Population pharmacokinetics of ivermectin after mass drug administration in lymphatic filariasis endemic communities of Tanzania.

Ivermectin (IVM) is a drug of choice used with albendazole (ALB) for Mass Drug Administration (MDA) to halt transmission of lymphatic filariasis. We investigated IVM pharmacokinetic (PK) variability for its dose optimization during MDA. PK samples were collected at 0, 2, 4 and 6 hours from individuals weighing > 15 Kg (n=468) receiving IVM (3-, 6-, 9-, or 12 mg) and ALB (400 mg) during MDA campaign in Tanzania. Individual characteristics including demographics, laboratory/clinical parameters and pharmacogenetic variations were assessed. IVM plasma concentrations were quantified by LC-MS/MS and analyzed using population-pharmacokinetic modeling. A two-compartment model with transit absorption kinetics, and allometrically scaled oral clearance (CL/F) and central volume (Vc/F) was adapted. Fitting of the model to the data identified 48% higher bioavailability for the 3mg dose compared to higher doses and identified a subpopulation with 97% higher mean transit time (MTT). The final estimates for CL/F, Vc/F, inter-compartment clearance (Q), peripheral volume (Vp), MTT, and absorption rate constant for a 70 Kg person (on dose other than 3 mg) were 7.7 L/h, 147 L, 20.4 L/h, 207 L, 1.5 h, and 0.71/h, respectively. Monte-carlo simulations indicated that weight-based dosing provides comparable exposure across weight bands, but height-based dosing with capping IVM dose at 12mg for individuals with height >160 cm under-doses those weighing >70 Kg. Variability in IVM PK is partly explained by body weight and dose. The established POPPK model can be used for IVM dose optimization. Height-based pole dosing results in varying IVM exposure in different weight bands, hence using weighing scales for IVM dosing during MDA is recommended.