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Malaria Journal
Published in: Malaria Journal 1/2012

Open Access 01-12-2012 | Research

Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

Authors: Joel Tarning, Frank Kloprogge, Patrice Piola, Mehul Dhorda, Sulaiman Muwanga, Eleanor Turyakira, Nitra Nuengchamnong, François Nosten, Nicholas PJ Day, Nicholas J White, Philippe J Guerin, Niklas Lindegardh

Published in: Malaria Journal | Issue 1/2012

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Abstract

Background

Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda.

Methods

Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies.

Results

The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches.

Conclusion

The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.
Appendix
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Literature
1.
World Health Organization: World malaria report. 2011
2.
Dellicour S, Tatem AJ, Guerra CA, Snow RW, ter Kuile FO: Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study. PLoS Med. 2010, 7: e1000221-10.1371/journal.pmed.1000221.PubMedCentralCrossRefPubMed
3.
Rogerson SJ, Hviid L, Duffy PE, Leke RF, Taylor DW: Malaria in pregnancy: pathogenesis and immunity. Lancet Infect Dis. 2007, 7: 105-117. 10.1016/S1473-3099(07)70022-1.CrossRefPubMed
4.
Douglas NM, Anstey NM, Angus BJ, Nosten F, Price RN: Artemisinin combination therapy for vivax malaria. Lancet Infect Dis. 2010, 10: 405-416. 10.1016/S1473-3099(10)70079-7.PubMedCentralCrossRefPubMed
5.
World Health Organization: Guidelines for the treatment of malaria. 2010
6.
El Tahir KE, Al-Kharji AM, Ageel AM: Influence of diethylcarbamazine and mefloquine on PGI2 synthesis by the rat thoracic aorta and myometrial tissues. Gen Pharmacol. 1991, 22: 837-846. 10.1016/0306-3623(91)90216-S.CrossRefPubMed
7.
Looareesuwan S, White NJ, Warrell DA, Forgo I, Dubach UG, Ranalder UB, Schwartz DE: Studies of mefloquine bioavailability and kinetics using a stable isotope technique: a comparison of Thai patients with falciparum malaria and healthy Caucasian volunteers. Br J Clin Pharmacol. 1987, 24: 37-42. 10.1111/j.1365-2125.1987.tb03133.x.PubMedCentralCrossRefPubMed
8.
Vyas N, Avery BA, Avery MA, Wyandt CM: Carrier-mediated partitioning of artemisinin into Plasmodium falciparum-infected erythrocytes. Antimicrob Agents Chemother. 2002, 46: 105-109. 10.1128/AAC.46.1.105-109.2002.PubMedCentralCrossRefPubMed
9.
McGready R, Stepniewska K, Lindegardh N, Ashley EA, La Y, Singhasivanon P, White NJ, Nosten F: The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria. Eur J Clin Pharmacol. 2006, 62: 1021-1031. 10.1007/s00228-006-0199-7.CrossRefPubMed
10.
McGready R, Stepniewska K, Ward SA, Cho T, Gilveray G, Looareesuwan S, White NJ, Nosten F: Pharmacokinetics of dihydroartemisinin following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria. Eur J Clin Pharmacol. 2006, 62: 367-371. 10.1007/s00228-006-0118-y.CrossRefPubMed
11.
Tarning J, Rijken MJ, McGready R, Phyo AP, Hanpithakpong W, Day NP, White NJ, Nosten F, Lindegardh N: Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and non-pregnant women with uncomplicated malaria. Antimicrob Agents Chemother. 2012, 56: 1997-2007. 10.1128/AAC.05756-11.PubMedCentralCrossRefPubMed
12.
Tarning J, McGready R, Lindegardh N, Ashley EA, Pimanpanarak M, Kamanikom B, Annerberg A, Day NP, Stepniewska K, Singhasivanon P, White NJ, Nosten F: Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria. Antimicrob Agents Chemother. 2009, 53: 3837-3846. 10.1128/AAC.00195-09.PubMedCentralCrossRefPubMed
13.
McGready R, Stepniewska K, Edstein MD, Cho T, Gilveray G, Looareesuwan S, White NJ, Nosten F: The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria. Eur J Clin Pharmacol. 2003, 59: 545-552. 10.1007/s00228-003-0652-9.CrossRefPubMed
14.
Nyunt MM, Adam I, Kayentao K, van Dijk J, Thuma P, Mauff K, Little F, Cassam Y, Guirou E, Traore B, Doumbo O, Sullivan D, Smith P, Barnes KI: Pharmacokinetics of sulfadoxine and pyrimethamine in intermittent preventive treatment of malaria in pregnancy. Clin Pharmacol Ther. 2010, 87: 226-234. 10.1038/clpt.2009.177.CrossRefPubMed
15.
Karunajeewa HA, Salman S, Mueller I, Baiwog F, Gomorrai S, Law I, Page-Sharp M, Rogerson S, Siba P, Ilett KF, Davis TM: Pharmacokinetic properties of sulfadoxine-pyrimethamine in pregnant women. Antimicrob Agents Chemother. 2009, 53: 4368-4376. 10.1128/AAC.00335-09.PubMedCentralCrossRefPubMed
16.
Green MD, van Eijk AM, van Ter Kuile FO, Ayisi JG, Parise ME, Kager PA, Nahlen BL, Steketee R, Nettey H: Pharmacokinetics of sulfadoxine-pyrimethamine in HIV-infected and uninfected pregnant women in Western Kenya. J Infect Dis. 2007, 196: 1403-1408. 10.1086/522632.CrossRefPubMed
17.
Na Bangchang K, Davis TM, Looareesuwan S, White NJ, Bunnag D, Karbwang J: Mefloquine pharmacokinetics in pregnant women with acute falciparum malaria. Trans R Soc Trop Med Hyg. 1994, 88: 321-323. 10.1016/0035-9203(94)90101-5.CrossRefPubMed
18.
van Luin M, Van der Ende ME, Richter C, Visser M, Faraj D, Van der Ven A, Gelinck L, Kroon F, Wit FW, Van Schaik RH, Kuks PF, Burger DM: Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. AIDS. 2010, 24: 1223-1226. 10.1097/QAD.0b013e3283389129.CrossRefPubMed
19.
Rijken MJ, McGready R, Phyo AP, Lindegardh N, Tarning J, Laochan N, Than HH, Mu O, Win AK, Singhasivanon P: Pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and non-pregnant women with uncomplicated falciparum malaria. Antimicrob Agents Chemother. 2011, 55: 5505-5506.
20.
Tarning J, Chotsiri P, Jullien V, Rijken MJ, Bergstrand M, Cammas M, McGready R, Singhasivanon P, Day NPJ, White NJ: Population pharmacokinetic and pharmacodynamic modeling of amodiaquine and desethylamodiaquine in women with Plasmodium vivax malaria during and after pregnancy. Antimicrob Agents Chemother. 2012, In press
21.
Sagara I, Rulisa S, Mbacham W, Adam I, Sissoko K, Maiga H, Traore OB, Dara N, Dicko YT, Dicko A, Djimdé A, Jansen FH, Doumbo OK: Efficacy and safety of a fixed dose artesunate-sulphamethoxypyrazine-pyrimethamine compared to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria across Africa: a randomized multi-centre trial. Malar J. 2009, 8: 63-10.1186/1475-2875-8-63.PubMedCentralCrossRefPubMed
22.
Abdulla S, Sagara I, Borrmann S, D'Alessandro U, Gonzalez R, Hamel M, Ogutu B, Martensson A, Lyimo J, Maiga H, Sasi P, Nahum A, Bassat Q, Juma E, Otieno L, Björkman A, Beck HP, Andriano K, Cousin M, Lefèvre G, Ubben D, Premji Z: Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial. Lancet. 2008, 372: 1819-1827. 10.1016/S0140-6736(08)61492-0.CrossRefPubMed
23.
Hatz C, Soto J, Nothdurft HD, Zoller T, Weitzel T, Loutan L, Bricaire F, Gay F, Burchard GD, Andriano K, Lefèvre G, De Palacios PI, Genton B: Treatment of acute uncomplicated falciparum malaria with artemether-lumefantrine in nonimmune populations: a safety, efficacy, and pharmacokinetic study. Am J Trop Med Hyg. 2008, 78: 241-247.PubMed
24.
McGready R, Tan SO, Ashley EA, Pimanpanarak M, Viladpai-Nguen J, Phaiphun L, Wustefeld K, Barends M, Laochan N, Keereecharoen L, Lindegardh N, Singhasivanon P, White NJ, Nosten F: A randomised controlled trial of artemether-lumefantrine versus artesunate for uncomplicated plasmodium falciparum treatment in pregnancy. PLoS Med. 2008, 5: e253-10.1371/journal.pmed.0050253.PubMedCentralCrossRefPubMed
25.
Piola P, Nabasumba C, Turyakira E, Dhorda M, Lindegardh N, Nyehangane D, Snounou G, Ashley EA, McGready R, Nosten F, Guerin PJ: Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial. Lancet Infect Dis. 2010, 10: 762-769. 10.1016/S1473-3099(10)70202-4.CrossRefPubMed
26.
Ashley EA, Stepniewska K, Lindegardh N, Annerberg A, Kham A, Brockman A, Singhasivanon P, White NJ, Nosten F: How much fat is necessary to optimize lumefantrine oral bioavailability?. Trop Med Int Health. 2007, 12: 195-200. 10.1111/j.1365-3156.2006.01784.x.CrossRefPubMed
27.
Hanpithakpong H, Kamanikom B, Singhasivanon P, White NJ, Day NPJ, Lindegardh N: A liquid chromatographic–tandem mass spectrometric method for determination of artemether and its metabolite dihydroartemisinin in human plasma. Bioanalysis. 2009, 1: 37-46. 10.4155/bio.09.6.CrossRefPubMed
28.
Beal SL, Boeckman AJ, Sheiner LB: NONMEM user's Guides. 1992, University of California at San Francisco: NONMEM Project Group
29.
Lindbom L, Pihlgren P, Jonsson EN: PsN-Toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. 2005, 79: 241-257. 10.1016/j.cmpb.2005.04.005.CrossRefPubMed
30.
Lindbom L, Ribbing J, Jonsson EN: Perl-speaks-NONMEM (PsN)–a Perl module for NONMEM related programming. Comput Methods Programs Biomed. 2004, 75: 85-94. 10.1016/j.cmpb.2003.11.003.CrossRefPubMed
31.
Wilkins JJ: NONMEMory: a run management tool for NONMEM. Comput Methods Programs Biomed. 2005, 78: 259-267. 10.1016/j.cmpb.2005.02.003.CrossRefPubMed
32.
Jonsson EN, Karlsson MO: Xpose–an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed. 1999, 58: 51-64.CrossRefPubMed
33.
Hietala SF, Martensson A, Ngasala B, Dahlstrom S, Lindegardh N, Annerberg A, Premji Z, Farnert A, Gil P, Bjorkman A, Ashton M: Population pharmacokinetics and pharmacodynamics of artemether and lumefantrine during combination treatment in children with uncomplicated falciparum malaria in Tanzania. Antimicrob Agents Chemother. 2010, 54: 4780-4788. 10.1128/AAC.00252-10.PubMedCentralCrossRefPubMed
34.
Salman S, Page-Sharp M, Griffin S, Kose K, Siba PM, Ilett KF, Mueller I, Davis TM: Population pharmacokinetics of artemether, lumefantrine, and their respective metabolites in Papua New Guinean children with uncomplicated malaria. Antimicrob Agents Chemother. 2011, 55: 5306-5313. 10.1128/AAC.05136-11.PubMedCentralCrossRefPubMed
35.
Gordi T, Xie R, Huong NV, Huong DX, Karlsson MO, Ashton M: A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction. Br J Clin Pharmacol. 2005, 59: 189-198. 10.1111/j.1365-2125.2004.02321.x.PubMedCentralCrossRefPubMed
36.
Ahn JE, Karlsson MO, Dunne A, Ludden TM: Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn. 2008, 35: 401-421. 10.1007/s10928-008-9094-4.CrossRefPubMed
37.
Beal SL: Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001, 28: 481-504. 10.1023/A:1012299115260.CrossRefPubMed
38.
Bergstrand M, Karlsson MO: Handling data below the limit of quantification in mixed effect models. AAPS J. 2009, 11: 371-380. 10.1208/s12248-009-9112-5.PubMedCentralCrossRefPubMed
39.
Jonsson EN, Karlsson MO: Automated covariate model building within NONMEM. Pharm Res. 1998, 15: 1463-1468. 10.1023/A:1011970125687.CrossRefPubMed
40.
Savic RM, Karlsson MO: Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J. 2009, 11: 558-569. 10.1208/s12248-009-9133-0.PubMedCentralCrossRefPubMed
41.
Bergstrand M, Hooker AC, Wallin JE, Karlsson MO: Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011, 13: 143-151. 10.1208/s12248-011-9255-z.PubMedCentralCrossRefPubMed
42.
Ali S, Najmi MH, Tarning J, Lindegardh N: Pharmacokinetics of artemether and dihydroartemisinin in healthy Pakistani male volunteers treated with artemether-lumefantrine. Malar J. 2010, 9: 275-10.1186/1475-2875-9-275.PubMedCentralCrossRefPubMed
43.
van Agtmael MA, Gupta V, van der Wosten TH, Rutten JP, van Boxtel CJ: Grapefruit juice increases the bioavailability of artemether. Eur J Clin Pharmacol. 1999, 55: 405-410. 10.1007/s002280050648.CrossRefPubMed
44.
Ilett KF, Ethell BT, Maggs JL, Davis TM, Batty KT, Burchell B, Binh TQ, le Thu TA, Hung NC, Pirmohamed M, Park BK, Edwards G: Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos. 2002, 30: 1005-1012. 10.1124/dmd.30.9.1005.CrossRefPubMed
45.
Tracy TS, Venkataramanan R, Glover DD, Caritis SN: Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy. Am J Obstet Gynecol. 2005, 192: 633-639. 10.1016/j.ajog.2004.08.030.CrossRefPubMed
46.
Pavek P, Ceckova M, Staud F: Variation of drug kinetics in pregnancy. Curr Drug Metab. 2009, 10: 520-529. 10.2174/138920009788897993.CrossRefPubMed
47.
Anderson GD: Using pharmacokinetics to predict the effects of pregnancy and maternal-infant transfer of drugs during lactation. Expert Opin Drug Metab Toxicol. 2006, 2: 947-960. 10.1517/17425255.2.6.947.CrossRefPubMed
48.
Anderson GD: Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005, 44: 989-1008. 10.2165/00003088-200544100-00001.CrossRefPubMed
49.
van Agtmael MA, Van Der Graaf CA, Dien TK, Koopmans RP, van Boxtel CJ: The contribution of the enzymes CYP2D6 and CYP2C19 in the demethylation of artemether in healthy subjects. Eur J Drug Metab Pharmacokinet. 1998, 23: 429-436. 10.1007/BF03192305.CrossRefPubMed
50.
van Agtmael MA, Gupta V, van der Graaf CA, van Boxtel CJ: The effect of grapefruit juice on the time-dependent decline of artemether plasma levels in healthy subjects. Clin Pharmacol Ther. 1999, 66: 408-414. 10.1053/cp.1999.v66.a101946.CrossRefPubMed
51.
van Agtmael MA, Cheng-Qi S, Qing JX, Mull R, van Boxtel CJ: Multiple dose pharmacokinetics of artemether in Chinese patients with uncomplicated falciparum malaria. Int J Antimicrob Agents. 1999, 12: 151-158. 10.1016/S0924-8579(99)00063-1.CrossRefPubMed
52.
Lefevre G, Looareesuwan S, Treeprasertsuk S, Krudsood S, Silachamroon U, Gathmann I, Mull R, Bakshi R: A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg. 2001, 64: 247-256.PubMed
53.
Lefevre G, Bindschedler M, Ezzet F, Schaeffer N, Meyer I, Thomsen MS: Pharmacokinetic interaction trial between co-artemether and mefloquine. Eur J Pharm Sci. 2000, 10: 141-151. 10.1016/S0928-0987(00)00060-9.CrossRefPubMed
54.
Karbwang J, Na-Bangchang K, Congpuong K, Thanavibul A, Wattanakoon Y, Molunto P: Pharmacokinetics of oral artemether in Thai patients with uncomplicated falciparum malaria. Fundam Clin Pharmacol. 1998, 12: 242-244. 10.1111/j.1472-8206.1998.tb00948.x.CrossRefPubMed
Metadata
Title
Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda
Authors
Joel Tarning
Frank Kloprogge
Patrice Piola
Mehul Dhorda
Sulaiman Muwanga
Eleanor Turyakira
Nitra Nuengchamnong
François Nosten
Nicholas PJ Day
Nicholas J White
Philippe J Guerin
Niklas Lindegardh
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2012
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/1475-2875-11-293

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