Reproductive and developmental safety of nirmatrelvir (PF-07321332), an oral SARS-CoV-2 Mpro inhibitor in animal models

Nirmatrelvir (PF-07321332;NMV) the antiviral component of PAXLOVID PACK is a potent and selective inhibitor of the SARSCoV- 2 main protease (Mpro), which plays a critical role in viral replication. PAXLOVID PACK, comprised of nirmatrelvir and ritonavir (used as a pharmacokinetic enhancer), is an oral therapy currently in development as a therapeutic option for those infected with SARS-CoV-2 to prevent progression to severe disease, hospitalization, and death. It is also being tested for its potential benefit in the post-exposure prophylactic setting. Given that males and females of reproductive age are included in the intended patient population, we assessed the potential effects of NMV up to the limit dose of 1000 mg/kg/day in ICH guideline embryo-fetal development studies in rats and rabbits, and a fertility and early embryonic development study in rats. There were no effects on male and female fertility or early embryonic development in rats, and no severe manifestations of developmental toxicity in rats or rabbits. The lack of adverse findings reported here in nonclinical species is consistent with the intended therapeutic target of NMV (a virus specific protein not present in mammalian cells), the favorable off-target selectivity profile, and lack of genetic toxicity. All procedures performed on the animals in these studies were in accordance with regulations and established guidelines and were reviewed and approved by an Institutional Animal Care and Use Committee or through an ethical review process.

Reproductive and developmental safety of nirmatrelvir (PF-07321332), an oral SARS-CoV-2 Mpro inhibitor in animal models.

Nirmatrelvir (PF-07321332; NMV) the antiviral component of PAXLOVID™ is a potent and selective inhibitor of the SARS-CoV-2 main protease (Mpro), which plays a critical role in viral replication. PAXLOVID, comprised of nirmatrelvir and ritonavir (used as a pharmacokinetic enhancer), is an oral therapy currently in development as a therapeutic option for those infected with SARS-CoV-2 to prevent progression to severe disease, hospitalization, and death. PAXLOVID has been shown to be efficacious against hospitalization and death in two Phase 2/3 clinical studies that evaluated non hospitalized patients both with and without high risk factors for progression to severe illness. Given that males and females of reproductive age are included in the intended patient population, we assessed the potential effects of NMV up to the limit dose of 1000 mg/kg/day in ICH guideline embryo-fetal development studies in rats and rabbits, and a fertility and early embryonic development study in rats. There were no effects on male and female fertility or early embryonic development in rats, and no severe manifestations of developmental toxicity in rats or rabbits. The lack of adverse findings reported here in nonclinical species is consistent with the intended therapeutic target of NMV (a virus specific protein not present in mammalian cells), the favorable off-target selectivity profile, and lack of genetic toxicity. The results of these nonclinical studies with NMV along with existing ritonavir safety information indicate that there are no clinically relevant risks associated with PAXLOVID administration during pregnancy and in males and females of reproductive age.

THE USE OF 5% IV ALBUMIN IN PATIENTS WITH SHOCK: DOES IT DECREASE VASOPRESSOR REQUIREMENT?

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: Circulatory shock often requires large volume fluid resuscitation as a part of treatment. While crystalloid fluids are more commonly used, many patients in intensive care are unable to receive crystalloid fluids due to conditions such as congestive heart failure and end stage renal disease. Utilizing traditional fluids in such patients often complicates hospital courses. There are many studies regarding the benefits, effects and potential harms of using IV albumin for fluid resuscitation. The 2004 SAFE study suggested some benefit of using IV albumin in sepsis but equivocal to conventional management in morbidity and mortality. The 2014 ALBIOS Study of IV albumin use resulted in 90 day mortality benefit and decreased vasopressor need in severely septic patients. Despite these studies, the use of IV albumin in the critically ill remains controversial with consensus or guidelines being established regarding its use. METHODS: We conducted a retrospective study of 70 critically ill patients admitted to MICU from 7/2019 to 5/2020 to assess the effects of IV albumin. Patients diagnosed with shock who received 5% IV albumin were included. Patients who received 25% IV albumin were excluded. We analyzed cases by type of shock, conditions limiting crystalloid bolus, serum albumin level before IV albumin, MAP pre- and post- albumin infusion, pressor requirement (type/duration), development of ARDS, HD/CRRT requirement, COVID status and mortality. RESULTS: Septic shock patients received IV albumin most, followed by cardiogenic shock. Those unable to receive fluid boluses were due to primarily cardiac etiology, followed by renal & hepatic. Increased MAP was observed after IV albumin infusion in many cases. Serum albumin <2.7-2.8 on ICU admission was associated with frequent vasopressor use, higher vasopressor requirement and multi-agent use. Serum albumin >2.8 on ICU admission responded better to IV albumin and had lower vasopressor requirements.IV albumin was not related with renal dysfunction and those receiving IV Albumin did not need HD/CRRT. 69.6% did not develop ARDS, 5.8% developed ARDS, 24.6% tested positive for COVID and they were excluded from the ARDS incidence rate. Survival rate was 65.7%, mortality rate 24.3% and 10% went to hospice CONCLUSIONS: The use of 5% IV albumin for volume resuscitation in patients with different forms of shock in ICU showed favorable results, especially in those with serum albumin >2.7-2.8. Our retrospective study showed low incidence of adverse events such as cardiogenic pulmonary edema, ARDS or a need for HD/CRRT, lower vasopressor requirement, in both duration and agents used. Further research should be done in this regard to solidify these findings and to establish clear guidelines/protocols regarding the use of albumin as a resuscitative fluid in the ICU setting. CLINICAL IMPLICATIONS: When treating patients with shock and specially patients with hypoalbuminemia, 5% IV albumin can potentially be used as a means to decrease vasopressor requirements and duration without increasing the risk of pulmonary edema, ARDS and renal dysfunction. Further research should be done in this regard to solidify these findings and to establish clear guidelines/protocols regarding the use of albumin as a resuscitative fluid in the ICU setting. DISCLOSURES: No relevant relationships by Andrew Ajemian, source=Web Response No relevant relationships by Muhammad Umer Altaf, source=Web Response No relevant relationships by Christopher Bowman, source=Web Response No relevant relationships by Gabriel Diaz, source=Web Response No relevant relationships by Jessica Obeahon, source=Web Response No relevant relationships by Travis Yamanaka, source=Web Response