Disease-Specific Differences in Pharmacokinetics of Paromomycin and Miltefosine Between Post-Kala-Azar Dermal Leishmaniasis and Visceral Leishmaniasis Patients in Eastern Africa.

Abstract

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.