Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019

Abstract

; for the Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee IMPORTANCE Children of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required. OBJECTIVE To define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment. DESIGN, SETTING, AND PARTICIPANTS Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population. INTERVENTIONS Simulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies. MAIN OUTCOMES AND MEASURES The primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration. RESULTS For hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL). CONCLUSIONS AND RELEVANCE This analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.

Comparison of antiviral effect for mild-to-moderate COVID-19 cases between lopinavir/ritonavir versus hydroxychloroquine: A nationwide propensity score-matched cohort study

“…There are no pharmacokinetic data on respiratory tract concentration of LPV/r. Although pharmacokinetic data indicate HCQ exhibits extensive tissue distribution, the tissue concentration of the respiratory tract might be variable depending on intestinal resorption and hepatic first-pass metabolism ( Klimke et al, 2020 , Maharaj et al, 2020 ). In comparison, there are several encouraging reports of HCQ on reducing mortality ( Arshad et al, 2020 , Catteau et al, 2020 , Di Castelnuovo et al, 2020 , Mikami et al, 2020 ).…”

A Narrative Review of Emerging Therapeutics for COVID-19

“…98 Pharmacokinetic simulations have highlighted potential safety concerns with current CQ and HCQ dosing and questioned their ability to achieve concentrations required for antiviral activity. 99,100 CONVALESCENT PLASMA THERAPY Virus-specific antibodies present in CPT have been used as late-line treatments in recent epidemics including SARS, Ebola, H1N1 influenza, and MERS and throughout the history of medicine. 101 A retrospective study of therapeutic plasma exchange in patients with sepsis and multiorgan failure that is currently under peer review suggests that for patients with pneumonia as the primary source of sepsis, this approach may improve mortality rates.…”

“… 98 Pharmacokinetic simulations have highlighted potential safety concerns with current CQ and HCQ dosing and questioned their ability to achieve concentrations required for antiviral activity. 99 , 100 …”

Development of a Physiologically-Based Pharmacokinetic (PBPK) Model of Nebulized Hydroxychloroquine for Pulmonary Delivery to COVID-19 Patients

“…Different publications have recently appeared relating the application of Pharmacokinetics modeling for prediction of the exposure of HCQ in plasma or in plasma and lung tissues [22][23][24]. Concerns were raised by the investigators regarding HCQ use for COVID-19 treatment because concentrations in plasma/ lung tissues were less than the concentrations proven effective in-vitro studies.…”