Population pharmacokinetics and pharmacodynamics of miltefosine in mono- and combination therapy regimens for visceral leishmaniasis in East Africa
Thomas P.C. Dorlo (1,2), Anke E. Kip (2,3), Fabiana Alves (4), Jorge Alvar (4), Ahmed Musa (5), Eltahir Khalil (5), Monique Wasunna (4,6), Mats O. Karlsson (1)
(1) Uppsala University, Uppsala, Sweden, (2) Utrecht University, Utrecht, The Netherlands, (3) Netherlands Cancer Institute, Amsterdam, The Netherlands, (4) Drugs for Neglected Diseases initiative, Geneva, Switzerland, (5) Institute of Endemic Diseases, Khartoum, Sudan, (6) Kenya Medical Research Institute, Nairobi, Kenya
Objectives: Miltefosine is the only oral drug available to treat the neglected tropical parasitic disease visceral leishmaniasis, with established efficacy of a miltefosine monotherapy regimen (28 days) on the Indian subcontinent. A recent trial investigated efficacy of this 28-day regimen (2.5 mg/kg/day) in an East African population (Sudan and Kenya) and compared to a shorter combination regimen of 10 days miltefosine following a single infusion of liposomal amphotericin B. The objective of the current analysis was to establish a PK-PD relationship for miltefosine in East African visceral leishmaniasis patients in Sudan and Kenya, focusing on the effect of miltefosine exposure on the time to recrudescent infection (i.e. relapse) using a time-to-event approach.
Methods: Plasma concentrations from 95 patients (48 monotherapy, 47 combination therapy) were included in the population PK modeling using NONMEM v7.3. Various structural, variability, covariate and error models were assessed using FOCE-I. BLOQ data were handled using the M3 likelihood-based method. Laplacian estimation was used to estimate parametric survival functions on the time to relapse data. Various summary PK parameters (AUC0-EOT, Time>EC50, Time>EC90), normalized within each treatment arm to allow simultaneous analysis, were evaluated as hazard-changing covariates.
Results: A two-compartment population model with first-order absorption fitted the miltefosine PK data adequately. Relative bioavailability was found to be decreased (-73%, RSE 3.1%) during the whole first week of treatment for the monotherapy arm but only on the first day of the shorter combination regimen. Time to relapse of infection could be described using a constant baseline hazard. A Weibull function did not improve the fit. Only normalized Time>EC90 improved the model significantly (p<0.05) when added in a sigmoidal maximum effect function on the baseline hazard (baseline 1.7 relapses/year, RSE 69.5%). The additional inhibiting effect of liposomal amphotericin B on the relapse hazard was estimated at 58% (RSE 19.2%).
Conclusions: The here established PK-PD relationship for miltefosine will be useful in informing the PK target-to-attain to further select new miltefosine dosing strategies in combination regimens for visceral leishmaniasis in East Africa.