This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features!
Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log in
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2017 Nov 1;72(11):3131-3140.
doi: 10.1093/jac/dkx283.

Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study

Affiliations
Clinical Trial

Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study

Thomas P C Dorlo et al. J Antimicrob Chemother. .

Abstract

Background: Low efficacy of miltefosine in the treatment of visceral leishmaniasis was recently observed in Eastern Africa.

Objectives: To describe the pharmacokinetics and establish a pharmacokinetic/pharmacodynamic relationship for miltefosine in Eastern African patients with visceral leishmaniasis, using a time-to-event approach to model relapse of disease.

Methods: Miltefosine plasma concentrations from 95 patients (48 monotherapy versus 47 combination therapy) were included in the population pharmacokinetic model using non-linear mixed effects modelling. Subsequently a time-to-event model was developed to model the time of clinical relapse. Various summary pharmacokinetic parameters (various AUCs, Time > EC50, Time > EC90), normalized within each treatment arm to allow simultaneous analysis, were evaluated as relapse hazard-changing covariates.

Results: A two-compartment population model with first-order absorption fitted the miltefosine pharmacokinetic data adequately. Relative bioavailability was reduced (-74%, relative standard error 4.7%) during the first week of treatment of the monotherapy arm but only the first day of the shorter combination regimen. Time to the relapse of infection could be described using a constant baseline hazard (baseline 1.8 relapses/year, relative standard error 72.7%). Miltefosine Time > EC90 improved the model significantly when added in a maximum effect function on the baseline hazard (half maximal effect with Time > EC90 6.97 days for monotherapy).

Conclusions: Miltefosine drug exposure was found to be decreased in Eastern African patients with visceral leishmaniasis, due to a (transient) initial lower bioavailability. Relapse hazard was inversely linked to miltefosine exposure. Significantly lower miltefosine exposure was observed in children compared with adults, further urging the need for implementation of dose adaptations for children.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Goodness-of-fit plots for the final miltefosine population pharmacokinetic model. Observed concentrations versus (a) population predicted concentrations and (b) individual predicted concentrations. Conditional weighted residuals versus (c) population predicted concentrations and (d) time. Solid line represents the line of identity or unity and the broken line is the locally weighted least square regression line to indicate trends.
Figure 2.
Figure 2.
Visual predictive check of the final miltefosine population pharmacokinetic model in Eastern African patients with VL receiving 10 days of miltefosine (2.5 mg/kg/day) in combination therapy (left plot) or 28 days of miltefosine (2.5 mg/kg/day) monotherapy (right plot). Insets in the top right corner show a magnification of the same plot during the initial treatment period (0–28 days). Circles represent the observed concentrations, the solid line the 50th percentile of the observed data and the dashed lines the 10th and 90th percentiles of the observed data. Shaded areas indicate the simulated 95% CI of the 10th and 90th (light grey) and 50th (dark grey) percentiles of the simulations (n = 1000 simulations).
Figure 3.
Figure 3.
Visual predictive check of the final time-to-event model with an inhibitory effect of miltefosine exposure (Time > EC90) on the hazard function. Left plot depicts the combination therapy regimen (10 days of miltefosine), the right plot the monotherapy arm (28 days of miltefosine). Solid black line is the Kaplan–Meier plot of the observed relapses of visceral leishmaniasis during the follow-up period, and the grey area is the 95% prediction interval of the simulated time to the relapse of disease (n = 1000 simulations).
Figure 4.
Figure 4.
Hazard ratio versus the duration of miltefosine concentration>EC90 (Time > EC90). Lines indicate the estimated hazard ratios for the combination therapy (left panel) and miltefosine monotherapy (right panel). Grey areas represent the respective computed 90% CI. Circles represent the observed individuals: open circles represent cured patients, while filled circles represent patients who relapsed and received rescue treatment.

References

    1. Harhay MO, Olliaro PL, Vaillant M. et al. Who is a typical patient with visceral leishmaniasis? Characterizing the demographic and nutritional profile of patients in Brazil, East Africa, and South Asia. Am J Trop Med Hyg 2011; 84: 543–50. - PMC - PubMed
    1. Boelaert M, Meheus F, Sanchez A. et al. The poorest of the poor: a poverty appraisal of households affected by visceral leishmaniasis in Bihar, India. Trop Med Int Health 2009; 14: 639–44. - PubMed
    1. Alvar J, Vélez ID, Bern C. et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One 2012; 7: e35671.. - PMC - PubMed
    1. Rijal S, Ostyn B, Uranw S. et al. Increasing failure of miltefosine in the treatment of Kala-azar in Nepal and the potential role of parasite drug resistance, reinfection, or noncompliance. Clin Infect Dis 2013; 56: 1530–8. - PubMed
    1. Dorlo TP, Balasegaram M, Beijnen JH. et al. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother 2012; 67: 2576–97. - PubMed

MeSH terms

Full text links
Silverchair Information Systems full text link Silverchair Information Systems Free PMC article
Cite

AltStyle によって変換されたページ (->オリジナル) /