Major planning directives related to the COVID-19 pandemic are coordinated through Ontario Health,# 
COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease of Nirmatrelvir dose and (b) that there is no known dose-related toxicity with Nirmatrelvir, suggesting the benefits of treatment are maintained with minimal increase in unintended harm. 6. Further studies on the safety of Paxlovid in advanced CKD are not likely to be available in any relevant time frame so we need to act on present available information, however limited. 7. On the basis of the above risks of serious morbidity and mortality from COVID-19 infection in patients with advanced CKD, and the small estimated incremental risks from extending the use of Paxlovid to these patients, we suggest providing Paxlovid after discussing these aspects with the patient.

# COVID-19 and Chronic Kidney Disease (CKD)
As of March 31, 2022, there have been 6.14 million deaths globally from Coronavirus disease (COVID- 19) due to the Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2), of which 37,653 have occurred in Canada . Additionally, there are other longer term consequences from COVID-19, including post critical illness syndromes, auto-immune diseases, cardiovascular disease, and other physical and neurocognitive sequelae . These numbers are expected to grow over the next few years and will have a major impact on life expectancy and healthcare utilization.
The burden of morbidity and mortality of COVID-19 is higher in immunocompromised patients including those with advanced CKD (stages 4 and 5) and those with end stage kidney disease (ESKD), receiving dialysis. Hemodialysis patients cannot self-isolate, usually receiving their life-sustaining treatment three times a week in a congregate setting. Kidney transplant recipients are immunosuppressed and have other comorbid conditions making them more susceptible as well. Presently, about 3 million people receive dialysis worldwide, 23,708 of them in Canada, and 13,330 in Ontario ; . Excluding Quebec, there are 18,052 kidney transplant recipients in Canada .
In the first year after the declaration of the pandemic, in the United States alone, the year-over-year decline in the dialysis census was 1.6%, representing a deficit of 3.8%, relative to the forecasted increasing trend . In Ontario over the first 5 months of the pandemic in 2020, 187 (1.5%) of 12,501 patients undergoing dialysis were diagnosed with SARS-CoV-2 infection. Of these, 117 (62.6%) were admitted to hospital and the case fatality rate was 28.3% . These data predate the availability of vaccination. While case fatality rates for patients on dialysis have fallen in more recent waves in Ontario (18% in Wave 3 and 6% in Wave 5) and are 12% overall during the pandemic, they remain markedly higher than those in the general population ; . Patients with advanced CKD, who attend Multi-Care Kidney Clinics (MCKCs) in Ontario have an even higher mortality rate of 18% overall during the pandemic.
The vaccines for COVID-19 are remarkably effective. However, their effectiveness is lower in the dialysis and transplant populations . The pooled estimate of early antibody formation in dialysis patients was 89% (95% confidence interval  85 to 91%)  relative to healthy controls, thus conferring incomplete protection which wanes over time . For kidney transplant recipients, these figures are much lower at 8% (95% CI 5 -15%) and 35% (95% CI 29 -42%) with multiple dosing resulting in progressively smaller incremental antibody responses . For newer variants (such as Omicron), which COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease require higher antibody titres for viral neutralization, a corollary is that vaccines alone will not be sufficient for protection against infection and disease in dialysis patients .

# 'Renalism' and CKD
Patients with CKD, especially those with glomerular filtration rate (GFR) < 30, patients on dialysis and kidney transplant recipients are frequently excluded from clinical trials, in particular those evaluating investigational drugs. Proposed explanations for this have included the high comorbidity burden and high complication rates with competing events, and in particular the concern with decreased renal clearance for newer drugs making dosing decisions difficult for a phase 3 trial. The consequence is that CKD patients are excluded initially at time of drug approval, and therapeutic nihilism occurs, whereby these patients are denied effective therapies until data emerges several years later on safety and efficacy . This phenomenon has been termed 'renalism', and has unfortunately recurred with COVID-19. A rapid review of trial registries with COVID-19 reported that 218 of 484 trials (45%) had an exclusion based on CKD status which was often poorly defined (such as 'kidney dysfunction' without a GFR cutoff) .
Several therapeutic options have been investigated, and some have been approved for early treatment of COVID-19, notably remdesivir (Velkury, Gilead Inc.) and nirmatrelvir/ritonavir (Paxlovid, Pfizer Inc.). However, patients with low GFR have been excluded from all clinical trials of nirmatrelvir/ritonavir (Paxlovid), and theoretical concerns about drug dosing and safety have led to GFR < 30 being labeled as a contraindication in the product monograph.

# Paxlovid Efficacy
Nirmatrelvir (PF-07321332) is an orally administered antiviral agent targeting the SARS-CoV-2 3chymotrypsin-like cysteine protease enzyme (Mpro). Coadministration of nirmatrelvir with a low dose (100 mg) of ritonavir, a CYP3A4 inhibitor, enhances nirmatrelvir concentration, allowing required therapeutic concentrations to be achieved (see next section for details). The EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) evaluated the safety and efficacy of nirmatrelvir plus ritonavir in non-hospitalized adults with mild-to-moderate COVID-19 at high risk for progression to severe disease .
The incidence of COVID-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval , 9.04 to 3.59; P<0.001; relative risk reduction, 89.1%). There were 13 deaths, all in the placebo group. Patients with CKD were excluded from this trial. The Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-SR) trial in 1140 patients at standard risk has finished enrolment with results expected in a few months.
On this basis, Paxlovid is indicated for the treatment of mild-to-moderate COVID-19 (i.e. for outpatient treatment) in adults with positive SARS-CoV-2 viral testing, and who are at high risk for progression to COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease severe COVID-19, including hospitalization or death. It is not recommended for those with 'serious renal impairment (eGFR < 30)'.

# Paxlovid Pharmacology

# Pharmacodynamics
Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of SARS-CoV-2 Mpro renders the protein incapable of processing polyprotein precursors which leads to the prevention of viral replication.
Nirmatrelvir was shown to be an inhibitor of SARS-CoV-2 Mpro (at a Ki=3.1 nM, or IC50=19.2 nM) in a biochemical enzymatic assay (in vitro) . Ki refers to how well the drug inhibits the enzyme (lower values are indicative of greater inhibition) and IC50 to the concentration required to inhibit 50% of the enzyme over baseline (lower is better). Nirmatrelvir is a competitive inhibitor, and the EC50 (i.e. effective concentration) may be more important, which was measured at 3 times higher, i.e. 61.8 nM. However, in a study in mice, it was reported that EC90 correlated with efficacy, and this concentration was 181nM (292 ng/mL). Hence the desired dose of nirmatrelvir is that which maintains a trough level above the required EC90 concentration of 292 ng/mL. This was the basis of the use of the 300 mg dose in the EPIC-HR trial (see figure 1). 

# Pharmacokinetics
Nirmatrelvir has a molecular weight of 499.5 Da, is about 35% renally excreted and is 70% protein bound. Ritonavir is mostly hepatically metabolized and is 99% protein bound. Hence it is expected that nirmatrelvir will accumulate with decreasing kidney function, while ritonavir will not. A small proportion of nirmatrelvir will be removed with dialysis as well.

# Paxlovid Pharmacokinetic Data in CKD
Study C4671005 included 8 patients with serious renal impairment (defined as GFR < 30, not on dialysis). After a single dose of 100 mg nirmatrelvir, the overall concentration at 24 hours was 694.2 (42) ng/mL , over 2 times the required 292 ng/mL (Table 1 and Figure 2). 

# Paxlovid Adverse Effects
From animal data, no adverse effects were observed at 1000 mg/kg/day, which correspond to an exposure approximately 8 times higher than clinical exposures at the authorized human dose. Nirmatrelvir-related findings following repeat oral dosing in monkeys at up to 600 mg/kg/day were limited to emesis, increase in fibrinogen, as well as increases in ALT and AST levels. These findings completely reversed at the end of the 2-week recovery period. In the EPIC-HR trial, serious adverse events were lower with Paxlovid (1.6%) compared to placebo (6.6%). Adverse events reported by more than 1% of the participants were dysgeusia, nausea, vomiting, headache, diarrhea and fever. In study C 2/8 (25%) reported dysgeusia and dry mouth compared to none in the other arms with higher renal function. One patient did report several serious adverse events (SAEs), namely acute kidney injury, pulmonary edema, and pneumonia, which were likely related to COVID-19 infection rather than the medication. Overall, Paxlovid has a favorable safety profile, with no evidence of dose-dependent toxicity. COVID-19 Supplemental Clinical Guidance for Patients with Chronic Kidney Disease

# Rationale for Dosing of Paxlovid in CKD and Dialysis Patients
A single dose of nirmatrelvir 100 mg provided adequate concentration of drug to inhibit Mpro enzymatic activity at 24 hours, based on study C4671005 in non-dialysis CKD patients with GFR < 30. Similar concentrations would be seen in dialysis, and it is expected that there will be some clearance of nirmatrelvir with hemodialysis, given its molecular size, 70% protein binding and volume of distribution. The safety profile of nirmatrelvir is quite favorable, with few SAEs, with the animal data not indicative of a higher dose dependent toxicity. Nirmatrelvir is currently formulated as a 150 mg tablet and dosed at 300 mg with 100 mg ritonavir twice a day for patients with normal kidney function, and at 150 mgs with 100 mg ritonavir twice a day in those with eGFR 30-60. A dose of 300 mg (with 100 mg ritonavir) followed by 150 mg daily, administered after hemodialysis on days of dialysis is predicted to provide effective blood concentrations for enzyme inhibition (figure 3). Minimal drug accumulation is expected based on the short duration of therapy and single dose pharmacokinetics. A lower dose of 150 mg every 48 hours could be considered for patients less than 40 kgs.
Patients receiving peritoneal dialysis often have greater residual renal function compared to those receiving hemodialysis and may therefore have slightly higher endogenous clearance of nirmatrelvir. However, the dialytic removal with peritoneal dialysis will be lower compared with hemodialysis. Hence similar doses to those discussed above for hemodialysis are expected to achieve effective concentrations in these patients. Additional considerations of drug interactions are also important, since ritonavir is a potent CYP3A4 inhibitor. Commonly used drugs with important drug interactions in CKD and dialysis patients include direct acting oral anticoagulants, some statins, calcium channel blockers and alpha-adrenergic antagonists. These interactions however, are not a contraindication to therapy, and may be mitigated with support from clinicians and pharmacy and temporary suspension or dose reduction of these medications, depending on the clinical context (see table 3).
We suggest that patients with advanced CKD (eGFR < 30) and those on dialysis who contract COVID-19 be offered the low dose nirmatrelvir/ritonavir (Paxlovid) regimens. Since the current product monograph does not recommend the use of nirmatrelvir/ritonavir (Paxlovid) in these patients, this should be preceded by a discussion between the prescribing physician and the patient emphasizing that the potential benefits of the treatment substantially exceed the theoretical risks of toxicity.

# Rationale for Dosing of Paxlovid in Kidney Transplant Recipients
In patients with a kidney transplant, drug-drug interactions are as much or more of a concern than the kidney function. The inhibition of drug metabolism due to ritonavir can result in extremely toxic levels (10-fold higher) of calcineurin inhibitors (CNIs), and prolonged half-life. To a lesser extent, levels of mycophenolic acid and sirolimus may also be affected (see table 3 for details). Hence even with eGFR > 30, CNIs must be held, and close monitoring of CNI levels is required even after the therapy is complete to decide on timing of restarting. Given this interaction, the use of nirmatrelvir/ritonavir (Paxlovid) in kidney transplant recipients with eGFR < 30 should be considered very cautiously. Though not discussed separately, similar considerations would also apply to patients with CKD due to glomerulonephritis receiving these immunosuppressive drugs.

# Summary
Patients with advanced CKD (stages 4 and 5) and patients on dialysis who contract COVID-19, are at markedly higher risk of developing severe symptomatic disease and of dying. They have a lower and less sustained immune response to vaccination and need access to potentially lifesaving medications. Nirmatrelvir/ritonavir (Paxlovid) is a very effective therapy in the early management of high risk patients with symptomatic disease; however it is renally cleared and is currently not recommended for those with GFR < 30. On the basis of available data and pharmacological principles, an adjusted dose given at a lower frequency is proposed for use in people with GFR < 30 and in those on dialysis after appropriate evaluation and discussion of risks and benefits with the patient.