Geographical Variability in Paromomycin Pharmacokinetics Does Not Explain Efficacy Differences between Eastern African and Indian Visceral Leishmaniasis Patients

Luka Verrest, Monique Wasunna, Gilbert Kokwaro, Rashid Aman, Ahmed M. Musa, Eltahir A.G. Khalil, Mahmoud Mudawi, Brima M. Younis, Asrat Hailu, Zewdu Hurissa, Workagegnehu Hailu, Samson Tesfaye, Eyasu Makonnen, Yalemtsehay Mekonnen, Alwin D.R. Huitema, Jos H. Beijnen, Smita A. Kshirsagar, Jaya Chakravarty, Madhukar Rai, Shyam SundarFabiana Alves, Thomas P.C. Dorlo

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

3 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)1463-1473
Aantal pagina's11
TijdschriftClinical Pharmacokinetics
Volume60
Nummer van het tijdschrift11
DOI's
StatusGepubliceerd - nov. 2021

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