The online version of this article (doi:10.1186/1475-2875-11-398) contains supplementary material, which is available to authorized users.
The Welcome Trust is a UK-based medical research charity and is independent of all drug companies. It has no financial links with the manufacturers of either the diagnostics tests or the drugs used in this study. The authors declare no conflict of interest.
IA, FN, ND, and NW conceived the project. WH, NL and JT quantified the drug concentrations. RH and JT performed the pharmacokinetic analysis and wrote the first draft of the manuscript. All authors revised the manuscript critically for important intellectual content and approved the final manuscript.
Pregnancy is associated with an increased risk of developing a malaria infection and a higher risk of developing severe malaria. The pharmacokinetic properties of many anti-malarials are also altered during pregnancy, often resulting in a decreased drug exposure. Piperaquine is a promising anti-malarial partner drug used in a fixed-dose combination with dihydroartemisinin. The aim of this study was to investigate the population pharmacokinetics of piperaquine in pregnant and non-pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria.
Symptomatic patients received a standard dose regimen of the fixed dose oral piperaquine-dihydroartemisinin combination treatment. Densely sampled plasma aliquots were collected and analysed using a previously described LC-MS/MS method. Data from 12 pregnant and 12 non-pregnant women were analysed using nonlinear mixed-effects modelling. A Monte Carlo Mapped Power (MCMP) analysis was conducted based on a previously published study to evaluate the power of detecting covariates in this relatively small study.
A three-compartment disposition model with a transit-absorption model described the observed data well. Body weight was added as an allometric function on all clearance and volume parameters. A statistically significant decrease in estimated terminal piperaquine half-life in pregnant compared with non-pregnant women was found, but there were no differences in post-hoc estimates of total piperaquine exposure. The MCMP analysis indicated a minimum of 13 pregnant and 13 non-pregnant women were required to identify pregnancy as a covariate on relevant pharmacokinetic parameters (80% power and p=0.05). Pregnancy was, therefore, evaluated as a categorical and continuous covariate (i.e. estimate gestational age) in a full covariate approach. Using this approach pregnancy was not associated with any major change in piperaquine elimination clearance. However, a trend of increasing elimination clearance with increasing gestational age could be seen.
The population pharmacokinetic properties of piperaquine were well described by a three-compartment disposition model in pregnant and non-pregnant women with uncomplicated malaria. The modelling approach showed no major difference in piperaquine exposure between the two groups and data presented here do not warrant a dose adjustment in pregnancy in this vulnerable population.
Authors’ original file for figure 112936_2012_2616_MOESM1_ESM.pdf
Authors’ original file for figure 212936_2012_2616_MOESM2_ESM.pdf
Authors’ original file for figure 312936_2012_2616_MOESM3_ESM.pdf
Authors’ original file for figure 412936_2012_2616_MOESM4_ESM.pdf
Authors’ original file for figure 512936_2012_2616_MOESM5_ESM.pdf
Authors’ original file for figure 612936_2012_2616_MOESM6_ESM.pdf
WHOS: World malaria report: 2011. 2011, Switzerland: World Health Organization
Lindsay S, Ansell J, Selman C, Cox V, Hamilton K, Walraven G: Effect of pregnancy on exposure to malaria mosquitoes. Lancet. 1972, 2000: 355-
Dafallah SE, El-Agib FH, Bushra GO: Maternal mortality in a teaching hospital in Sudan. Saudi Med J. 2003, 24: 369-372. PubMed
White NJ: Delaying antimalarial drug resistance with combination chemotherapy. Parasitologica. 1999, 41: 301-308.
Ashley EA, Krudsood S, Phaiphun L, Srivilairit S, McGready R, Leowattana W, Hutagalung R, Wilairatana P, Brockman A, Looareesuwan S, Nosten F, White NJ: Randomized, controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. J Infect Dis. 2004, 190: 1773-1782. 10.1086/425015. CrossRefPubMed
Ashley EA, McGready R, Hutagalung R, Phaiphun L, Slight T, Proux S, Thwai KL, Barends M, Looareesuwan S, White NJ, Nosten F: A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria. Clin Infect Dis. 2005, 41: 425-432. 10.1086/432011. CrossRefPubMed
Tran TH, Dolecek C, Pham PM, Nguyen TD, Nguyen TT, Le HT, Dong TH, Tran TT, Stepniewska K, White NJ, Farrar J: Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial. Lancet. 2004, 363: 18-22. 10.1016/S0140-6736(03)15163-X. CrossRefPubMed
Tarning J, Ashley EA, Lindegardh N, Stepniewska K, Phaiphun L, Day NP, McGready R, Ashton M, Nosten F, White NJ: Population pharmacokinetics of piperaquine after two different treatment regimens with dihydroartemisinin-piperaquine in patients with Plasmodium falciparum malaria in Thailand. Antimicrob Agents Chemother. 2008, 52: 1052-1061. 10.1128/AAC.00955-07. PubMedCentralCrossRefPubMed
Annerberg A, Lwin KM, Lindegardh N, Khrutsawadchai S, Ashley E, Day NP, Singhasivanon P, Tarning J, White NJ, Nosten F: A small amount of fat does not affect piperaquine exposure in patients with malaria. Antimicrob Agents Chemother. 2011, 55: 3971-3976. 10.1128/AAC.00279-11. PubMedCentralCrossRefPubMed
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 nonpregnant women with uncomplicated malaria. Antimicrob Agents Chemother. 2012, 56: 1997-2007. 10.1128/AAC.05756-11. PubMedCentralCrossRefPubMed
Tarning J, Zongo I, Somé FA, Rouamba N, Parikh S, Rosenthal PJ, Hanpithakpong W, Jongrak N, Day NP, White NJ, Nosten F, Ouedraogo JB, Lindegardh N: Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria. Clin Pharmacol Ther. 2012, 91: 497-505. 10.1038/clpt.2011.254. PubMedCentralCrossRefPubMed
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
McGready R, Ashley EA, Moo E, Cho T, Barends M, Hutagalung R, Looareesuwan S, White NJ, Nosten F: A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy. J Infect Dis. 2005, 192: 846-853. 10.1086/432551. CrossRefPubMed
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
Tarning J, McGready R, Lindegardh N, Ashley EA, Pimanpanarak M, Kamanikom B, Annerberg A, Day NP, Stepniewska K, Singhasivanon P: 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
Tarning J, Kloprogge F, Piola P, Dhorda M, Muwanga S, Turyakira E, Nuengchamnong N, Nosten F, Day NP, White NJ: Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda. Malar J. 2012, 11: 293-10.1186/1475-2875-11-293. PubMedCentralCrossRefPubMed
Rijken MJ, McGready R, Jullien V, Tarning J, Lindegardh N, Phyo AP, Win AK, Hsi P, Cammas M, Singhasivanon P, White NJ, Nosten F: Pharmacokinetics of amodiaquine and desethylamodiaquine in pregnant and postpartum women with Plasmodium vivax malaria. Antimicrob Agents Chemother. 2011, 55: 4338-4342. 10.1128/AAC.00154-11. PubMedCentralCrossRefPubMed
Tarning J, Chotsiri P, Jullien V, Rijken MJ, Bergstrand M, Cammas M, McGready R, Singhasivanon P, Day NP, White NJ, Nosten F, Lindegardh N: Population pharmacokinetic and pharmacodynamic modeling of amodiaquine and desethylamodiaquine in women with Plasmodium vivax malaria during and after pregnancy. Antimicrob Agents Chemother. 2012, 56: 5764-5773. 10.1128/AAC.01242-12. PubMedCentralCrossRefPubMed
Rijken MJ, McGready R, Phyo AP, Lindegardh N, Tarning J, Laochan N, Than HH, Mu O, Win AK, Singhasivanon P, White N, Nosten F: Pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated falciparum malaria. Antimicrob Agents Chemother. 2011, 55: 5500-5506. 10.1128/AAC.05067-11. PubMedCentralCrossRefPubMed
Adam I, Tarning J, Lindegardh N, Mahgoub H, McGready R, Nosten F: Pharmacokinetics of piperaquine in pregnant women in Sudan with uncomplicated Plasmodium falciparum malaria. AmJTrop Med Hyg. 2012, 87: 35-40. 10.4269/ajtmh.2012.11-0410. CrossRef
Lindegardh N, Annerberg A, White NJ, Day NP: Development and validation of a liquid chromatographic-tandem mass spectrometric method for determination of piperaquine in plasma stable isotope labeled internal standard does not always compensate for matrix effects. J Chromatogr B Analyt Technol Biomed Life Sci. 2008, 862: 227-236. 10.1016/j.jchromb.2007.12.011. CrossRefPubMed
Beal SLLBS, Boeckmann AJ: NONMEM Users Guides. 2006, City, Maryland, USA: Ellicott City, Maryland, USA
Beal AJB SL, Sheiner LB: NONMEM users guides. University of Califonia. 1992, San Fransisco, CA: NONMEM project group
Beal SL, Sheiner LB: Estimating population kinetics. Crit Rev Biomed Eng. 1982, 8: 195-222. PubMed
Holford N: A degenerative predictive check [abstract]. 14th annual Meeting Population approach group Europe. 2005, 738: 14-
Karunajeewa HA, Ilett KF, Mueller I, Siba P, Law I, Page-Sharp M, Lin E, Lammey J, Batty KT, Davis TM: Pharmacokinetics and efficacy of piperaquine and chloroquine in Melanesian children with uncomplicated malaria. Antimicrob Agents Chemother. 2008, 52: 237-243. 10.1128/AAC.00555-07. PubMedCentralCrossRefPubMed
Salman S, Page-Sharp M, Batty KT, Kose K, Griffin S, Siba PM, Ilett KF, Mueller I, Davis TM: Pharmacokinetic comparison of two piperaquine-containing artemisinin combination therapies in Papua New Guinean children with uncomplicated malaria. Antimicrob Agents Chemother. 2012, 56: 3288-3297. 10.1128/AAC.06232-11. PubMedCentralCrossRefPubMed
- A population pharmacokinetic model of piperaquine in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Sudan
Richard M Hoglund
Nicholas PJ Day
Nicholas J White
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II