Disease-Specific Differences in Pharmacokinetics of Paromomycin and Miltefosine Between Post-Kala-Azar Dermal Leishmaniasis and Visceral Leishmaniasis Patients in Eastern Africa
Treatment regimens for post-kala-azar dermal leishmaniasis (PKDL) are usually extrapolated from those for visceral leishmaniasis (VL), but drug pharmacokinetics (PK) can differ due to disease-specific variations in absorption, distribution, and elimination. This study characterized PK differences in paromomycin and miltefosine between 109 PKDL and 264 VL patients from Eastern Africa. VL patients showed 0.55-fold (95% confidence interval [CI], .41-.74) lower capacity for paromomycin saturable reabsorption in renal tubules, and required a 1.44-fold (95% CI, 1.23-1.71) adjustment when relating renal clearance to creatinine-based estimated glomerular filtration rate. Miltefosine bioavailability in VL patients was lowered by 69% (95% CI, 62%-76%) at treatment start. Comparing PKDL to VL patients on the same regimen, paromomycin plasma exposures were 0.74- to 0.87-fold, while miltefosine exposure until the end of treatment day was 1.4-fold. These pronounced PK differences between PKDL and VL patients in Eastern Africa highlight the challenges of directly extrapolating dosing regimens from one leishmaniasis presentation to another.
Authors
- Joseph Olobo (ORCID: https://orcid.org/0000-0001-5148-8876)
- Ignace C. Roseboom (ORCID: https://orcid.org/0000-0003-2684-890X)
- Alwin D. R. Huitema (ORCID: https://orcid.org/0000-0003-1939-4639)
- Alexandra Solomos
- Luka Verrest (ORCID: https://orcid.org/0000-0001-7312-5902)
- Koert Ritmeijer (ORCID: https://orcid.org/0000-0001-5924-872X)
- Thomas P. C. Dorlo (ORCID: https://orcid.org/0000-0003-3076-8435)
- Rezika Mohammed (ORCID: https://orcid.org/0000-0002-1410-0454)
- Monique Wasunna
- Jane Mbui (ORCID: https://orcid.org/0000-0002-8759-5689)
- Séverine Monnerat
- Wan‐Yu Chu (ORCID: https://orcid.org/0000-0002-0402-8807)
- Fabiana Alves (ORCID: https://orcid.org/0000-0001-6213-5224)
- Ahmed Musa (ORCID: https://orcid.org/0000-0003-0590-6170)
- Brima M. Younis
Institutions
- Uppsala University (SE)
- Drugs for Neglected Diseases Initiative (CH)
- University of Khartoum (SD)
- Utrecht University (NL)
- Kenya Medical Research Institute (KE)
- The Netherlands Cancer Institute (NL)
- University Medical Center Utrecht (NL)
- Oncode Institute (NL)
- Kenya AIDS Vaccine Initiative (KE)
- Médecins Sans Frontières (GB)
- Princess Máxima Center (NL)
- Makerere University (UG)
- University of Gondar (ET)
Publication Details
- Journal
- The Journal of Infectious Diseases
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1093/infdis/jiae413
- Citations
- 3
- Primary Topic
- Research on Leishmaniasis Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- Médecins Sans Frontières
- European Commission
- Bundesministerium für Bildung und Forschung
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Vetenskapsrådet
- Ministerie van Buitenlandse Zaken
- Direktion für Entwicklung und Zusammenarbeit
- European and Developing Countries Clinical Trials Partnership