Wan-Yu Chu (1), Ignace Roseboom (1), Shyam Sundar (2), Dinesh Mondal (3), Pradeep Das (4), Krishna Pandey (4), Alwin Huitema (1)(5)(6), Fabiana Alves (7), Thomas Dorlo (1)
(1) Netherlands Cancer Institute, Amsterdam, the Netherlands; (2) Banaras Hindu University, Varanasi, India; (3) Centre for Nutrition and Food Security (CNFS), International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh; (4) Rajendra Memorial Research Institute of Medical Sciences (RMRIMS), Patna, India; (5) Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; (6) University Medical Centre Utrecht, Utrecht, the Netherlands, (7) Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland
Objectives:
Leishmaniasis is a neglected parasitic tropical disease, clinically characterized by a large production of macrophages in which Leishmania parasites reside and replicate. Post kala-azar dermal leishmaniasis (PKDL) is a clinical complication following a primary episode of visceral leishmaniasis manifests as skin lesions. The efficacy and safety of shortened liposomal amphotericin B (Ambisome®; LAmB) regimens in PKDL is under investigation on the Indian subcontinent. The pharmacokinetic (PK) properties of LAmB in leishmaniasis patients remain unclear. While it is known that the mononuclear phagocyte system (MPS) generally plays a pivotal role in the disposition of liposomes, the influence of PKDL pathophysiology on the plasma and skin target-site pharmacokinetics of LAmB has not been characterized. This study aimed to characterize the PK of LAmB in plasma and skin of PKDL patients and the effects of disease recovery using a semi-mechanistic approach.
Methods:
The analyzed data originated from a clinical trial studying short course LAmB monotherapy versus LAmB plus miltefosine combination therapy for PKDL treatment in Bangladesh and India. LAmB was given intravenously twice per week for 2 weeks at a total dose of 20 mg/kg (5 x 4 mg/kg). Total amphotericin B concentrations, including free, tissue-bound, protein-bound and liposomal amphotericin B, in plasma and skin were analyzed using LC-MS/MS. Plasma samples were collected after the first and the last LAmB administration. One skin biopsy was taken at the end of last LAmB infusion for patients allocated in the monotherapy arm, and at 1 week after last infusion for patients allocated in the combination therapy arm. Population PK analysis was performed with NONMEM.
Results:
PK data from 60 patients were analyzed. Non-linearities in LAmB PK within and between sampling intervals were observed. A two-compartment model with saturable distribution towards the peripheral compartment, described by a maximal binding capacity (Bmax) function, best described the data. Bmax, representing the maximal drug accumulation in the peripheral compartment, assumed to reflect macrophage liposomal uptake, was estimated at 91±7 mg. kin and kout, first-order rate constants representing uptake and subsequent release by the peripheral compartment, were estimated at 0.46±0.08 1/h and 0.02±0.002 1/h, receptively. CL and Vd of the central compartment were 0.41±0.02 L/h and 4.68±0.13 L, respectively. A decrease in Bmax over time was found resulting in a 25% lower Bmax at end of treatment, reflecting a treatment effect on the activity of macrophages. Between occasion variability on Bmax further improved the model fit with a 19-unit OFV drop. Median amphotericin B concentration in skin at end of treatment was 7.11 µg/g (range 1-360 µg/g). In total, 96% of the LAmB skin concentrations were above the reported in vitro IC50 against intracellular Leishmania amastigotes (0.09-0.36 mg/L) [1]. A trend of higher Cmax in plasma after the last infusion with higher exposure in skin was observed. Skin was implemented as an effect compartment of the central plasma compartment with an estimated rate of distribution to skin tissue 0.0012±0.0002 1/h. Drug elimination half-life in skin was 43-fold longer compared to plasma (346 hour in skin versus 8 hours in plasma), indicating a much longer residence time of the drug at the target site in skin tissue compared to plasma.
Conclusions:
PK of LAmB in plasma and skin were elucidated in leishmaniasis patients for the first time. The present model suggested that LAmB follows non-linear PK characteristics of liposome disposition, driven by saturation of macrophage uptake and opsonization. Additionally, the model suggested a decrease in the maximal LAmB accumulation in macrophages during the treatment period. A much longer residence time of LAmB in the skin than in plasma was identified, indicating that drug exposure at the skin target site cannot be simply informed by plasma PK. This highlights the importance of target site PK studies in PKDL patients and other dermal forms of leishmaniasis.
References:
[1] Vermeersch M et al. Antimicrob Agents Chemother. 2009 Sep;53(9):3855-9.
Reference: PAGE 30 (2022) Abstr 9970 [www.page-meeting.org/?abstract=9970]
Poster: Drug/Disease Modelling - Infection