverse events in any of the patients. After intravenous infusion, the concentration of the parent drug rapidly declined, and the AS was converted to DHA. AS and DHA showed mean elimination half-lives of 0.17 hours and 1.30 hours, respectively. The high mean peak concentration (Cmax) of AS was shown to be 28,558 ng/mL while the Cmax of DHA was determined to be 2,932 ng/mL. Significant variability was noted in the PK profiles of the 28 patients tested. For example, Cmax values of AS were calculated to range from 3,362 to 55,873 ng/mL, and the Cmax value of DHA was noted to vary from 1,493 to 5,569 ng/mL. The mean area under the curve (AUC) of AS was shown to be approximately half that of DHA (1,878 ng · h/mL vs 3,543 ng · h/mL). The DHA/AS ratio observed was 1.94 during the one-day single treatment, and the AUC and half- life measured for DHA were significantly larger and longer than for AS. CONCLUSIONS:Intravenous AS can provide much higher peak concentrations of AS when compared to concentrations achieved with oral therapy; this may be crucial for the rapid elimination of parasites in patients with severe malaria. Given the much longer half-life of DHA compared to the short half-life of AS, DHA also plays a significant role in treatment of severe malaria.

Dataset Information

Pharmacokinetics and pharmacodynamics of intravenous artesunate during severe malaria treatment in Ugandan adults.

Publications

Pharmacokinetics and pharmacodynamics of intravenous artesunate during severe malaria treatment in Ugandan adults.

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