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

Abstract

BackgroundLow efficacy of miltefosine in the treatment of visceral leishmaniasis was recently observed in Eastern Africa.ObjectivesTo 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.MethodsMiltefosine 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.ResultsA 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).ConclusionsMiltefosine 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.

Characterizing the non-linear pharmacokinetics of miltefosine in paediatric visceral leishmaniasis patients from Eastern Africa

“…This value was established by in vitro experiments investigating intracellular susceptibility of Leishmania donovani amastigotes from Eastern Africa to miltefosine. 14 …”

“… 13 The highest probability of treatment success was for 29.5 days >EC 90 for miltefosine therapy. 14 …”

Macrophage Activation Marker Neopterin: A Candidate Biomarker for Treatment Response and Relapse in Visceral Leishmaniasis

“…Neopterin concentrations were determined as part of a randomized multicentre trial (registered as NCT01067443) assessing the safety and efficacy of different VL treatments in Eastern Africa. The clinical results and pharmacokinetic analysis have been published elsewhere (Wasunna et al, 2016 ; Dorlo et al, 2017 ). The study was carried out at three VL treatment centers located in endemic areas: two in Sudan (Dooka and Kassab hospitals) and one in Kenya (Kimalel health center).…”

“…To decrease the invasiveness of sampling for patients, neopterin concentrations were quantified in the same samples collected for miltefosine pharmacokinetic analysis (Wasunna et al, 2016 ; Dorlo et al, 2017 ). For this reason, baseline samples were taken on the first day of miltefosine treatment before the first miltefosine dose, which in the combination therapy was 1 day after the L-AMB infusion (study day 2).…”

Immunomodulatory Therapy of Visceral Leishmaniasis in Human Immunodeficiency Virus-Coinfected Patients

“…Less than 5% of immunocompetent individuals who initially cure develop a relapse, most commonly within 6–12 months after treatment ( 5 ). Treatment outcomes, however, vary substantially between different geographic regions and depend on the drug(s) used, drug exposure, parasite susceptibility to the drug, severity of disease, host immunity, and the presence of coinfections ( 11 – 13 ).…”