TY - JOUR
T1 - Geographical Variability in Paromomycin Pharmacokinetics Does Not Explain Efficacy Differences between Eastern African and Indian Visceral Leishmaniasis Patients
AU - Verrest, Luka
AU - Wasunna, Monique
AU - Kokwaro, Gilbert
AU - Aman, Rashid
AU - Musa, Ahmed M.
AU - Khalil, Eltahir A.G.
AU - Mudawi, Mahmoud
AU - Younis, Brima M.
AU - Hailu, Asrat
AU - Hurissa, Zewdu
AU - Hailu, Workagegnehu
AU - Tesfaye, Samson
AU - Makonnen, Eyasu
AU - Mekonnen, Yalemtsehay
AU - Huitema, Alwin D.R.
AU - Beijnen, Jos H.
AU - Kshirsagar, Smita A.
AU - Chakravarty, Jaya
AU - Rai, Madhukar
AU - Sundar, Shyam
AU - Alves, Fabiana
AU - Dorlo, Thomas P.C.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/11
Y1 - 2021/11
N2 - Introduction: Intramuscular paromomycin monotherapy to treat visceral leishmaniasis (VL) has been shown to be effective for Indian patients, while a similar regimen resulted in lower efficacy in Eastern Africa, which could be related to differences in paromomycin pharmacokinetics. Methods: Pharmacokinetic data were available from two randomized controlled trials in VL patients from Eastern Africa and India. African patients received intramuscular paromomycin monotherapy (20 mg/kg for 21 days) or combination therapy (15 mg/kg for 17 days) with sodium stibogluconate. Indian patients received paromomycin monotherapy (15 mg/kg for 21 days). A population pharmacokinetic model was developed for paromomycin in Eastern African and Indian VL patients. Results: Seventy-four African patients (388 observations) and 528 Indian patients (1321 observations) were included in this pharmacokinetic analysis. A one-compartment model with first-order kinetics of absorption and elimination best described paromomycin in plasma. Bioavailability (relative standard error) was 1.17 (5.18%) times higher in Kenyan and Sudanese patients, and 2.46 (24.5%) times higher in Ethiopian patients, compared with Indian patients. Ethiopian patients had an approximately fourfold slower absorption rate constant of 0.446 h–1 (18.2%). Area under the plasma concentration-time curve for 24 h at steady-state (AUCτ,SS) for 15 mg/kg/day (median [interquartile range]) was higher in Kenya and Sudan (172.7 µg·h/mL [145.9–214.3]) and Ethiopia (230.1 µg·h/mL [146.3–591.2]) compared with India (97.26 µg·h/mL [80.83–123.4]). Conclusion: The developed model provides detailed insight into the pharmacokinetic differences among Eastern African countries and India, however the resulting differences in paromomycin exposure do not seem to explain the geographical differences in paromomycin efficacy in the treatment of VL patients.
AB - Introduction: Intramuscular paromomycin monotherapy to treat visceral leishmaniasis (VL) has been shown to be effective for Indian patients, while a similar regimen resulted in lower efficacy in Eastern Africa, which could be related to differences in paromomycin pharmacokinetics. Methods: Pharmacokinetic data were available from two randomized controlled trials in VL patients from Eastern Africa and India. African patients received intramuscular paromomycin monotherapy (20 mg/kg for 21 days) or combination therapy (15 mg/kg for 17 days) with sodium stibogluconate. Indian patients received paromomycin monotherapy (15 mg/kg for 21 days). A population pharmacokinetic model was developed for paromomycin in Eastern African and Indian VL patients. Results: Seventy-four African patients (388 observations) and 528 Indian patients (1321 observations) were included in this pharmacokinetic analysis. A one-compartment model with first-order kinetics of absorption and elimination best described paromomycin in plasma. Bioavailability (relative standard error) was 1.17 (5.18%) times higher in Kenyan and Sudanese patients, and 2.46 (24.5%) times higher in Ethiopian patients, compared with Indian patients. Ethiopian patients had an approximately fourfold slower absorption rate constant of 0.446 h–1 (18.2%). Area under the plasma concentration-time curve for 24 h at steady-state (AUCτ,SS) for 15 mg/kg/day (median [interquartile range]) was higher in Kenya and Sudan (172.7 µg·h/mL [145.9–214.3]) and Ethiopia (230.1 µg·h/mL [146.3–591.2]) compared with India (97.26 µg·h/mL [80.83–123.4]). Conclusion: The developed model provides detailed insight into the pharmacokinetic differences among Eastern African countries and India, however the resulting differences in paromomycin exposure do not seem to explain the geographical differences in paromomycin efficacy in the treatment of VL patients.
UR - http://www.scopus.com/inward/record.url?scp=85107643226&partnerID=8YFLogxK
U2 - 10.1007/s40262-021-01036-8
DO - 10.1007/s40262-021-01036-8
M3 - Article
C2 - 34105063
AN - SCOPUS:85107643226
SN - 0312-5963
VL - 60
SP - 1463
EP - 1473
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 11
ER -