Andres Mazariegos Herrera (1), Mats O. Karlsson (1), Elin M. Svensson (1, 2), Thomas P.C. Dorlo (1)
(1) Department of Pharmacy, Uppsala University, Sweden. (2) Department of Pharmacy, Radboud university medical center, The Netherlands.
Introduction: Achieving adequate levels of miltefosine exposure in pediatric patients in the neglected tropical disease leishmaniasis has been challenging. Conventional 2.5 mg/kg/day dosing resulted in a lack of efficacy in pediatric visceral leishmaniasis (VL) patients in Eastern Africa and an increased model-based allometric dosing regimen reliant on fat-free mass (FFM) was therefore introduced resulting in equivalent exposure between children and adults and adequate efficacy in children1,2. This allometric FFM-based dose, dependent on sex, weight and height, is, however, impractical to implement in remote endemic areas and a weight-band (WB) based dose would be preferable.
Objectives: To develop a WB based dose regimen for allometric miltefosine optimized for pediatric VL patients in Eastern Africa up to 30 kg body weight.
Methods: Real-world growth curves and their distributions were developed for pediatric VL patients from Eastern Africa. To simulate virtual patients WHO and/or CDC growth curves are often used, but they do not capture the weight- and height-for-age profile of the typical pediatric Eastern African patient, who often suffers malnourishment and stunted growth3,4. Demographic data (height, weight, age and sex) was collected from patient cohorts in Sudan (n = 1371), Ethiopia (n = 660), South Sudan (n = 6396), Uganda (n = 170) and Kenya (n = 782). Height and weight z-scores and their correlation coefficient were calculated. Eastern African VL-specific adjustment factors were fitted using a polynomial function and combined with the WHO-CDC growth charts’ LMS parameters to enable simulation of realistic pediatric VL patients5.
A uniform distribution of ages 1 to 18 years old was generated to conduct PK simulations of different miltefosine regimens, either FFM- or simplified WB-based. Patients under 1 year old were excluded as our demographical data had only a few individuals and occurrences of congenital VL reported cases are rare6. To simulate PK profiles, an established two-compartment population PK model based on a clinical study using the FFM-based regimen, was used2. The WBs followed the recent proposal by the WHO GAP-f harmonizing of WBs across disease areas7. Doses for children weighing less than 30 kg were simulated and pharmacokinetic targets were derived from simulated PK profiles obtained with the FFM-based dosing. As upper limit (safety), the 95th percentile of AUC till end of treatment (AUCEOT) was used. As lower limit, the 5th percentile of time over the EC90 till end of treatment (T>EC90_EOT) was used.
A utility score (Eq. 1) using the exposure thresholds was used to select the best dose for each weight band. The % of patients outside the exposure limits for either FFM- or WB-based dosing was calculated for each kg unit (weight unit, WU). The sum of all WUs yields the final score; the lower, the less % of patients there were below the lower (% OutsideLower limit) and above (% OutsideUpper limit) limits.
Eq. 1 ∑WU %IDWU x (%OutsideLower limit + OutsideUpper limit)
Results: Eastern African pediatric VL patients exhibited a lower FFM across all ages compared to the WHO-CDC growth charts: in infants and toddlers (1-3 y/o) 0.78 – 2.48 kg lower, children (4 – 12 y/o) 2.71 – 7.77 kg lower, and teenagers (13 – 18 y/o) 5.33 – 8.42 kg lower. After adjustment, the median values and distribution of the WHO-CDC adjusted population accurately resembled those of the pediatric VL population, enabling virtual population simulations.
The final utility score combined the percentages of patients outside the limits, and dosing recommendations were made for a 14- and 28-day regimen. The dose proposed for all WB in both cases were matched to be the same. In the proposed WB-based regimen, the percentage of patients over the upper limit were 10.67 and 8.72% for the 14- and 28-day respectively, higher than the 3.71 and 4.96 from the FFM-based for both days. On the lower threshold the values were 2.27 and 2.42% for the 14- and 28-day WB-based, lower than those of the FFM-based (4.27 and 4.26%) and the conventional linear 2.5mg/kg/day dosing (36.64% for 28-days). The final proposed WB-based regimen is: 20mg to children below 6kg, 40 mg to 6-9 kg, 50 mg to 10-14 kg, 60mg to 15-19 kg, 80mg to 20 – 24 kg and 100mg to 25 – 30 kg.
Conclusions: The WB-based dosing regimen for miltefosine presents a streamlined approach, reducing over 50 potential dosing categories to six, compared to the FFM-based regimen. This adaptation maintains sufficient pharmacokinetic target attainment in pediatric VL patients in Eastern Africa.
References:
[1] Musa, et. al. Paromomycin and Miltefosine Combination as an Alternative to Treat Patients with Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial. Clinical Infectious Diseases. 2023; 76(3):e1177-e1185
[2] Verrest L, et.al. Population pharmacokinetics of a combination of miltefosine and paromomycin in Eastern African children and adults with visceral leishmaniasis. Journal of Antimicrobial Chemotherapy. 2023; 78(11):2702-2714. Doi: 10.1093/jac/dkad286.
[3] WHO Child Growth Standards Length/Height-for-Age, Weight-for-Age, Weight-for-Length, Weight-for-Height and Body Mass Index-for-Age: Methods and Development. France: World Health Organization; 2006;369:1-312. https://www.who.int/publications/i/item/924154693X
[4] Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000 CDC growth charts for the United States: methods and development. Vital Health Stat 11. 2002;11(246):1-190.
[5] Wassman RE, et.al. Constructing a representative in‐silico population for paediatric simulations: Application to HIV‐positive African children. British Journal of Clinical Pharmacology. 2021; 87(7): 2847-2854. Doi: 10.1111/bcp.14694.
[6] Murray W, Tanowitz HB. Leishmaniasis in infants and children. Seminars in Pediatric Infectious Diseases. 2000; 11(3): 196-201. Doi: 10.1053/pi.2000.6231.
[7] WHO. Shaping the global innovation and access landscape for better paediatric medicines: Global Accelerator for Paediatric Formulations 2022–2024 business plan. Geneva, 2022.
Reference: PAGE 32 (2024) Abstr 11173 [www.page-meeting.org/?abstract=11173]
Poster: Drug/Disease Modelling - Paediatrics