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

Pauline Byakika-Kibwika, Mohammed Lamorde, Jonathan Mayito, Lillian Nabukeera, Harriet Mayanja-Kizza, Elly Katabira, Warunee Hanpithakpong, Celestino Obua, Nadine Pakker, Niklas Lindegardh, Joel Tarning, Peter J de Vries, Concepta Merry, Pauline Byakika-Kibwika, Mohammed Lamorde, Jonathan Mayito, Lillian Nabukeera, Harriet Mayanja-Kizza, Elly Katabira, Warunee Hanpithakpong, Celestino Obua, Nadine Pakker, Niklas Lindegardh, Joel Tarning, Peter J de Vries, Concepta Merry

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: Plasma concentrations of artesunate and dihydroartemisinin were achieved rapidly with rapid and complete symptom resolution and parasite clearance with no adverse events.

Figures

Figure 1
Figure 1
Individual plots of parasite density against time post start of treatment.
Figure 2
Figure 2
Mean artesunate and dihydroartemisinin plasma concentration versus time. Vertical bars represent standard error.

References

    1. WHO. Guidelines for the treatment of malaria. Geneva: WHO; 2010.
    1. Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ. AQUAMAT group. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010;376:1647–1657. doi: 10.1016/S0140-6736(10)61924-1.
    1. Dondorp ANFSK, Day N, White N. South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: A randomized trial. Lancet. 2005;366:717–725.
    1. Sinclair D, Donegan S, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev. 2011;3:CD005967.
    1. Hess KM, Goad JA, Arguin PM. Intravenous artesunate for the treatment of severe malaria. Ann Pharmacother. 2010;44:1250–1258. doi: 10.1345/aph.1M732.
    1. Checkley AM, Whitty CJ. Artesunate, artemether or quinine in severe Plasmodium falciparum malaria? Expert Rev Anti Infect Ther. 2007;5:199–204. doi: 10.1586/14787210.5.2.199.
    1. Krudsood S, Wilairatana P, Vannaphan S, Treeprasertsuk S, Silachamroon U, Phomrattanaprapin W, Gourdeuk VR, Brittenham GM, Looareesuwan S. Clinical experience with intravenous quinine, intramuscular artemether and intravenous artesunate for the treatment of severe malaria in Thailand. Southeast Asian J Trop Med Public Health. 2003;34:54–61.
    1. Batty KT, Le AT, Ilett KF, Nguyen PT, Powell SM, Nguyen CH, Truong XM, Vuong VC, Huynh VT, Tran QB. et al.A pharmacokinetic and pharmacodynamic study of artesunate for vivax malaria. Am J Trop Med Hyg. 1998;59:823–827.
    1. Batty KT, Ashton M, Ilett KF, Edwards G, Davis TM. The pharmacokinetics of artemisinin (ART) and artesunate (ARTS) in healthy volunteers. Am J Trop Med Hyg. 1998;58:125–126.
    1. Batty KT, Thu LT, Davis TM, Ilett KF, Mai TX, Hung NC, Tien NP, Powell SM, Thien HV, Binh TQ, Kim NV. A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria. Br J Clin Pharmacol. 1998;45:123–129.
    1. Davis TM, Phuong HL, Ilett KF, Hung NC, Batty KT, Phuong VD, Powell SM, Thien HV, Binh TQ. Pharmacokinetics and pharmacodynamics of intravenous artesunate in severe falciparum malaria. Antimicrob Agents Chemother. 2001;45:181–186. doi: 10.1128/AAC.45.1.181-186.2001.
    1. Timothy M, Davis E, Hoang Lan Phuong, Kenneth Fl, Nguyen CH, Kevin TB, Vu Duong BP, Shane MP, Huynh Van a Thien, Binh TQ. Pharmacokinetics and Pharmacodynamics of Intravenous Artesunate in Severe Falciparum Malaria. Antimicrob Agents Chemother. 2001;45:181–186. doi: 10.1128/AAC.45.1.181-186.2001.
    1. de Vries P, Dien TK. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs. 1996;52:818–836. doi: 10.2165/00003495-199652060-00004.
    1. Qigui Li, Louis RC, Kevin JL, George AS, Scott Miller R, Victor M, Weina PJ. Pharmacokinetic profiles of artesunate after single intravenous doses at 0.5, 1, 2, 4, and 8 mg/kg in healthy volunteers: a phase I study. Am J Trop Med Hyg. 2009;81:615–621. doi: 10.4269/ajtmh.2009.09-0150.
    1. Benakis A, Paris M, Loutan L, Plessas CT, Plessas ST. Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers. Am J Trop Med Hyg. 1997;56:17–23.
    1. Teja-Isavadharm P, Watt G, Eamsila C, Jongsakul K, Li Q, Keeratithakul G, Sirisopana N, Luesutthiviboon L, Brewer TG, Kyle DE. Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria. Am J Trop Med Hyg. 2001;65:717–721.
    1. Hanpithakpong W, Kamanikom B, Dondorp AM, Singhasivanon P, White NJ, Day NPJ, Lindegardh N. A liquid chromatographic-tandem mass spectrometric method for determination of artesunate and its metabolite dihydroartemisinin in human plasma. J Chromatography B. 2008;876:61–68. doi: 10.1016/j.jchromb.2008.10.018.
    1. Navaratnam V, Mansor SM, Sit NW, Grace J, Li Q, Olliaro P. Pharmacokinetics of artemisinin-type compounds. Clin Pharmacokinet. 2000;39:255–270. doi: 10.2165/00003088-200039040-00002.
    1. Newton PN, Barnes KI, Smith PJ, Evans AC, Chierakul W, Ruangveerayuth R, White NJ. The pharmacokinetics of intravenous artesunate in adults with severe falciparum malaria. Eur J Clin Pharmacol. 2006;62:1003–1009. doi: 10.1007/s00228-006-0203-2.
    1. Newton P, Suputtamongkol Y, Teja-Isavadharm P, Pukrittayakamee S, Navaratnam V, Bates I, White N. Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria. Antimicrob Agents Chemother. 2000;44:972–977. doi: 10.1128/AAC.44.4.972-977.2000.
    1. Singh NB, Bhagyabati DS, Singh TB, Singh MA. Artemether vs quinine therapy in Plasmodium falciparum malaria in Manipur--a preliminary report. J Commun Dis. 2001;33:83–87.
    1. Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, Rosenthal PJ, D’Alessandro U. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10:144. doi: 10.1186/1475-2875-10-144.
    1. Achan J, Tibenderana J, Kyabayinze D, Mawejje H, Mugizi R, Mpeka B, Talisuna A, D’Alessandro U. Case management of severe malaria–a forgotten practice: experiences from health facilities in Uganda. PLoS One. 2011;6:e17053. doi: 10.1371/journal.pone.0017053.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere