Ivermectin Dosing Strategy to Achieve Equivalent Exposure Coverage in Children and Adults

Brussee, Janneke M.; Schulz, Jessica D.; Coulibaly, Jean T.; Keiser, Jennifer; Pfister, Marc

doi:10.1002/cpt.1456

Cited by 17 publications

(16 citation statements)

References 43 publications

(120 reference statements)

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“…An open-label pharmacokinetic study of 12 adult volunteers studied multiple covariates including age, sex, height, body weight, body surface area, percentage body fat, gall bladder volume, kidney volume, liver volume, haematocrit, plasma albumin, and MDR1 polymorphism (associated with lower P-glycoprotein pump expression in the intestinal tract) and found only body weight to be significant [20]. The only other study of ivermectin pharmacokinetics in children reported a clearance/kg of 0.35 L/h/kg in children, similar to our results (0.18 L/h/kg) with the difference likely explained by different study populations [13].…”

Section: Discussionsupporting

confidence: 87%

“…Our study results are similar to the only other pharmacokinetic study of ivermectin in young children. That study of children living in rural Cote d'Ivoire with Trichuris trichuria infection, showed that doses of 300 μg/kg were required in children aged 2 to 5 years [13]. Previous pharmacokinetic studies in both adults and children have found body weight to be the only significant covariate influencing ivermectin pharmacokinetics, as we found in our study [13,20].…”

Section: Discussionsupporting

confidence: 68%

“…However, for children weighing less than 11 kg, this dose led to lower drug exposures than those observed in the study group with a median AUC of 620 (IQR 469-849) μg�h/L. A recently published dosing strategy of one 3 mg tablet for children weighing less than 15 kg was also evaluated [13]. This dosing regimen resulted in median AUC of 976 (IQR 671-1384) μg�h/L.…”

Section: Resultsmentioning

confidence: 99%

“…That study of children living in rural Cote d'Ivoire with Trichuris trichuria infection, showed that doses of 300 μg/kg were required in children aged 2 to 5 years [13]. Previous pharmacokinetic studies in both adults and children have found body weight to be the only significant covariate influencing ivermectin pharmacokinetics, as we found in our study [13,20]. An open-label pharmacokinetic study of 12 adult volunteers studied multiple covariates including age, sex, height, body weight, body surface area, percentage body fat, gall bladder volume, kidney volume, liver volume, haematocrit, plasma albumin, and MDR1 polymorphism (associated with lower P-glycoprotein pump expression in the intestinal tract) and found only body weight to be significant [20].…”

Section: Discussionmentioning

confidence: 99%

“…The area under the concentration-time curve (AUC) was calculated using trapezoidal integration over the concentration-time profile for each patient. Two different dosing scenarios were evaluated with: (i) a dose of 200 μg/kg, rounded to the nearest half or whole 3 mg tablet; and (ii) one 3 mg tablet, as suggested by a recent publication for children weighing less than 15 kg [13]. Simulations were performed in R version 3.5.3 to determine the dose required to achieve an equivalent exposure (AUC) in children aged between two and four years and weighing less than 15 kg to those aged five to 15 years and weighing at least 15 kg.…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

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Population pharmacokinetics of ivermectin for the treatment of scabies in Indigenous Australian children

et al. 2020

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Ivermectin is a broad-spectrum antiparasitic agent used for the treatment and control of neglected tropical diseases. In Australia, ivermectin is primarily used for scabies and is licensed in children aged ≥5 years weighing >15 kg. However, young children, aged <5 years, are particularly vulnerable to scabies and its secondary complications. Therefore, this study aimed to determine an appropriate ivermectin dose for children aged 2 to 4 years and weighing ≤15 kg. We conducted a prospective, pharmacokinetic study of ivermectin in Indigenous Australian children aged between 5 and 15 years and weighing >15 kg. Doses of 200 μg/kg rounded to the nearest whole or half 3 mg tablet were given to children with scabies and ivermectin concentrations determined at two time points after dosing. A population pharmacokinetic model was developed using non-linear mixed effects modelling. A separate covariate database of children aged 2 to 4 years and weighing <15 kg was used to generate 1000 virtual patients and simulate the dose required to achieve equivalent drug exposure in young children as those aged ≥5 years. Overall, 26 children who had 48 ivermectin concentrations determined were included, 11 (42%) were male, the median age was 10.9 years and median body weight 37.6 kg. The final model was a two-compartment model with first-order absorption and linear elimination. For simulated children aged 2 to 4 years, a dose of 3 mg in children weighing 10–15 kg produced similar drug exposures to those >5 years. The median simulated area under the concentration-time curve was 976 μg∙h/L. Using modelling, we have identified a dosing strategy for ivermectin in children aged 2 to 4 years and weighing less than 15 kg that can be prospectively evaluated for safety and efficacy.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

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Population pharmacokinetics of ivermectin for the treatment of scabies in Indigenous Australian children

et al. 2020

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Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults

Algorta,

Kepha,

Krolewiecki

et al. 2024

Clin Pharma and Therapeutics

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Trichuris trichiura is a soil‐transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co‐administered with ivermectin. A fixed‐dose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure–response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T. trichiura. Nonlinear mixed‐effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure–response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two‐compartmental model with first‐order absorption and the pharmacokinetics of ivermectin was described using a two‐compartmental model with zero‐order followed by first‐order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure–response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T. trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.

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Pharmacometric Analysis to Describe Pharmacokinetics and Exposure‐Efficacy Response of Ivermectin in Adolescents Infected with Trichuris trichiura

Ajayi,

Orherhe,

Pillai

et al. 2024

The Journal of Clinical Pharma

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The efficacy of the combination therapy of albendazole and ivermectin against Trichuris trichiura infection is higher in Tanzania than in Côte d'Ivoire. This study therefore aimed to investigate the difference between the population pharmacokinetics (PK) at these study sites and to determine if an exposure‐response analysis could explain the low efficacy of the combination therapy in Côte d'Ivoire. Twenty‐four participants (aged 12‐19 years) receiving single doses of ivermectin (200 µg/kg) and albendazole (400 mg) were included in the population PK modeling. A regression analysis was performed to investigate the relationship between the reduction of fecal whipworm eggs and different exposure metrics (peak concentration, area under the plasma drug concentration‐time curve [AUC], and time above a certain threshold). The PK profile of ivermectin was best described by a one‐compartment model, first‐order absorption, and no delay in absorption, with the absorption rate constant estimated as 0.26 per h, an apparent volume of distribution of 162.43 L, and an apparent clearance of 7.82 L/h. In Tanzania, all patients showed a very high reduction in egg count independent of exposure. In Côte d'Ivoire, a relationship was found between higher ivermectin exposure and egg reduction, although not statistically significant. There was no significant difference between the PK profiles at both study sites, despite a difference in clinical outcome. Model‐based simulations indicate that higher ivermectin doses such as 400 and 600 µg/kg may be associated with reduced egg count. Larger clinical studies are warranted to explore further the exposure‐efficacy response relationship at 200 µg/kg and higher ivermectin doses in adults and children.

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Ivermectin Dosing Strategy to Achieve Equivalent Exposure Coverage in Children and Adults

Cited by 17 publications

References 43 publications

Population pharmacokinetics of ivermectin for the treatment of scabies in Indigenous Australian children

Population pharmacokinetics of ivermectin for the treatment of scabies in Indigenous Australian children

Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults

Pharmacometric Analysis to Describe Pharmacokinetics and Exposure‐Efficacy Response of Ivermectin in Adolescents Infected with Trichuris trichiura

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