Disease-specific differences in pharmacokinetics of paromomycin and miltefosine between post-kala-azar dermal leishmaniasis and visceral leishmaniasis patients in Eastern Africa
Wan-Yu Chu (1), Luka Verrest (1), Brima M. Younis (2), Ahmed M. Musa (2), Jane Mbui (3), Rezika Mohammed (4), Joseph Olobo (5), Koert Ritmeijer (6), Séverine Monnerat (7), Monique Wasunna (8), Ignace C. Roseboom (1), Alexandra Solomos (7), Alwin D.R. Huitema (1)(9)(10), Fabiana Alves (7), Thomas P.C. Dorlo (1)(11)
(1) Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands (2) Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan (3) Kenya Medical Research Institute, Nairobi, Kenya (4) Leishmaniasis Research and Treatment Center, University of Gondar, Gondar, Ethiopia (5) Makerere University, Kampala, Uganda (6) Médecins Sans Frontières, Amsterdam, the Netherlands (7) Drugs for Neglected Diseases initiative, Geneva, Switzerland (8) Drugs for Neglected Diseases initiative - Africa, Nairobi, Kenya (9) Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands (10) Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (11) Department of Pharmacy, Uppsala University, Uppsala, Sweden
Objectives: Post-kala-azar dermal leishmaniasis (PKDL) is a skin complication following a primary visceral leishmaniasis (VL) infection. Treatment and dosing regimens for PKDL are usually extrapolated from VL, often with an extended treatment duration due to the slow clearance of lesions. However, it should be noted that VL patients are ill and usually suffer from malnutrition, while PKDL patients are generally well except for their skin condition and have a better renal function. Therefore, the pharmacokinetics (PK) of drugs may be different between VL and PKDL patients due to disease-specific differences in absorption, distribution and metabolism. This study aimed to characterize the PK of paromomycin and miltefosine in PKDL patients and compare them with VL patients in Eastern Africa.
Methods: Pharmacokinetic data from one PKDL study (NCT03399955) [1] and one VL study (NCT03129646) [2] in Eastern African patients were included. In the PKDL study, patients were given a combination of paromomycin for 14 days plus miltefosine for 42 days, or liposomal amphotericin B for 7 days plus miltefosine for 28 days. In the VL study, patients were given paromomycin for 14 days plus miltefosine for 14 days or 28 days. Plasma concentrations of paromomycin and miltefosine were analyzed using LC-MS/MS [3-4] and were used for population PK analysis performed by nonlinear mixed effects modeling.
Results: Miltefosine and paromomycin plasma concentrations were measured in available samples from 109 PKDL and 264 VL patients. In the population PK analysis, 328 paromomycin observations from 40 patients and 1516 miltefosine observations from 373 patients were included. The PK of paromomycin was best described by a three-compartment model including one saturable peripheral compartment. The saturable distribution was described by a maximal binding capacity function resembling drug accumulation in tissues with high megalin expression (e.g., renal tubule). PKDL patients had a 1.7-fold (95%CI: 1.21-2.45) higher capacity for accumulation compared to VL patients. The change in paromomycin clearance was found to follow the individual change in creatinine levels during the 14-day treatment period. The PK of miltefosine was best described by a two-compartment model with first-order absorption and elimination. Only in VL patients, the bioavailability was decreased by 69% (62-76) at the treatment start. The rates of absorption in PKDL and VL patients were 5.43 1/day (4.54-6.26) and 0.99 1/day (0.84-1.17), respectively. The bioavailability decreased exponentially with cumulative dose, resulting in a maximum of 40.6% drop in patients given 42-day miltefosine. When co-administered with liposomal amphotericin B, the bioavailability of miltefosine decreased by 8.6% (2-15), suggesting a drug-drug interaction. PKDL patients given the same regimen as VL patients presented 26% lower paromomycin plasma exposure (AUC0-24 hours, D14) and 38% higher miltefosine exposure (AUC0-28D) at the end of the treatment.
Conclusions: The population PK of paromomycin and miltefosine in Eastern African PKDL patients were characterized for the first time and were compared to the PK in VL patients. Various effects of VL disease on the distribution and clearance of paromomycin and the absorption and bioavailability of miltefosine were identified. Besides, a potential interaction between liposomal amphotericin B and miltefosine was underlined. Although substantial differences in drug exposure between diseases and combination regimens were quantified, justification of subsequent dose adaptations in PKDL patients requires future pharmacokinetic-pharmacodynamic studies to further define the therapeutic window for this neglected dermal infection.
References:
[1] https://clinicaltrials.gov/ct2/show/study/NCT03399955. An Open Label, Randomized, Parallel Arm Clinical Trial of Two Regimens to Assess the Safety and Efficacy for Treatment of Post Kala-azar Dermal Leishmaniasis (PKDL) Patients in Sudan.
[2] Musa AM et al. (2022). Paromomycin and Miltefosine Combination as an Alternative to Treat Patients With Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial.
[3] Roseboom IC et al. (2020). Highly sensitive UPLC-MS/MS method for the quantification of paromomycin in human plasma.
[4] Dorlo TPC et al. (2008). Development and validation of a quantitative assay for the measurement of miltefosine in human plasma by liquid chromatography-tandem mass spectrometry.