The online version of this article (doi:10.1186/1475-2875-11-303) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
JAS developed the idea for a simulation study with AH, SC, RP, JM, JG-B, JMcC and SZ making contributions to the concept and design of the study. SC, AH and RP were involved in the acquisition of data required to obtain estimates of (or ranges for) the model parameters. SZ wrote the R code to run the simulation-based decision tool with contributions from JMcC, KS and KJ. JAS and SZ wrote the first draft of the paper and together with AH, SC, RP, JM, JG-B, JMcC, KJ and KS contributed to the interpretation of the simulated output. All authors reviewed the paper and approved the final version.
Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD) model for predicting within-host parasite response was performed.
Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50), derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach.
The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours) and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle). The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i.e. the infection became more asynchronous).
This simulation study demonstrates that the PD effect predicted from in vitro growth inhibition assays does not accord well with the PD effect of the anti-malarials observed within the patient. This simulation-based PK-PD modelling approach should not be considered as a replacement to conducting clinical trials but instead as a decision tool to improve the design of a clinical trial during drug development.
Additional file 1: Age distribution of initial parasites burden. Simulated number of parasites (/μL of blood) at each stage of the life cycle – for a patient with a pre-treatment parasite burden of 1011 parasites, a mean parasite age of 8 hours and a standard deviation of 12 hours. (PDF 2 KB)12936_2012_2599_MOESM1_ESM.pdf
Additional file 2: Simulated pharmacokinetic profiles. Simulated pharmacokinetic profiles of dihydroartemisinin, artemether, mefloquine, lumefantrine and piperaquine for the 100 hypothetical patients used by the Latin hypercube sampling (LHS). Superimposed on the profiles (in a different colour) is the mean population PK profile. (PDF 1 MB)12936_2012_2599_MOESM2_ESM.pdf
Additional file 3: Tornado plots. Tornado plots of partial rank correlation coefficients, indicating the importance of each drug dependent parameter’s (EC50, kmax and γ) uncertainty in contributing to the variability in the proportion cured (left) and parasite clearance time (PCT) (right) for each artemisinin combination therapy. (PDF 4 KB)12936_2012_2599_MOESM3_ESM.pdf
Additional file 4: A-B: Proportion cured and parasite clearance time (PCT) for 100 hypothetical patients treated with artesunate (ARS) and mefloquine (MQ) combination therapy. Proportion cured and PCT were calculated for each set of Latin hypercube sampled (LHS) pharmacodynamic parameter values over 100 hypothetical patients with varying ARS and MQ pharmacokinetic profiles. Panel A: Pharmacodynamic parameters sampled using LHS versus proportion cured. Panel B: Pharmacodynamic parameters sampled using LHS versus PCT. (PDF 537 KB)12936_2012_2599_MOESM4_ESM.pdf
Additional file 5: A-B: Proportion cured and parasite clearance time (PCT) for 100 hypothetical patients treated with dihydroartemisinin (DHA) and piperaquine (PQ) combination therapy. Proportion cured and PCT were calculated for each set of Latin hypercube sampled (LHS) pharmacodynamic parameter values over 100 hypothetical patients with varying DHA and PQ pharmacokinetic profiles. Panel A: Pharmacodynamic parameters sampled using LHS versus proportion cured. Panel B: Pharmacodynamic parameters sampled using LHS versus PCT. (PDF 694 KB)12936_2012_2599_MOESM5_ESM.pdf
Additional file 6: Distribution of proportion cured for a simplified artemether-lumefantrine dosing regimen. Distribution of proportion cured within the EC50 and kmax deciles derived from the first 500 of the 5000 parameter sets for the antimalarial combination therapy, artemether (ART) and lumefantrine (LM) where artemether was given at 0, 24 and 48 hours and lumefantrine was given at 0, 8, 24, 36, 48 and 60 hours. Top panels are for artemether (EC50 – left hand side, kmax right hand side) and bottom panels are for lumefantrine (EC50 – left hand side, kmax right hand side). (PDF 207 KB)12936_2012_2599_MOESM6_ESM.pdf
Additional file 7: A-B: Proportion cured and parasite clearance time (PCT) for 100 hypothetical patients treated with artemether (ART) and lumefantrine (LF) combination therapy. Proportion cured and PCT were calculated for each set of Latin hypercube sampled (LHS) pharmacodynamic parameter values over 100 hypothetical patients with varying ART and lumefantrine LF pharmacokinetic profiles. Panel A: Pharmacodynamic parameters sampled using LHS versus proportion cured. Panel B: Pharmacodynamic parameters sampled using LHS versus PCT. (PDF 545 KB)12936_2012_2599_MOESM7_ESM.pdf
Authors’ original file for figure 112936_2012_2599_MOESM8_ESM.pdf
Authors’ original file for figure 212936_2012_2599_MOESM9_ESM.pdf
Authors’ original file for figure 312936_2012_2599_MOESM10_ESM.pdf
Authors’ original file for figure 412936_2012_2599_MOESM11_ESM.pdf
Authors’ original file for figure 512936_2012_2599_MOESM12_ESM.pdf
Authors’ original file for figure 612936_2012_2599_MOESM13_ESM.pdf
Authors’ original file for figure 712936_2012_2599_MOESM14_ESM.pdf
Authors’ original file for figure 812936_2012_2599_MOESM15_ESM.pdf
Authors’ original file for figure 912936_2012_2599_MOESM16_ESM.pdf
WHO: World Malaria Report 2011. 2011, Geneva, Geneva: Available: http://www.who.int/malaria/world_malaria_report_2011/en/,
WHO: Guidelines for the treatment of malaria. 2010, Geneva, Available: http://www.who.int/malaria/publications/atoz/9789241547925/en/index.html, 2,
Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ: Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009, 361: 455-467. 10.1056/NEJMoa0808859. PubMedCentralCrossRefPubMed
Noedl H, Se Y, Sriwichai S, Schaecher K, Teja-Isavadharm P, Smith B, Rutvisuttinunt W, Bethell D, Surasri S, Fukuda MM, Socheat D, Chan Thap L: Artemisinin resistance in Cambodia: a clinical trial designed to address an emerging problem in Southeast Asia. Clin Infect Dis. 2010, 51: e82-e89. 10.1086/657120. CrossRefPubMed
Hoshen MB, Na-Bangchang K, Stein WD, Ginsburg H: Mathematical modelling of the chemotherapy of Plasmodium falciparum malaria with artesunate: postulation of 'dormancy', a partial cytostatic effect of the drug, and its implication for treatment regimens. Parasitology. 2000, 121 (Pt 3): 237-246. CrossRefPubMed
Saralamba S, Pan-Ngum W, Maude RJ, Lee SJ, Tarning J, Lindegardh N, Chotivanich K, Nosten F, Day NP, Socheat D, White NJ, Dondorp AM, White LJ: Intrahost modeling of artemisinin resistance in Plasmodium falciparum. Proc Natl Acad Sci U S A. 2011, 108: 397-402. 10.1073/pnas.1006113108. PubMedCentralCrossRefPubMed
R, Development, Core, Team: R: A language and environment for statistical computing. 2009, Austria: R Foundation for Statistical Computing V
Davis TME, Hamzah J, Ilett KF, Karunajeewa HA, Reeder JC, Batty KT, Hackett S, Barrett PHR: In Vitro Interactions between Piperaquine, Dihydroartemisinin, and Other Conventional and Novel Antimalarial Drugs. Antimicrob Agents Chemother. 2006, 50: 2883-2885. 10.1128/AAC.00177-06. PubMedCentralCrossRefPubMed
Fivelman QL, Waiden JC, Smith PJ, Folb PI, Barnes KI: The effect of artesunate combined with standard antimalarials against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro. Trans R Trop Med Hyg. 1999, 93: 429-432. 10.1016/S0035-9203(99)90147-5. CrossRef
Hassan Alin M, Björkman A, Wernsdorfer WH: Synergism of benflumetol and artemether in Plasmodium falciparum. Am J Trop Med Hyg. 1999, 61: 439-445. PubMed
Ashley EA, Stepniewska K, Lindegardh N, McGready R, Hutagalung R, Hae R, Singhasivanon P, White NJ, Nosten F: Population pharmacokinetic assessment of a new regimen of mefloquine used in combination treatment of uncomplicated falciparum malaria. Antimicrob Agents Chemother. 2006, 50: 2281-2285. 10.1128/AAC.00040-06. PubMedCentralCrossRefPubMed
Tarning J, Ashley EA, Lindegardh N, Stepniewska K, Phaiphun L, Day NPJ, 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
Dietz K, Raddatz G, Molineaux L: Mathematical model of the first wave of Plasmodium falciparum asexual parasitemia in non-immune and vaccinated individuals. Am J Trop Med Hyg. 2006, 75: 46-55. PubMed
Cousin M, Kummerer S, Lefevre G, Marrast AC, Stein D, Weaver M: Coartem (artemether-lumefantrine) Tablets for the treatment of malaria in patients with acute, uncomplicated infections due to Plasmodium falciparum or mixed infections including P. falciparum. 2008, Novartis: Advisory Committee Briefing Book
Geary TG, Divo AA, Jensen JB: Stage specific actions of antimalarial drugs on Plasmodium falciparum in culture. Am J Trop Med Hyg. 1989, 40: 240-244. PubMed
Russell B, Chalfein F, Prasetyorini B, Kenangalem E, Piera K, Suwanarusk R, Brockman A, Prayoga P, Sugiarto P, Cheng Q, Tjitra E, Anstey NM, Price RN: Determinants of in vitro drug susceptibility testing of Plasmodium vivax. Antimicrobial Agents Chemother. 2008, 52: 1040-1045. 10.1128/AAC.01334-07. CrossRef
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
- Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development
Susan A Charman
Ric N Price
Kris M Jamsen
Julie A Simpson
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II