Coronavirus disease 2019 (COVID‐19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID‐19 antivirals are needed urgently. Nirmatrelvir (PF‐07321332), the first orally bioavailable, severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) M pro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. We report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double‐blind, placebo‐controlled, phase I study. Two interleaving single‐ascending dose (SAD) cohorts were evaluated in a three‐period crossover. Multiple‐ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (b.i.d.) dosing was evaluated over 10 days in five parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase II/III clinical trials were supported by integrating modeling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well‐tolerated. Nirmatrelvir exposure and half‐life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase II/III trials (300/100 mg b.i.d.), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro . The QSP model suggested that a 5‐day regimen would significantly decrease viral load in SARS‐CoV‐2‐infected patients which may prevent development of severe disease, hospitalization, and death. In conclusion, an innovative and seamless trial design expedited establishment of phase I safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase II/III dose selection and accelerated pivotal trials’ initiation (NCT04756531).

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires the rapid development of efficacious treatments for patients with life-threatening coronavirus disease (COVID-19). Quantitative Systems Pharmacology (QSP) models are mathematical representations of pathophysiology for simulating and predicting the effects of existing or putative therapies. The application of model-based approaches, including QSP, have accelerated the development of some novel therapeutics. Nevertheless, the development of disease-scale mechanistic models can be a slow process, often taking years to be validated and considered mature. Furthermore, emerging data may make any QSP model quickly obsolete. We present a prototype QSP model to facilitate further development by the scientific community. The model accounts for the interactions between viral dynamics, the major host immune response mediators, and tissue damage and regeneration. The immune response is determined by viral activation of innate and adaptive immune processes that regulate viral clearance and cell damage. The prototype model captures two physiologically relevant outcomes following infection: a 'healthy' immune response that appropriately defends against the virus, and an uncontrolled alveolar inflammatory response that is characteristic of acute respiratory distress syndrome. We aim to significantly shorten the typical QSP model development and validation timeline by encouraging community use, testing, and refinement of this prototype model. It is our expectation that the model will be further advanced in an open science approach; i.e. by multiple contributions towards a validated quantitative platform in an open forum, with the ultimate goal of informing and accelerating the development of safe and effective treatment options for patients.

Background: Ductal-dependent cyanotic newborns require a secure source of pulmonary blood flow. There has been a recent migration to selective ductal (patent ductus arteriosus [PDA]) stenting for some of these children. Universal (nonselective) ductal stenting for all infants with ductal-dependent pulmonary blood flow is controversial. We examine outcomes from a single center with this practice change. Methods: We compare outcomes of all ductal-dependent pulmonary blood flow infants (2013–2020 [January–June]) in the following treatment eras: Era 1 (selective PDA stenting; 2013–2017) or Era 2 (universal PDA stenting; 2018–2020 [January–June]). Results: Eighty-eight patients (Blalock-Taussig shunt, n=41; PDA stent, n=47) met inclusion criteria. In Era 1, most received Blalock-Taussig shunt (62% [41/66]). In Era 2, all received PDA stents (100% [22/22]). There were more females in Era 2, but otherwise no demographic differences between eras. There were no differences in mortality, treatment failures, complications, or reinterventions between eras. Postprocedure length of stay was shorter in Era 2 (8 versus 22 days, P =0.02). There were less surgical revisions for PDA stent patients (2% versus 20%, P =0.02). Postprocedure recovery surrogate end points favored Era 2 and PDA stenting. Additional analysis revealed PDA stent (compared with Blalock-Taussig shunt) patients had shorter post-procedure (10 versus 29 days, P≤ 0.001) length of stay and more symmetrical branch pulmonary arteries (0.9 versus 0.7, P =0.001) at subsequent surgery. Conclusions: PDA stenting for almost all ductal dependent cyanotic newborns can be safe and effective and may have lower morbidity than selective PDA stenting.

PHACES association is a spectrum of anomalies that might occur in infants with large facial hemangiomas. Most infants with PHACES association have segmental hemangiomas of the head or neck. Cardiac and cerebrovascular anomalies might be the most important association, as they carry a significant risk of complications. This article summarizes the dermatologic, cardiac, and cerebral vascular findings in a cohort of infants diagnosed with PHACES association. All had large segmental facial hemangiomas and aortic arch abnormalities. Four of the five were not suspected of having arch obstruction prior to imaging studies because of the aberrant origin of both subclavian arteries, and 4/5 required either interventional or surgical repair for arch obstruction. In contrast to classic aortic coarctation, the aortic anomalies found in the cohort had unusually complex and unpredictable anatomic involvement. Cerebral vascular anomalies were identified in 5/5, and 2/5 had neurologic complications secondary to abnormal cerebral vascular supply. It is important for care providers to recognize this association that presents with a cutaneous stigma, as it is associated with potentially lethal and often unrecognized vascular anomalies. Earlier recognition of the associated vascular pathologies might enable preemptive treatments before potentially devastating and irreversible sequelae.