Effect of Food on the Pharmacokinetics of Piperaquine and Dihydroartemisinin

Reuter, Stephanie E; Evans, Allan M.; Shakib, Sepehr; Lungershausen, Yvonne; Francis, Barbara; Valentini, Giovanni; Bacchieri, Antonella; Ubben, David; Pace, Silvia

doi:10.1007/s40261-015-0312-8

Cited by 24 publications

(21 citation statements)

References 20 publications

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“…The PPQ PK properties are in good agreement with other studies in healthy volunteers administered the drug alone [33][34][35][36] or coadministered with DHA. 37,38 Similar to other studies, multiple peaks were observed in the PPQ concentration-time profiles of 82% (18 of 22) of participants.…”

Section: Discussionsupporting

confidence: 88%

Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate–Amodiaquine and Artemisinin–Piperaquine in Healthy Volunteers for Preselection Malaria Therapy

Quang

Chavchich²,

Anh

et al. 2018

The American Journal of Tropical Medicine and Hygiene

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The pharmacokinetics (PK) and ex vivo activity (pharmacodynamics [PD]) of two artemisinin combination therapies (ACTs) (artemisinin-piperaquine [ARN-PPQ] [Artequick] and artesunate-amodiaquine [ARS-AQ] [Coarsucam]) in healthy Vietnamese volunteers were compared following 3-day courses of the ACTs for the preselection of the drugs for falciparum malaria therapy. For PK analysis, serial plasma samples were collected from two separate groups of 22 volunteers after ACT administration. Of these volunteers, ex vivo activity was assessed in plasma samples from seven volunteers who received both ACTs. The area under the concentration-time curve (AUC) was 3.6-fold higher for dihydroartemisinin (active metabolite of ARS) than that for ARN, whereas the AUC of desethylamodiaquine (active metabolite of AQ) was 2.0-fold lower than that of PPQ. Based on the 50% inhibitory dilution values of the volunteers' plasma samples collected from 0.25 to 3 hours after the last dose, the ex vivo activity of ARS-AQ was 2.9- to 16.2-fold more potent than that of ARN-PPQ against the drug-sensitive D6 line. In addition, at 1.5, 4.0, and 24 hours after the last dose, the ex vivo activity of ARS-AQ was 20.8-, 3.5-, and 8.5-fold more potent than that of ARN-PPQ against the ARN-sensitive MRA1239 line. By contrast, at 1.5 hours, the ex vivo activity of ARS-AQ was 5.4-fold more active than that of ARN-PPQ but had similar activities at 4 and 24 hours against the ARN-resistant MRA1240 line. The PK-PD data suggest that ARS-AQ possesses superior antimalarial activity than that of ARN-PPQ and would be the preferred ACT for further in vivo efficacy testing in multidrug-resistant falciparum malaria areas.

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Section: Discussionsupporting

confidence: 88%

Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate–Amodiaquine and Artemisinin–Piperaquine in Healthy Volunteers for Preselection Malaria Therapy

Quang

Chavchich²,

Anh

et al. 2018

The American Journal of Tropical Medicine and Hygiene

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“…The oral clearance and apparent oral volume of distribution of PQ have been found to be lower in patients than in healthy subjects (29). PQ exposure was increased (ϳ3-fold) when administered with a high-fat/high-calorie meal (30). In addition, a shorter half-life (14 days) of PQ was found in children, and children had a CL/F (1.8 liters/h/kg) more rapid than that in adults (31), which probably reflects higher rates of hepatic metabolism and/or biliary excretion in children.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Piperaquine to Its Antiplasmodial Metabolites and Their Pharmacokinetic Profiles in Healthy Volunteers

Liu

Cai

Yang

et al. 2018

Antimicrob Agents Chemother

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As a partner antimalarial for artemisinin drug-based combination therapy (ACT), piperaquine (PQ) can be metabolized into two major metabolites, including piperaquine -oxide (M1) and piperaquine,-dioxide (M2). To better understand the antimalarial potency of PQ, the antimalarial activity of the PQ metabolites (M1 and M2) was studied (in strains 3D7 andDd2) and (in the murine species) in this study. The recrudescence and survival time of infected mice were also recorded after drug treatment. The pharmacokinetic profiles of PQ and its two metabolites (M1 and M2) were investigated in healthy subjects after oral doses of two widely used ACT regimens, i.e., dihydroartemisinin plus piperaquine phosphate (Duo-Cotecxin) and artemisinin plus piperaquine (Artequick). Remarkable antiplasmodial activity was found for PQ (50% growth-inhibitory concentration [IC], 4.5 nM against 3D7 and 6.9 nM againstDd2; 90% effective dose [ED], 1.3 mg/kg of body weight), M1 (IC, 25.5 nM against 3D7 and 38.7 nM againstDd2; ED, 1.3 mg/kg), and M2 (IC, 31.2 nM against 3D7 and 33.8 nM againstDd2; ED, 2.9 mg/kg). Compared with PQ, M1 showed comparable efficacy in terms of recrudescence and survival time and M2 had relatively weaker antimalarial potency. PQ and its two metabolites displayed a long elimination half-life (∼11 days for PQ, ∼9 days for M1, and ∼4 days for M2), and they accumulated after repeated administrations. The contribution of the two PQ metabolites to the efficacy of piperaquine as a partner drug of ACT for the treatment of malaria should be considered for PQ dose optimization.

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“…The pharmacokinetics observed for piperaquine in this study were similar to those previously reported for multiple dosing in healthy volunteers (20). Piperaquine exposure is known to be increased with the consumption of a high-fat, high-calorie meal (21). However, the low-fat food provided in the present study did not appear to have any noticeable effect on piperaquine pharmacokinetics compared to data from previous studies of unfed healthy volunteers (20).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interactions between Tafenoquine and Dihydroartemisinin-Piperaquine or Artemether-Lumefantrine in Healthy Adult Subjects

Green

Mohamed

Goyal

et al. 2016

Antimicrob Agents Chemother

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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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Effect of Food on the Pharmacokinetics of Piperaquine and Dihydroartemisinin

Cited by 24 publications

References 20 publications

Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate–Amodiaquine and Artemisinin–Piperaquine in Healthy Volunteers for Preselection Malaria Therapy

Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate–Amodiaquine and Artemisinin–Piperaquine in Healthy Volunteers for Preselection Malaria Therapy

Metabolism of Piperaquine to Its Antiplasmodial Metabolites and Their Pharmacokinetic Profiles in Healthy Volunteers

Pharmacokinetic Interactions between Tafenoquine and Dihydroartemisinin-Piperaquine or Artemether-Lumefantrine in Healthy Adult Subjects

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