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Effect of Food on the Pharmacokinetics of Piperaquine and Dihydroartemisinin

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Abstract

Background and Objective

Piperaquine–dihydroartemisinin combination therapy has established efficacy for the treatment of malaria; however, a more comprehensive understanding of the pharmacokinetic properties and factors contributing to inter- and intra-individual variability is critical to optimize clinical use. This study assessed the effects of food on the pharmacokinetics of combination piperaquine–dihydroartemisinin administration in healthy volunteers.

Methods

This was an open-label, single-dose, parallel-group study. Participants were randomly allocated to receive oral piperaquine–dihydroartemisinin either after an overnight fast or immediately after a standardized, high-fat, high-calorie meal. Blood samples were collected for analysis of plasma piperaquine and dihydroartemisinin concentrations, which were utilized for calculation of pharmacokinetic parameters, using a standard model-independent approach.

Results

Consumption of a high-fat, high-calorie meal resulted in substantial increases in the extent of exposure to piperaquine (ratio between area under the plasma concentration–time curve [AUC] values from 0 to 168 h in the fed and fasted states [AUC0–168 h FED/AUC0–168 h FASTED] = 299 %, 90 % confidence interval [CI] 239–374 %). This likely reflects an increase in the oral bioavailability of the drug, directly related to the fat content of the meal. Co-administration of food was also found to result in both delayed and enhanced absorption of dihydroartemisinin (ratio between AUC values from time zero to infinity in the fed and states [AUC∞ FED/AUC∞ FASTED] = 142 %, 90 % CI 113–178 %; ratio between mean transit time [MTT] values in the fed and fasted states [MTTFED/MTTFASTED] = 135 %, 90 % CI 114–160 %).

Conclusion

Although food was found to significantly impact on the pharmacokinetics of piperaquine and dihydroartemisinin, given the low fat content of standard meals within endemic regions and the anorexic effects of malaria infection, these results are unlikely to impact on the clinical utility of these drugs. However, co-administration of food with these anti-malarials by populations consuming a typical Western diet should be avoided to reduce the risk of toxic side effects. It is therefore a general recommendation that piperaquine–dihydroartemisinin not be administered within ±3 h of food consumption.

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Authors and Affiliations

  1. School of Pharmacy and Medical Sciences, University of South Australia, GPO Box 2471, Adelaide, SA, 5001, Australia

    Stephanie E. Reuter & Allan M. Evans

  2. Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia

    Stephanie E. Reuter & Allan M. Evans

  3. CMAX, a Division of IDT Australia Ltd, Adelaide, SA, Australia

    Sepehr Shakib

  4. CPR Pharma Services Pty Ltd, Adelaide, SA, Australia

    Yvonne Lungershausen & Barbara Francis

  5. Sigma-Tau Industrie Farmaceutiche Riunite SpA, Rome, Italy

    Giovanni Valentini, Antonella Bacchieri & Silvia Pace

  6. Medicines for Malaria Venture, Geneva, Switzerland

    David Ubben

Authors
  1. Stephanie E. Reuter
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  2. Allan M. Evans
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Corresponding author

Correspondence to Stephanie E. Reuter.

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Funding

This study was co-funded by Sigma-Tau Farmaceutiche Riunite SpA and the Medicines for Malaria Venture.

Disclosure of potential conflicts of interest

The authors SER, AME and DU declare that they have no conflict of interest. SS, YL and BF are employed by institutions that received funding (commercial sponsorship of contract research) from Sigma-Tau Industrie Farmaceutiche Riunite SpA for the submitted research. GV, AB and SP are employees of Sigma-Tau Industrie Farmaceutiche Riunite SpA.

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Reuter, S.E., Evans, A.M., Shakib, S. et al. Effect of Food on the Pharmacokinetics of Piperaquine and Dihydroartemisinin. Clin Drug Investig 35, 559–567 (2015). https://doi.org/10.1007/s40261-015-0312-8

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  • DOI: https://doi.org/10.1007/s40261-015-0312-8

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