Semra Palic (1), Anke E. Kip (1), Jos H. Beijnen(1), Monique Wasunna (2), Fabiana Alves(3), Thomas P.C. Dorlo (1)
(1) Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands (2) Drugs for Neglected Diseases initiative, Nairobi, Kenya (3) Drugs for Neglected Diseases initiative, Geneva, Switzerland
Objectives:
Miltefosine is currently the only oral drug available for treatment of the neglected tropical parasitic disease visceral leishmaniasis (VL). Conventional 2.5 mg/kg/day dosing of miltefosine was recently shown to be less effective in pediatric VL patients compared to adults in Eastern Africa, and a PKPD relationship between exposure (AUC 191–767 ug*day/mL ) and VL relapse was established.[1],[2] Therefore, an open-label clinical trial (LEAP0714) with increased mg/kg miltefosine dosing based on an allometric formula was conducted in pediatric VL patients in Uganda and Kenya. Results of this trial unexpectedly indicated a lower than dose-proportional increase in AUCd0-28. The main objective of the current analysis was to investigate the reasons underlying the observed phenomenon; therefore a pooled analysis of pediatric data with the two different dosing regimens was performed to further characterize observed non-linearities.
Methods:
From the previous LEAP0208 trial 18 pediatric patients (age 7-11) were selected receiving the conventional miltefosine dose of 2.5 mg/kg/day p.o. for 28 days.[2] In LEAP0714, 30 pediatric patients (age 4-11) received miltefosine p.o. based on an allometric dosing formula (equivalent to 2.7 to 3.9 mg/kg/day). Plasma samples were nominally collected on the screening day, during the treatment days 1, 7, 14, 28, and at follow-up period at days 56 and 210, while in LEAP0714 a sample on day 21 was also collected. A total of 325 miltefosine plasma concentrations were analyzed by liquid chromatography tandem mass spectrometry. Data were analyzed in a population approach using the first-order conditional estimation with interaction (FOCE+I) in NONMEM (version 7.3.0, Globomax, USA) using Pirana as interface (version 2.9.6). Both total amount miltefosine mg/day (AMTT) and cumulative mg/kg/day dose (CD) were explored as a covariate on PK parameters using various parameterizations.
Results:
The previously developed two-compartmental PK model with first-order absorption and elimination showed overprediction of miltefosine accumulation in the last week of treatment for the allometric dose PK data.[2] Similar to the previous model developed on the 2.5 mg/kg data, a lower bioavailability (F) of -68.6% (RSE 8%) in the first treatment week was required (ΔOFV -19.4), presumably due to initial malnourishment and malabsorption. This decrease in F appeared highly variable between subjects (BSV 83.9%, RSE 10%, ΔOFV -223.9). AMTT and CD were additionally tested as covariate on all PK parameters to explain observed non-linearities in the later part of the treatment and CD? was found to have the most impact again on F. A piece-wise linear function best fitted the data, where a CD higher than 25 mg/kg decreased F by 3.5% (RSE 13%) for every 5 mg/kg increase (ΔOFV -17.2). Residual variability was described by a proportional error of 32.7% (RSE 11%). Model predicted individual PK profiles were used to estimate individual miltefosine exposures. In the first week of treatment median AUCd0-7 was 8.56μg*ml/day (range 0.53 to 28.6) and 20.5μg*ml/day (range 4.1 to 95.1), for the linear and allometric dosing regimen, respectively; while the median AUCd0-28 was 322.1 (range 263.7.6- 472.3) μg*ml/day and 361.9 (range 206.1- 627.1) μg*ml/day, respectively. Despite these nonlinearities, the increased exposure in the first part of the treatment following the allometric dosing regimen might have contributed to the observed efficacy for this regimen.
Conclusions:
The results indicate that miltefosine F is dose-dependent, with two separate non-linearities observed: a decrease in F at the start of treatment independent of dose and an effect of CD on F in the later phase of treatment. The latter effect might possibly be explained by slow accumulation of miltefosine in the gastrointestinal membrane cells and subsequent dose-dependent saturation of paracellular transport, corroborated by the extremely slow absorption rate of miltefosine.
References:
[1] T. P. C. Dorlo et al., “Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study,” J. Antimicrob. Chemother. 2017; 72(11):3131–3140.
[2] M. Wasunna et al., “Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial,” PLoS Negl. Trop. Dis. 2016;10(9):e0004880.
Reference: PAGE 27 (2018) Abstr 8619 [www.page-meeting.org/?abstract=8619]
Poster: Drug/Disease Modelling - Infection