Physiologically‐Based Pharmacokinetic Modelling to Investigate Baricitinib and Tofacitinib Dosing Recommendations for COVID‐19 in Geriatrics

Abstract

Janus kinase (JAK) inhibitors baricitinib and tofacitinib are recommended by the US National Institutes of Health as immunomodulatory drugs for coronavirus disease 2019 (COVID‐19) treatment. In addition, baricitinib has recently received Emergency Use Authorization from the US Food and Drug Administration, although the instruction provided dosing information only for adults. Geriatrics with organ dysfunction are one of the most vulnerable cohorts when combating the pandemic. The aim of the present work was to evaluate current dosing strategies of baricitinib and tofacitinib for potential COVID‐19 treatment for White and Chinese geriatric patients with chronic renal impairment. An established physiologically‐based pharmacokinetic (PBPK) modeling framework for age‐dependent simulations was utilized. PBPK drug models adopted from literature were first verified. Several population models representing different age groups, ethnicities, and stages of renal impairment were used for prospective simulations. Notwithstanding the increase in systemic exposure of both drugs resulting from renal dysfunction was more pronounced for geriatrics than general White populations, our simulations confirmed their current dosage adjustments based on renal functions are broadly adequate. The exception being White older subjects with mild renal impairment where current recommendation of 4 mg baricitinib yielded a 2.31‐fold increase in systemic exposure, and reduction to 2 mg could mitigate the potential risk to an acceptable 1.15‐fold. Comparable relationships between systemic exposure and renal dysfunction were observed for both drugs in the Chinese population. In summary, PBPK modeling of both JAK inhibitors supports the rational and prudent dose adjustments of these COVID‐19 therapeutics among adult patients of different age groups and renal functions.

Physiologically‐Based Pharmacokinetic Modeling‐Guided Dose Management of Oral Anticoagulants when Initiating Nirmatrelvir/Ritonavir (Paxlovid) for COVID‐19 Treatment

“… 15 Our quantitative and mechanistical simulations verified the potent inhibition by both dosage regimens of ritonavir against enzymes and transporters associated with elimination of rivaroxaban, especially the comparable inhibition potency against CYP3A4 ( Figure S2 A,B ). Corroborating our previous studies, 19 , 20 prospective simulations revealed that geriatric patients with moderate renal dysfunction were more susceptible to the DDDIs between rivaroxaban and ritonavir, who could potentially benefit from a further dose adjustment to 10 mg daily rivaroxaban while receiving nirmatrelvir/ritonavir treatment. Considering the enzyme half‐lives of 20–30 hours for CYP3A4 and CYP2J2 and simulated recoveries of CYP3A4 (liver), CYP3A4 (gut), and CYP2J2 activities post‐MBI by ritonavir were 62.4%, 82.1%, and 77.6%, respectively, the reduced dose of rivaroxaban could be maintained for 3 days post‐nirmatrelvir/ritonavir treatment, which was in accordance with recommendations by Marzolini et al .…”

“… 5 Healthy population (Healthy Volunteers), general White population (NEurCaucasian) and geriatric population (Geriatric NEC) provided in Simcyp were adopted as population models. The moderate renal impairment (creatinine clearance (CrCL) 30 to 49 mL/min) population model modified previously 19 , 20 were utilized for simulations. Each simulation was designed as a total size of 100 subjects (10 trials with 10 subjects for each).…”

“…Age is a critical factor that contributed to the COVID‐19‐related severe illness and deaths, 12 and could substantially affect the PK of compounds as revealed by our previous studies. 19 , 20 Prospective DDDI simulations were performed using both general population (20–65 years) and geriatric subjects (65–85 years). Because nirmatrelvir/ritonavir is prescribed for the treatment of mild to moderate COVID‐19, we postulated that the impact of COVID‐19 related cytokine storm on enzymes and transporters (e.g., CYP3A4) is marginal.…”

“…Physiologically-Based Pharmacokinetic Modeling-Guided Dose Management of Oral Anticoagulants when Initiating Nirmatrelvir/ Ritonavir (Paxlovid) for COVID- 19 Treatment Ziteng Wang 1 and Eric Chun Yong Chan 1, * Patients with coronavirus disease 2019 (COVID- 19) with cardiovascular diseases who are at higher risk of progressing to critical illness should be treated with nirmatrelvir/ritonavir (Paxlovid). Ritonavir, the booster in nirmatrelvir/ ritonavir, modulates multiple drug metabolizing enzymes and transporters, complicating its use in real-world clinics.…”

Diversity in Clinical Pharmacology Coming of Age

“…1 The latter is the topic of a series of articles in the current issue of CPT, which covers therapeutic treatment and evaluation in patient groups across the full age range, from preterm infants to geriatrics (Figure 1). [2][3][4][5][6] On one end of the patient age spectrum, Engbers et al 2 examine the exposure-response relationship of ibuprofen on closure of the patent ductus arteriosus in preterm infants. Their model-based analysis provides new insights into the role of ibuprofen exposure, covariates, and timing of treatment on clinical outcomes.…”