Treatment of symptomatic COVID-19 with nirmatrelvir/ritonavir in children at least 6 years of age who are at risk of progression to severe disease appears to be safe and well-tolerated, with pharmacokinetic data from the open-label phase 2/3 EPIC-Peds* study indicating suitable dosing regimens for two distinct weight categories of this population.

Among 75 paediatric patients weighing ≥40 kg (cohort 1, n=61) or ≥20 to <40 kg (cohort 2, n=14), 27 percent had an all-causality treatment-emergent adverse event (TEAE) over 34 days, with diarrhoea (4 percent) and headache (4 percent) being the most frequently reported. [IDWeek 2024, abstract 580]

“TEAEs were mostly mild or moderate in severity, nonserious, and unrelated to treatment,” noted one of the study authors Dr Jaqueline Gerhart from Pfizer in Collegeville, Pennsylvania, US.

Seven TEAEs reported in six patients were deemed related to treatment, and none of which led to treatment discontinuation. One patient discontinued treatment due to a viral infection, and a second patient had grade 4 serious TEAE of a decrease in haemoglobin and platelet count.

Pharmacokinetics

The two dosing schemes of nirmatrelvir/ritonavir?300 mg/100 mg twice a day for cohort 1 and 150 mg/100 mg twice a day for cohort 2?provided patients with adequate drug exposure. Gerhart pointed out that the efficacy in paediatrics was extrapolated from adults by matching paediatric exposure for trough concentration (C_trough), the area under the concentration time curve over the dosing interval (AUC_tau), and maximum concentration (C_max).

“Pediatric patients in cohorts 1 and 2 achieved comparable exposure to adults receiving 300 mg/100 mg nirmatrelvir/ritonavir dose,” she said.

In the pharmacokinetic model-predicted day-5 nirmatrelvir exposure for simulated adults and children with COVID-19, the percentage of patients achieving trough concentration (C_trough) values above the 90 percent effective concentration (EC₉₀) for SARS?CoV?2 was 93.2 percent in cohort 1 and 92.8 percent in cohort 2 relative to 89.5 percent in adults. The AUC_tau was 36.5 μg*h/mL in cohort 1, 37.3 μg*h/mL in cohort 2, and 27.7 μg*h/mL in adults. The C_max was 4.19, 4.24, and 3.22 μg/mL, respectively.

Antiviral efficacy

“Supportive secondary endpoints suggest that nirmatrelvir/ritonavir is efficacious in paediatric patients,” Gerhart said.

No COVID-19?related hospitalizations or all-cause deaths were documented through day 28. Furthermore, the adjusted mean reduction in SARS-CoV-2 viral load from baseline to day 5 and day 6 of ≥3.4 log₁₀ copies/mL was numerically greater than in adults.

Taken together, these findings demonstrate that in paediatric patients at least 6 years of age, 300 mg/100 mg twice daily and 150 mg/100 mg twice daily nirmatrelvir/ritonavir dosing for those weighing ≥40 kg and ≥20 to < 40 kg, respectively, was safe and effective, according to Gerhart. At these dosing regimens, a 5-day treatment course is expected to yield nirmatrelvir C_trough values above EC₉₀ in more than 90 percent of the population, she added.

EPIC-Peds

EPIC-Peds enrolled 75 children with confirmed SARS-CoV-2 infection and symptom onset within the previous 5 days and had at least risk factor for severe COVID-19 progression. The median age was 13.0 years, 52 percent were female, 59 percent were White, 33 percent received complete COVID-19 vaccination, 81 percent had one risk factor for progression to severe disease, and the median viral load at baseline was 6.3 log₁₀ copies/mL. The median weight was 62.5 kg in cohort 1 and 28.9 kg in cohort 2.

Gerhart shared that the study is ongoing and will establish three additional cohorts to include patients from younger age groups: ≥2 to <6 years (cohort 3), ≥1 month to <2 years (cohort 4), and birth to <1 month (cohort 5).

*Evaluation of Protease Inhibition for COVID-19 in Pediatric Patients