Anke E Kip1, Séverine Blesson2, Fabiana Alves2, Monique Wasunna3, Robert Kimutai3, Peninah Menza3, Bewketu Mengesha4, Jos H Beijnen1,5, Asrat Hailu6, Ermias Diro7, Thomas P C Dorlo1. 1. Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands. 2. Drugs for Neglected Diseases Initiative, Geneva, Switzerland. 3. Drugs for Neglected Diseases initiative, Nairobi, Kenya. 4. Leishmaniasis Research and Treatment Center, University of Gondar, Gondar, Ethiopia. 5. Faculty of Science, Utrecht University, Utrecht, The Netherlands. 6. Department of Microbiology, Immunology, and Parasitology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia. 7. Department of Internal Medicine, University of Gondar, Gondar, Ethiopia.
Abstract
BACKGROUND: Despite high HIV co-infection prevalence in Ethiopian visceral leishmaniasis (VL) patients, the adequacy of antileishmanial drug exposure in this population and effect of HIV-VL co-morbidity on pharmacokinetics of antileishmanial and antiretroviral (ARV) drugs is still unknown. METHODS: HIV-VL co-infected patients received the recommended liposomal amphotericin B (LAmB) monotherapy (total dose 40 mg/kg over 24 days) or combination therapy of LAmB (total dose 30 mg/kg over 11 days) plus 28 days 100 mg/day miltefosine, with possibility to extend treatment for another cycle. Miltefosine, total amphotericin B and ARV concentrations were determined in dried blood spots or plasma using LC-MS/MS. RESULTS: Median (IQR) amphotericin B Cmax on Day 1 was 24.6 μg/mL (17.0-34.9 μg/mL), which increased to 40.9 (25.4-53.1) and 33.2 (29.0-46.6) μg/mL on the last day of combination and monotherapy, respectively. Day 28 miltefosine concentration was 18.7 (15.4-22.5) μg/mL. Miltefosine exposure correlated with amphotericin B accumulation. ARV concentrations were generally stable during antileishmanial treatment, although efavirenz Cmin was below the 1 μg/mL therapeutic target for many patients. CONCLUSIONS: This study demonstrates that antileishmanial drug exposure was low in this cohort of HIV co-infected VL patients. Amphotericin B Cmax was 2-fold lower than previously observed in non-VL patients. Miltefosine exposure in HIV-VL co-infected patients was 35% lower compared with adult VL patients in Eastern Africa, only partially explained by a 19% lower dose, possibly warranting a dose adjustment. Adequate drug exposure in these HIV-VL co-infected patients is especially important given the high proportion of relapses.
BACKGROUND: Despite high HIV co-infection prevalence in Ethiopian visceral leishmaniasis (VL) patients, the adequacy of antileishmanial drug exposure in this population and effect of HIV-VL co-morbidity on pharmacokinetics of antileishmanial and antiretroviral (ARV) drugs is still unknown. METHODS:HIV-VL co-infectedpatients received the recommended liposomal amphotericin B (LAmB) monotherapy (total dose 40 mg/kg over 24 days) or combination therapy of LAmB (total dose 30 mg/kg over 11 days) plus 28 days 100 mg/day miltefosine, with possibility to extend treatment for another cycle. Miltefosine, total amphotericin B and ARV concentrations were determined in dried blood spots or plasma using LC-MS/MS. RESULTS: Median (IQR) amphotericin B Cmax on Day 1 was 24.6 μg/mL (17.0-34.9 μg/mL), which increased to 40.9 (25.4-53.1) and 33.2 (29.0-46.6) μg/mL on the last day of combination and monotherapy, respectively. Day 28 miltefosine concentration was 18.7 (15.4-22.5) μg/mL. Miltefosine exposure correlated with amphotericin B accumulation. ARV concentrations were generally stable during antileishmanial treatment, although efavirenz Cmin was below the 1 μg/mL therapeutic target for many patients. CONCLUSIONS: This study demonstrates that antileishmanial drug exposure was low in this cohort of HIV co-infectedVLpatients. Amphotericin B Cmax was 2-fold lower than previously observed in non-VLpatients. Miltefosine exposure in HIV-VL co-infectedpatients was 35% lower compared with adult VLpatients in Eastern Africa, only partially explained by a 19% lower dose, possibly warranting a dose adjustment. Adequate drug exposure in these HIV-VL co-infectedpatients is especially important given the high proportion of relapses.
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