Serum ganciclovir drug exposure in children receiving standard ganciclovir dosing.

Intravenous ganciclovir (GCV) is used for the treatment of cytomegalovirus (CMV) infection in immunocompromised children. Although the therapeutic target for treatment is unclear, studies have shown a serum area under the concentration-time curve (AUC24h) ≥40 mg/L·h correlates with effective CMV prevention. This study aimed to externally validate existing GCV population pharmacokinetic (PopPK) models and develop a model if needed and evaluate the serum AUC24h achieved with standard GCV dosing and propose an optimized dosing strategy for immunocompromised children. Ganciclovir drug monitoring data from two pediatric hospitals were retrospectively collected, and published pediatric PopPK models were externally validated. The population AUC24h with standard GCV dosing (5 mg/kg twice daily) was calculated, and an optimized dosing strategy was determined using Monte Carlo simulations to achieve an AUC24h between 40 and 100 mg/L·h. Overall, 161 samples from 23 children with a median (range) age of 9.0 years (0.4-17.0) and weight of 28.2 kg (5.6-73.3) were analyzed. Transferability of published pediatric PopPK models was limited. Thus, a one-compartment model with first-order absorption and elimination with weight and serum creatinine as covariates was developed. The median (5th-95th percentiles) steady state AUC24h with standard dosing was 38.3 mg/L·h (24.8-329.2) with 13 children having an AUC24h <40 mg/L·h, particularly those aged <4 years (8/13). An optimized simulated GCV dosing regimen, ranging from 2 to 13 mg/kg twice daily for children with normal renal function, achieved 61%-78% probability of target attainment. Standard GCV dosing likely results in inadequate drug exposure in more than half of the children, particularly those aged <4 years. An optimized dosing regimen has been proposed for clinical validation.

Ivermectin therapy for young children with scabies infection: a multicentre phase 2 non-randomized trial.

Background: Ivermectin, an effective treatment for scabies, is not licensed for children weighing <15 kg. Pharmacokinetic modelling has shown a 3 mg dose in young children (2-4 years, weighing 10-14 kg) achieves comparable drug exposure to a 200 µg/kg dose in children aged ≥5 years. This trial evaluated a 3 mg dose in young children. Methods: Multicentre, phase 2 trial in five health centres in Lao PDR. Children aged 2-4 years, weighing 10-14 kg with scabies received 3 mg ivermectin and had two plasma concentrations determined (Clinicaltrials.gov ID NCT05500326). On day 14, clinical outcomes and adverse effects were assessed, and a second dose given to complete treatment. The primary outcome was the mean plasma ivermectin exposure (AUC0-∞) after the first dose (compared to a historical control of Indigenous Australian children aged ≥5 years weighing ≥15 kg receiving 200 µg/kg). Secondary outcomes were clinical improvement and adverse effects. Findings: Overall, 100 children with a median age of 3.0 years (IQR 2.6-3.9) and weight of 11.9 kg (IQR 11.0-13.1) were enrolled. The mean observed ivermectin AUC0-∞ was comparable to the historical control group aged 5-11 years (815 µg h/L vs 953 µg h/L, p = 0.256). Complete resolution of scabies occurred in 90/99 children by day 14. Adverse effects were mild, occurring in 7/99. Interpretation: A 3 mg ivermectin dose in children aged 2-4 years and weighing 10-14 kg achieved a mean plasma AUC0-∞ comparable to older children, was highly effective in treating scabies and well tolerated. This study supports extending ivermectin treatment to younger children improving global efforts to control this neglected disease. Funding: Project funding provided by a Thrasher Foundation Early Career Research Award.