Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Brussels, Belgium
Pharmacotherapeutic group: {group}
ATC code: not yet assigned
PF-07321332 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 the SARS-CoV-2 Mpro renders the protein incapable of processing polyprotein precursors which leads to the prevention of viral replication.
Ritonavir inhibits the CYP3A-mediated metabolism of PF-07321332, thereby providing increased plasma concentrations of PF-07321332.
PF-07321332 exhibited antiviral activity against SARS-CoV-2 infection of dNHBE cells, a primary human lung alveolar epithelial cell line (EC50 value of 61.8 nM and EC90 value of 181 nM) after 3 days of drug exposure. PF-07321332 had cell culture antiviral activity (with EC50 values in the low nanomolar range ≤3-fold relative to USA-WA1/2020) against SARS-CoV-2 isolates belonging to the Alpha (B.1.1.7), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1.621) and Omicron (B.1.1.529) variants. The Beta (B.1.351) variant was the least susceptible tested variant with approximately 3.3-fold reduced susceptibility relative to the USA-WA1/2020 isolate.
No information on antiviral resistance is currently available to PF-07321332 with SARS-CoV-2. Studies to evaluate selection of resistance to PF-07321332 with SARS-CoV-2 in cell culture and clinical studies have not been completed. Only in vitro resistance selection study with murine hepatitis virus (MHV)Mpro is available. It showed a 4.4 to 5-fold decrease in PF-07321332 susceptibility against mutant viruses with 5 mutations (Pro55Leu, Ser144Ala, Thr129Met, Thr50Lys, Pro15Ala) in the MHV-Mpro following 10 passages in cell culture. The relevance for this to SARS-CoV-2 is not known.
The efficacy of Paxlovid is based on the interim analysis and the supporting final analysis of EPIC-HR, a Phase 2/3, randomised, double-blind, placebo-controlled study in non-hospitalised, symptomatic adult participants with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible participants were 18 years of age and older with at least 1 of the following risk factors for progression to severe disease: diabetes, overweight (BMI >25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically-related technological dependence, or were 60 years of age and older regardless of comorbidities. Participants with COVID-19 symptom onset of ≤5 days were included in the study. The study excluded individuals with a history of prior COVID-19 infection or vaccination.
Participants were randomised (1:1) to receive Paxlovid (PF-07321332 300 mg/ritonavir 100 mg) or placebo orally every 12 hours for 5 days. The primary efficacy endpoint was the proportion of participants with COVID-19 related hospitalisation or death from any cause through Day 28. The analysis was conducted in the modified intent-to-treat (mITT) analysis set [all treated subjects with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody (mAb) treatment], the mITT1 analysis set (all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), and the mITT2 analysis set (all treated subjects with onset of symptoms ≤5 days).
A total of 2,246 participants were randomised to receive either Paxlovid or placebo. At baseline, mean age was 46 years with 13% of participants 65 years of age and older (3% were 75 years of age and older); 51% were male; 72% were White, 5% were Black, and 14% were Asian; 45% were Hispanic or Latino; 66% of participants had onset of symptoms ≤3 days from initiation of study treatment; 81% had a BMI >25 kg/m² (37% a BMI >30 kg/m²); 12% had diabetes mellitus; less than 1% of the study population had immune deficiency, 47% of participants were serological negative at baseline and 51% were serological positive. The mean (SD) baseline viral load was 4.63 log10 copies/mL (2.87); 26% of participants had a baseline viral load of >107 (copies/mL); 6.2% of participants either received or were expected to receive COVID-19 therapeutic mAb treatment at the time of randomisation and were excluded from the mITT and mITT1 analyses. The primary SARS-CoV-2 variant across both treatment arms was Delta (98%), mostly clade 21J (based on interim analysis).
The baseline demographic and disease characteristics were balanced between the Paxlovid and placebo groups.
The determination of primary efficacy was based on a planned interim analysis of 774 subjects in mITT population. The estimated risk reduction was -6.3% with unadjusted 95% CI of (-9.0%, -3.6%) and a 95% CI of (-10.61%, -2.02%) when adjusting for multiplicity. The 2-sided p-value was <0.0001 with 2-sided significance level of 0.002.
Table 3 provides results of the primary endpoint in the mITT1 analysis population for the full data set at final study completion.
Table 3. Efficacy results in non-hospitalised adults with COVID-19 dosed within 5 days of symptom onset who did not receive COVID-19 monoclonal antibody treatment at baseline (mITT1 analysis set):
| Paxlovid (N=1,039) | Placebo (N=1,046) | |
|---|---|---|
| COVID-19 related hospitalisation or death from any cause through Day 28 | ||
| n (%) Reduction relative to placeboa [95% CI], % | 8 (0.8%) -5.62 (-7.21, -4.03) | 66 (6.3%) |
| All-cause mortality through Day 28, % | 0 | 12 (1.1%) |
Abbreviations: CI=confidence interval.
a The estimated cumulative proportion of participants hospitalised or death by Day 28 was calculated for each treatment group using the Kaplan-Meier method, where subjects without hospitalisation and death status through Day 28 were censored at the time of study discontinuation.
The estimated risk reduction was -5.8% with 95% CI of (-7.8%, -3.8%) in participants dosed within 3 days of symptom onset, and –5.2% with 95% CI of (-7.9%, -2.5%) in the mITT1 subset of participants dosed >3 days from symptom onset.
Consistent results were observed in the final mITT and mITT2 analysis populations. A total of 1,379 subjects were included in the mITT analysis population. The event rates were 5/697 (0.72%) in the Paxlovid group, and 44/682 (6.45) in the placebo group.
Table 4. Progression of COVID-19 (hospitalisation or death) through Day 28 in symptomatic adults at increased risk of progression to severe illness; mITT1 analysis set:
| Paxlovid 300 mg/100 mg | Placebo | |
|---|---|---|
| Number of patients | N=1,039 | N=1,046 |
| Serology Negative | n=487 | n=505 |
| Patients with hospitalisation or deatha () Estimated proportion over 28 days [95 CI], % Reduction relative to placebo [95% CI] p-value | 7 (1.4%) 1.47 (0.70, 3.05) -10.25 (-13.28, -7.21) p<0.0001 | 58 (11.5%) 11.71 (9.18, 14.89) |
| Serology Positive | n=540 | n=528 |
| Patients with hospitalisation or deatha () Estimated proportion over 28 days [95 CI], % Reduction relative to placebo [95% CI] p-value | 1 (0.2%) 0.19 (0.03, 1.31) -1.34 (-2.45, -0.23) p=0.0180 | 8 (1.5%) 1.52 (0.76, 3.02) |
Abbreviations: CI=confidence interval; mITT=modified intent-to-treat. All participants randomly assigned to study intervention, who took at least 1 dose of study intervention, who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody treatment, and were treated ≤5 days after COVID-19 symptom onset.
Seropositivity was defined if results were positive in a serological immunoassay specific for host antibodies to either S or N viral proteins.
The difference of the proportions in the 2 treatment groups and its 95% confidence interval based on normal approximation of the data are presented.
a COVID-19 related hospitalisation or death from any cause.
Efficacy results for mITT1 were consistent across subgroups of participants including age (≥65 years) and BMI (BMI >25 and BMI >30) and diabetes.
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The European Medicines Agency has deferred the obligation to submit the results of studies with Paxlovid in one or more subsets of the paediatric population in treatment of COVID-19 (see section 4.2 for information on paediatric use).
The pharmacokinetics of PF-07321332/ritonavir have been studied in healthy participants.
Ritonavir is administered with PF-07321332 as a pharmacokinetic enhancer resulting in higher systemic concentrations of PF-07321332.
Upon repeat-dose of PF-07321332/ritonavir 75 mg/100 mg, 250 mg/100 mg, and 500 mg/100 mg administered twice daily, the increase in systemic exposure at steady-state appears to be less than dose proportional. Multiple dosing over 10 days achieved steady-state on Day 2 with approximately 2-fold accumulation. Systemic exposures on Day 5 were similar to Day 10 across all doses.
Following oral administration of PF-07321332/ritonavir 300 mg/100 mg after a single dose, the geometric mean PF-07321332 Cmax and AUCinf at steady-state was 2.21 µg/mL and 23.01 µg*hr/mL, respectively. The median time to Cmax (Tmax) was 3.00 hrs. The arithmetic mean terminal elimination half-life was 6.1 hours.
Following oral administration of PF-07321332/ritonavir 300 mg/100 mg after a single dose, the geometric mean ritonavir Cmax and AUCinf was 0.36 µg/mL and 3.60 µg*hr/mL, respectively. The median time to Cmax (Tmax) was 3.98 hrs. The arithmetic mean terminal elimination half-life was 6.1 hours.
Dosing with a high fat meal modestly increased the exposure of PF-07321332 (approximately 15% increase in mean Cmax and 1.6% increase in mean AUClast) relative to fasting conditions following administration of a suspension formulation of PF-07321332 coadministered with ritonavir tablets.
The protein binding of PF-07321332 in human plasma is approximately 69%.
The protein binding of ritonavir in human plasma is approximately 98-99%.
In vitro studies assessing PF-07321332 without concomitant ritonavir suggest that PF-07321332 is primarily metabolised by CYP3A4. PF-07321332 does not reversibly inhibit CYP2D6, CYP2C9, CYP2C19, CYP2C8 or CYP1A2 in vitro at clinically relevant concentrations. PF-07321332 is not an inducer or substrate of other CYP enzymes other than CYP3A of which PF-07321332/ritonavir is an inhibitor. Administration of PF-07321332 with ritonavir inhibits the metabolism of PF-07321332. In plasma, the only medicinal product-related entity observed was unchanged PF-07321332. Minor oxidative metabolites were observed in the faeces and urine.
In vitro studies utilising human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of oxidation metabolite M–2.
Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence the pharmacokinetics of ritonavir.
The primary route of elimination of PF-07321332 when administered with ritonavir was renal excretion of intact medicinal product. Approximately 49.6% and 35.3% of the administered dose of PF-07321332 300 mg was recovered in urine and faeces, respectively. PF-07321332 was the predominant drug-related entity with small amounts of metabolites arising from hydrolysis reactions in excreta. In plasma, the only drug-related entity quantifiable was unchanged PF-07321332.
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir.
The pharmacokinetics of PF-07321332/ritonavir based on age and gender have not been evaluated.
Systemic exposure in Japanese participants was numerically lower but not clinically meaningfully different than those in Western participants.
Compared to healthy controls with no renal impairment, the Cmax and AUC of PF-07321332 in patients with mild renal impairment was 30% and 24% higher, in patients with moderate renal impairment was 38% and 87% higher, and in patients with severe renal impairment was 48% and 204% higher, respectively.
Compared to healthy controls with no hepatic impairment, the PK of PF-07321332 in subjects with moderate hepatic impairment was not significantly different. Adjusted geometric mean ratio (90% CI) of AUCinf and Cmax of PF-07321332 comparing moderate hepatic impairment (test) to normal hepatic function (reference) was 98.78% (70.65%, 138.12%) and 101.96% (74.20%, 140.11%), respectively.
PF-07321332/ritonavir has not been studied in patients with severe hepatic impairment.
CYP3A4 was the major contributor to the oxidative metabolism of PF-07321332, when PF-07321332 was tested alone in human liver microsomes. Ritonavir is an inhibitor of CYP3A and increases plasma concentrations of PF-07321332 and other drugs that are primarily metabolised by CYP3A. Despite being coadministered with ritonavir as a pharmacokinetic enhancer, there is potential for strong inhibitors and inducers to alter the pharmacokinetics of PF-07321332.
PF-07321332 does not reversibly inhibit CYP2D6, CYP2C9, CYP2C19, CYP2C8, or CYP1A2 in vitro at clinically relevant concentrations. In vitro study results showed PF-07321332 may be inducer of CYP3A4, CYP2B6, CYP2C8 and CYP2C9. The clinical relevance is unknown. Based on in vitro data, PF-07321332 has a low potential to inhibit BCRP, MATE2K, OAT1, OAT3, OATP1B3 and OCT2. There is a potential for PF-07321332 to inhibit MDR1, MATE1, OCT1 and OATP1B1 at clinically relevant concentrations.
No nonclinical safety studies have been conducted with PF-07321332 in combination with ritonavir.
Studies of repeated dose toxicity and genotoxicity revealed no risk due to PF-07321332. No adverse effects were observed in fertility and embryo-foetal development studies in rats. A study in pregnant rabbits showed an adverse decrease in foetal body weight, in the absence of significant maternal toxicity. Systemic exposure (AUC24) in rabbits at the maximum dose without adverse effect in foetal body weight was estimated to be approximately 3 times higher than exposure in humans at recommended therapeutic dose of Paxlovid.
No carcinogenicity studies have been conducted with PF-07321332.
Repeat-dose toxicity studies of ritonavir in animals identified major target organs as the liver, retina, thyroid gland and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and were accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigment epithelium and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have not been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary to phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced ocular changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir. Clinical investigation in humans has revealed no clinically significant alteration in thyroid function tests.
Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted in rats and are considered to be attributable to species-specific spontaneous disease. Furthermore, no clinically significant renal abnormalities were noted in clinical trials.
Genotoxicity studies revealed no risk due to ritonavir. Long-term carcinogenicity studies of ritonavir in mice and rats revealed tumourigenic potential specific for these species, but are regarded as of no relevance for humans. Ritonavir produced no effects on fertility in rats. Developmental toxicity observed in rats (embryo-lethality, decreased foetal body weight and ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a maternally toxic dosage. Developmental toxicity in rabbits (embryo-lethality, decreased litter size and decreased foetal weights) occurred at a maternally toxic dosage.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
