Dataset Information

Assessment of pharmacokinetic compatibility of short acting CDRI candidate trioxane derivative, 99-411, with long acting prescription antimalarials, lumefantrine and piperaquine.

ABSTRACT: The pharmacokinetic compatibility of short-acting CDRI candidate antimalarial trioxane derivative, 99-411, was tested with long-acting prescription antimalarials, lumefantrine and piperaquine. LC-ESI-MS/MS methods were validated for simultaneous bioanalysis of lumefantrine and 99-411 and of piperaquine and 99-411 combinations. The interaction studies were performed in rats using these validated methods. The total systemic exposure of 99-411 increased when administered with either lumefantrine or piperaquine. However, co-administration of 99-411 significantly decreased the systemic exposure of piperaquine by half-fold while it had no effect on the kinetics of lumefantrine. 99-411, thus, seemed to be a good alternative to artemisinin derivatives for combination treatment with lumefantrine. To explore the reason for increased plasma levels of 99-411, an in situ permeability study was performed by co-perfusing lumefantrine and 99-411. In presence of lumefantrine, the absorption of 99-411 was significantly increased by 1.37 times than when given alone. Lumefantrine did not affect the metabolism of 99-411 when tested in vitro in human liver microsomes. Additionally, ATPase assay suggest that 99-411 was a substrate of human P-gp, thus, indicating the probability of interaction at the absorption level in humans as well.

SUBMITTER: Taneja I

PROVIDER: S-EPMC4658560 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Assessment of pharmacokinetic compatibility of short acting CDRI candidate trioxane derivative, 99-411, with long acting prescription antimalarials, lumefantrine and piperaquine.

Taneja Isha I Raju Kanumuri Siva Rama KS Singh Sheelendra Pratap SP Wahajuddin Muhammad M

Scientific reports 20151125

The pharmacokinetic compatibility of short-acting CDRI candidate antimalarial trioxane derivative, 99-411, was tested with long-acting prescription antimalarials, lumefantrine and piperaquine. LC-ESI-MS/MS methods were validated for simultaneous bioanalysis of lumefantrine and 99-411 and of piperaquine and 99-411 combinations. The interaction studies were performed in rats using these validated methods. The total systemic exposure of 99-411 increased when administered with either lumefantrine or ...[more]

PMID: 26602250

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Project description:ObjectivesTo compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda.DesignRandomized single-blinded clinical trial.SettingApac, Uganda, an area of very high malaria transmission intensity.ParticipantsChildren aged 6 mo to 10 y with uncomplicated falciparum malaria.InterventionTreatment of malaria with AL or DP, each following standard 3-d dosing regimens.Outcome measuresRisks of recurrent parasitemia at 28 and 42 d, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections.ResultsOf 421 enrolled participants, 417 (99%) completed follow-up. The unadjusted risk of recurrent falciparum parasitemia was significantly lower for participants treated with DP than for those treated with AL after 28 d (11% versus 29%; risk difference [RD] 18%, 95% confidence interval [CI] 11%-26%) and 42 d (43% versus 53%; RD 9.6%, 95% CI 0%-19%) of follow-up. Similarly, the risk of recurrent parasitemia due to possible recrudescence (adjusted by genotyping) was significantly lower for participants treated with DP than for those treated with AL after 28 d (1.9% versus 8.9%; RD 7.0%, 95% CI 2.5%-12%) and 42 d (6.9% versus 16%; RD 9.5%, 95% CI 2.8%-16%). Patients treated with DP had a lower risk of recurrent parasitemia due to non-falciparum species, development of gametocytemia, and higher mean increase in hemoglobin compared to patients treated with AL. Both drugs were well tolerated; serious adverse events were uncommon and unrelated to study drugs.ConclusionDP was superior to AL for reducing the risk of recurrent parasitemia and gametocytemia, and provided improved hemoglobin recovery. DP thus appears to be a good alternative to AL as first-line treatment of uncomplicated malaria in Uganda. To maximize the benefit of artemisinin-based combination therapy in Africa, treatment should be integrated with aggressive strategies to reduce malaria transmission intensity.

Project description:Tafenoquine is in development as a single-dose treatment for relapse prevention in individuals with Plasmodium vivax malaria. Tafenoquine must be coadministered with a blood schizonticide, either chloroquine or artemisinin-based combination therapy (ACT). This open-label, randomized, parallel-group study evaluated potential drug interactions between tafenoquine and two ACTs: dihydroartemisinin-piperaquine and artemether-lumefantrine. Healthy volunteers of either sex aged 18 to 65 years without glucose-6-phosphate dehydrogenase deficiency were randomized into five cohorts (n = 24 per cohort) to receive tafenoquine on day 1 (300 mg) plus once-daily dihydroartemisinin-piperaquine on days 1, 2, and 3 (120 mg/960 mg for 36 to <75 kg of body weight and 160 mg/1,280 mg for ?75 to 100 kg of body weight), or plus artemether-lumefantrine (80 mg/480 mg) in two doses 8 h apart on day 1 and then twice daily on days 2 and 3, or each drug alone. The pharmacokinetic parameters of tafenoquine, piperaquine, lumefantrine, artemether, and dihydroartemisinin were determined by using noncompartmental methods. Point estimates and 90% confidence intervals were calculated for area under the concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) comparisons of tafenoquine plus ACT versus tafenoquine or ACT. All subjects receiving dihydroartemisinin-piperaquine experienced QTc prolongation (a known risk with this drug), but tafenoquine coadministration had no clinically relevant additional effect. Tafenoquine coadministration had no clinically relevant effects on dihydroartemisinin, piperaquine, artemether, or lumefantrine pharmacokinetics. Dihydroartemisinin-piperaquine coadministration increased the tafenoquine Cmax by 38% (90% confidence interval, 25 to 52%), the AUC from time zero to infinity (AUC0-?) by 12% (1 to 26%), and the half-life (t1/2) by 29% (19 to 40%), with no effect on the AUC from time zero to the time of the last nonzero concentration (AUC0-last). Artemether-lumefantrine coadministration had no effect on tafenoquine pharmacokinetics. Tafenoquine can be coadministered with dihydroartemisinin-piperaquine or artemether-lumefantrine without dose adjustment for any of these compounds. (This study has been registered at ClinicalTrials.gov under registration no. NCT02184637.).

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Dataset Information

Assessment of pharmacokinetic compatibility of short acting CDRI candidate trioxane derivative, 99-411, with long acting prescription antimalarials, lumefantrine and piperaquine.

Publications

Assessment of pharmacokinetic compatibility of short acting CDRI candidate trioxane derivative, 99-411, with long acting prescription antimalarials, lumefantrine and piperaquine.

Similar Datasets

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