Sign Out
Pharmacology: Pharmacodynamics: Mechanism of action: Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as coronavirus 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 is not active against SARS-CoV-2 Mpro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, thereby providing increased plasma concentrations of nirmatrelvir.
Antiviral activity: In vitro antiviral activity: Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 infection of differentiated normal human bronchial epithelial (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.
The antiviral activity of nirmatrelvir against the Omicron sub-variants BA.2, BA.2.12.1, BA.4, BA.4.6, BA.5, BF.7 (P252L+F294L), BF.7 (T243I), BQ.1.11, BQ.1, and XBB.1.5 was assessed in Vero E6-TMPRSS2 cells in the presence of a P-gp inhibitor. Nirmatrelvir had a median EC50 value of 83 nM (range: 39-146 nM) against the Omicron sub-variants, reflecting EC50 value fold-changes ≤1.5 relative to the USA-WA1/2020 isolate.
In addition, the antiviral activity of nirmatrelvir against the SARS-CoV-2 Alpha, Beta, Gamma, Delta, Lambda, Mu, and Omicron BA.1 variants was assessed in Vero E6 P-gp knockout cells. Nirmatrelvir had a median EC50 value of 25 nM (range: 16-141 nM). The Beta variant was the least susceptible variant tested, with an EC50 value fold-change of 3.7 relative to USA-WA1/2020. The other variants had EC50 value fold-changes ≤1.1 relative to USA-WA1/2020.
Antiviral resistance in cell culture and biochemical assays: SARS-CoV-2 Mpro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods, including SARS-CoV-2 resistance selection, testing of recombinant SARS-CoV-2 viruses with Mpro substitutions, and biochemical assays with recombinant SARS-CoV-2 Mpro containing amino acid substitutions. Table 1 indicates Mpro substitutions and combinations of Mpro substitutions that have been observed in nirmatrelvir-selected SARS-CoV-2 in cell culture. Individual Mpro substitutions are listed regardless of whether they occurred alone or in combination with other Mpro substitutions. Note that the Mpro S301P and T304I substitutions overlap the P6 and P3 positions of the nsp5/nsp6 cleavage site located at the C-terminus of Mpro. Substitutions at other Mpro cleavage sites have not been associated with nirmatrelvir resistance in cell culture. The clinical significance of these substitutions is unknown. (See Table 1.)
Click on icon to see table/diagram/imageIn a biochemical assay using recombinant SARS-CoV-2 Mpro containing amino acid substitutions, the following SARS-CoV-2 Mpro substitutions led to ≥3-fold reduced activity (fold change based on Ki values) of nirmatrelvir: Y54A (25), F140A (21), F140L (7.6), F140S (260), G143S (3.6), S144A (46), S144E (480), S144T (170), H164N (6.7), E166A (35), E166G (6.2), E166V (7,700), H172Y (250), A173S (4.1), A173V (16), R188G (38), Q192L (29), Q192P (7.8), and V297A (3.0). In addition, the following combinations of Mpro substitutions led to ≥3-fold reduced nirmatrelvir activity: T21I+S144A(20), T21I+E166V (11,000), T21I+A173V (15), L50F+E166V (4,500), E55L+S144A (56), T135I+T304I (5.1), F140L+A173V (95), H172Y+P252L (180), A173V+T304I (28), T21I+S144A+T304I (51), T21I+A173V+T304I (55), L50F+E166A+L167F (210), T21I+L50F+A193P+S301P (7.3), L50F+F140L+L167F+T304I (190), and T21I+C160F+A173V+V186A+T304I (28). The following substitutions and substitution combinations emerged in cell culture but conferred <3-fold reduced nirmatrelvir activity in biochemical assays: T21I (1.6), L50F (0.2), P108S (2.9), T135I (2.2), C160F (0.6), L167F (0.9), T169I (1.4), V186A (0.8), A191V(0.8), A193P (0.9), P252L (0.9), S301P (0.2), T304I (1.0), T21I+T304I (1.8), and L50F+T304I (1.3). The clinical significance of these substitutions is unknown.
Most single and some double Mpro amino acid substitutions identified which reduced the susceptibility of SARS-CoV-2 to nirmatrelvir resulted in an EC50 shift of <5-fold compared to wild type SARS-CoV-2 in an antiviral cell assay. Virus containing E166V shows the greatest reduction in susceptibility to nirmatrelvir and appears to have replication defect since it either could not be generated or had a very low virus titer. In general, triple and some double Mpro amino acid substitutions led to EC50 changes of >5-fold to that of wild type. The clinical significance needs to be further understood, particularly in the context of nirmatrelvir high clinical exposure (~≥5x EC90). Thus far, these substitutions have not been identified as treatment-emergent substitutions associated with hospitalisation or death from the EPIC-HR or EPIC-SR studies.
Treatment-emergent substitutions were evaluated among participants in clinical trials EPIC-HR/SR with sequence data available at both baseline and a post-baseline visit (n=907 Paxlovid-treated participants, n=946 placebo-treated participants). SARS-CoV-2 Mpro amino acid changes were classified as Paxlovid treatment-emergent substitutions if they were absent at baseline, occurred at the same amino acid position in 3 or more Paxlovid-treated participants and were ≥2.5-fold more common in Paxlovid-treated participants than placebo-treated participants post-dose. The following Paxlovid treatment-emergent Mpro substitutions were observed: T98I/R/del (n=4), E166V (n=3), and W207L/R/del (n=4). Within the Mpro cleavage sites, the following Paxlovid treatment-emergent substitutions were observed: A5328S/V(n=7) and S6799A/P/Y (n=4). These cleavage site substitutions were not associated with the co-occurrence of any specific Mpro substitutions.
None of the treatment-emergent substitutions listed previously in Mpro or Mpro cleavage sites occurred in Paxlovid-treated participants who experienced hospitalization. Thus, the clinical significance of these substitutions is unknown.
Viral load rebound: Post-treatment increases in SARS-CoV-2 nasal RNA levels (i.e., viral RNA rebound) were observed on Day 10 and/or Day 14 in a subset of Paxlovid and placebo recipients in EPIC-HR and EPIC-SR, irrespective of COVID-19 symptoms. The frequency of detection of post-treatment nasal viral RNA rebound varied according to analysis parameters but was generally similar among Paxlovid and placebo recipients. A similar or smaller percentage of placebo recipients compared to Paxlovid recipients had nasal viral RNA results < lower limit of quantitation (LLOQ) at all study timepoints in both the treatment and post-treatment periods.
Post-treatment viral RNA rebound was not associated with the primary clinical outcome of COVID-19-related hospitalization or death from any cause through Day 28 following the single 5-day course of Paxlovid treatment. The clinical relevance of post-treatment increases in viral RNA following Paxlovid or placebo treatment is unknown.EPIC-HR and EPIC-SR were not designed to evaluate symptomatic viral RNA rebound, and most episodes of symptom rebound occurred after Day 14 (the last day SARS-CoV-2 RNA levels were routinely assessed). The frequency of symptom rebound through Day 28, irrespective of viral RNA results, was similar among Paxlovid and placebo recipients.
Cross-resistance: Cross-resistance is not expected between nirmatrelvir and anti-SARS-CoV-2 monoclonal antibodies(mAb) or remdesivir based on their different mechanisms of action.
Pharmacodynamic effects: Cardiac electrophysiology: No clinically relevant effect of nirmatrelvir on QTcF interval was observed in a double-blind, randomised, placebo-controlled, crossover study in 10 healthy adults. The model predicted upper bound of 90% confidence interval (CI) for baseline and ritonavir adjusted QTcF estimate was 1.96 ms at approximately 4-fold higher concentration than the mean steady-state peak concentration after a therapeutic dose of nirmatrelvir/ritonavir 300 mg/100 mg.
Effects on viral RNA levels: Changes from baseline relative to placebo at Day 5 in viral RNA levels in nasopharyngeal samples are summarised by study in Table 2. (See Table 2.)
Click on icon to see table/diagram/imageThe degree of reduction in viral RNA levels relative to placebo following 5 days of Paxlovid treatment was similar across studies, including those enrolling unvaccinated participants (EPIC-HR) and those enrolling both unvaccinated and vaccinated participants (EPIC-SR and EPIC-PEP).
Effect on lipids: The changes in lipids in nirmatrelvir/ritonavir treated group were not statistically different than placebo/ritonavir treated group in an exploratory analysis of lipids in multiple ascending dose cohorts in which healthy participants were randomised to receive either escalating doses (75, 250 and 500 mg) of nirmatrelvir (n=4 per cohort) or placebo (n=2 per cohort), enhanced with ritonavir 100 mg, twice a day for 10 days.
In participants receiving placebo/ritonavir twice a day, a modest increase in cholesterol (≤27.2 mg/dL), LDL cholesterol (≤23.2 mg/dL), triglycerides (≤64.3 mg/dL) and decrease in HDL cholesterol(≤4 mg/dL) was observed. The clinical significance of such changes with short-term treatment is unknown.
Clinical efficacy and safety: Efficacy in participants at high risk of progressing to severe COVID-19 illness (EPIC-HR): The efficacy of Paxlovid is based on the 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.
Participants were randomized (1:1) to receive Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo orally every 12 hours for 5 days. The study excluded individuals with a history of prior COVID-19 infection or vaccination. The primary efficacy endpoint is 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 participants with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment, the mITT1 analysis set (all treated participants 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 participants with onset of symptoms ≤5 days).
A total of 2,113 participants were randomised to receive either Paxlovid or placebo. At baseline, mean age was 45 years; 51% were male; 71% were White, 4% were Black or African American, 41% were Hispanic or Latino and 15% were Asian; 67% of participants had onset of symptoms ≤3 days from initiation of study treatment; 49% of participants were serological negative at baseline. The most frequently reported risk factors were BMI ≥25 kg/m2 (1,792 [80.6%] participants), tobacco use (865 [38.9%] participants), hypertension (733 [33.0%] participants), age ≥60 years (484 [21.8%] participants), and diabetes mellitus (272 [12.2%] participants). Other risk factors were chronic lung disease (101 [4.5%] participants), cardiovascular disorder (91 [4.1%] participants), chronic kidney disease (14 [0.6%] participants), immunosuppression (13 [0.6%] participants), cancer (11 [0.5%] participants), device dependency (7 [0.3%] participants), neurodevelopmental disorders (3 [0.1%] participants), and HIV infection (1 [<0.1%] participant). The mean (SD) baseline viral load was 4.71 log10 copies/mL (2.78); 27% of participants had a baseline viral load of ≥7 log10 copies/mL; 6% 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.
Table 3 provides results of the primary endpoint in the mITT1 analysis population. For the primary endpoint, the relative risk reduction in the mITT1 analysis population for Paxlovid compared to placebo was 86% (95% CI: 72%, 93%). (See Table 3.)
Click on icon to see table/diagram/imageThrough Week 24, no deaths were reported in the Paxlovid group compared with 15 deaths in the placebo group. The proportions of participants who discontinued treatment due to an adverse event were 2.0% in the Paxlovid group and 4.3% in the placebo group.
Consistent results were observed in the mITT and mITT2 analysis populations. A total of 1318 participants were included in the mITT analysis population. The event rates were 5/671 (0.75%) in the Paxlovid group and 44/647 (6.80%) in the placebo group.
Similar trends have been observed across subgroups of participants (see figure).
Click on icon to see table/diagram/imageEfficacy in vaccinated participants with at least 1 risk factor for progression to severe COVID-19 illness: (EPIC-SR) EPIC-SR was a phase 2/3, randomized, double-blind, placebo-controlled study in non-hospitalized symptomatic adult participants with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible participants were 18 years of age and older with COVID-19 symptom onset of ≤5 days who were at standard risk for progression to severe disease. The study included previously unvaccinated participants without risk factors or fully vaccinated participants with at least 1 of the risk factors for progression to severe disease (as defined in the previously mentioned EPIC-HR and by local regulations and practices). A total of 1296 participants were randomized (1:1) to receive Paxlovid or placebo orally every 12 hours for 5 days; of these, 57% were vaccinated at baseline.
Analyses of efficacy presented as follows is based on vaccinated participants with at least 1 risk factor for progression to severe disease. In vaccinated participants, Table 4 provides results of the proportion of participants with COVID-19 related hospitalization or death from any cause through Day 28 (secondary endpoint of EPIC-SR). The relative risk reduction in the mITT1 analysis population for Paxlovid compared to placebo was 58%. The result did not reach statistical significance. (See Table 4.)
Click on icon to see table/diagram/imagePost-exposure prophylaxis (EPIC-PEP): EPIC-PEP was a phase 2/3, randomized, double-blind, double-dummy, placebo-controlled study assessing the efficacy of Paxlovid (administered 5 days or 10 days) in post-exposure prophylaxis of COVID-19 in household contacts of symptomatic individuals infected with SARS-CoV-2. Eligible participants were asymptomatic adults 18 years of age and older who were SARS-CoV-2 negative at screening and who lived in the same household with symptomatic individuals with a recent diagnosis of SARS-CoV-2. A total of 2,736 participants were randomized (1:1:1) to receive Paxlovid orally every 12 hours for 5 days, Paxlovid orally every 12 hours for 10 days, or placebo.
Compared with placebo, the Paxlovid 5-day and 10-day regimens led to a 30% and 36% relative risk reduction, respectively, in the risk of developing a symptomatic, reverse transcriptase-polymerase chainreaction (RT-PCR) or rapid antigen test (RAT) confirmed SARS-CoV-2 infection through household contact; these results did not reach statistical significance. In a post hoc analysis, the risk of developing a symptomatic or asymptomatic confirmed SARS-Cov-2 infection was reduced by 31% and 35% with the Paxlovid 5-day and 10-day regimens, respectively, compared with placebo (Table 5). (See Table 5.)
Click on icon to see table/diagram/imageThis medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The local Authority will review new information on this medicinal product at least every year and this Product Information will be updated as necessary.
Pharmacokinetics: The pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy participants and in participants with mild to moderate COVID-19.
Ritonavir is administered with nirmatrelvir as a pharmacokinetic enhancer resulting in higher systemic concentrations and longer half-life of nirmatrelvir. In healthy participants in the fasted state, the mean half-life (t½) of a single dose of 150 mg nirmatrelvir administered alone was approximately 2 hours compared to 7 hours after administration of a single dose of 250 mg/100 mg nirmatrelvir/ritonavir, thereby supporting a twice-daily administration regimen.
Upon administration of single dose of nirmatrelvir/ritonavir 250 mg/100 mg to healthy participants in the fasted state, the geometric mean (CV%) maximum concentration (Cmax) and area under the plasma concentration-time curve from 0 to the time of last measurement (AUClast) was 2.88 ug/mL (25%) and 27.6 ug*hr/mL (13%), respectively. Upon repeat-dose of nirmatrelvir/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. Simulated repeat-dose exposures of nirmatrelvir/ritonavir 300 mg/100 mg administered twice daily in adult participants from EPIC-HR suggested the mean AUCtau was 30.4 μg*hr/mL, mean Cmax was 3.43 μg/mL, and mean Cmin was 1.57 μg/mL.
Absorption: Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean nirmatrelvir (CV%) Cmax and area under the plasma concentration-time curve from 0 to infinity (AUCinf) at steady-state was 2.21 μg/mL (33) and 23.01 μg*hr/mL (23), respectively. The median (range) time to Cmax (Tmax) was 3.00 hrs (1.02-6.00). The arithmetic mean (+SD) terminal elimination half-life was 6.1 (1.8) hours.
Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean ritonavir (CV%) Cmax and AUCinf was 0.36 μg/mL (46) and 3.60 μg*hr/mL (47), respectively. The median (range) time to Cmax (Tmax) was 3.98 hrs (1.48-4.20). The arithmetic mean (+SD) terminal elimination half-life was 6.1 (2.2) hours.
Effect of food on oral absorption: Dosing with a high fat meal increased the exposure of nirmatrelvir (approximately 61% increase in mean Cmax and 20% increase in mean AUClast) relative to fasting conditions following administration of 300 mg nirmatrelvir (2 x 150 mg)/100 mg ritonavir tablets.
Distribution: The protein binding of nirmatrelvir in human plasma is approximately 69%.
The protein binding of ritonavir in human plasma is approximately 98-99%.
Biotransformation: In vitro studies assessing nirmatrelvir without concomitant ritonavir suggest that nirmatrelvir is primarily metabolised by CYP3A4. Nirmatrelvir is not a substrate of other CYP enzymes. Administration of nirmatrelvir with ritonavir inhibits the metabolism of nirmatrelvir. In human plasma, the only drug-related entity observed was unchanged nirmatrelvir.
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.
Elimination: The primary route of elimination of nirmatrelvir when administered with ritonavir was renal excretion of intact drug. Approximately 49.6% and 35.3% of the administered dose of nirmatrelvir 300 mg was recovered in urine and faeces, respectively. Nirmatrelvir was the predominant drug-related entity with small amounts of metabolites arising from hydrolysis reactions in excreta.
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.
Specific populations: Age and gender: In a population PK analysis, age and gender did not affect the pharmacokinetics of nirmatrelvir.
Racial or ethnic groups: Systemic exposure in Japanese participants was numerically lower but not clinically meaningfully different than those in Western participants. In a population PK analysis, race did not affect the pharmacokinetics of nirmatrelvir.
Patients with renal impairment: Compared to healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir 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.
Patients with hepatic impairment: Compared to healthy controls with no hepatic impairment, the pharmacokinetics of nirmatrelvir in subjects with moderate hepatic impairment were not significantly different. Adjusted geometric mean ratio (90% CI) of AUCinf and Cmax of nirmatrelvir comparing moderate hepatic impairment (test) to normal hepatic function (reference) were 98.78% (70.65%, 138.12%) and 101.96% (74.20%,140.11%), respectively.
Nirmatrelvir/ritonavir has not been studied in patients with severe hepatic impairment.
Interaction studies conducted with nirmatrelvir/ritonavir: Interaction studies conducted with nirmatrelvir: In vitro data indicates that nirmatrelvir is a substrate for human MDR1 (P-gp) and CYP3A4, but not a substrate for human BCRP, MATE1, MATE2K, NTCP, OAT1, OAT2, OAT3, OCT1, OCT2, PEPT1, OATPs 1B1, 1B3, 2B1, or 4C1.
Nirmatrelvir does not reversibly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 in vitro at clinically relevant concentrations. Nirmatrelvir has the potential to reversibly and time-dependently inhibit CYP3A4 and inhibit MDR1 (P-gp) and OATP1B1.
Nirmatrelvir does not induce any CYPs at clinically relevant concentrations.
Interaction studies conducted with ritonavir: In vitro studies indicate that ritonavir is mainly a substrate of CYP3A. Ritonavir also appears to be a substrate of CYP2D6 which contributes to the formation of isopropylthiazole oxidation metabolite M-2.
Ritonavir is an inhibitor of CYP3A and to a lesser extent CYP2D6. Ritonavir appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyltransferase.
The effects of co-administration of Paxlovid with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer) on the nirmatrelvir AUC and Cmax are summarised in Table 6. (See Table 6.)
Click on icon to see table/diagram/imageThe effects of co-administration of Paxlovid with oral midazolam (CYP3A4 substrate) or dabigatran (P-gp substrate) on the midazolam and dabigatran AUC and Cmax, respectively, are summarized in Table 7. (See Table 7.)
Click on icon to see table/diagram/imagePreclinical safety data: Toxicology: Repeat-dose toxicity studies up to 1 month duration of nirmatrelvir in rats and monkeys resulted in no adverse findings.
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 proteinuria were noted in rats and are felt to be attributable to species-specific spontaneous disease. Furthermore, no clinically significant renal abnormalities were noted in clinical trials.
Carcinogenesis: Nirmatrelvir has not been evaluated for the potential to cause carcinogenicity.
Long-term carcinogenicity studies of ritonavir in mice and rats revealed tumorigenic potential specific for these species, but are regarded as of no relevance for humans.
Genotoxicity: Nirmatrelvir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome aberration using human lymphoblastoid TK6 cells and in vivo rat micronucleus assays.
Ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.
Reproductive toxicity: Nirmatrelvir: In a fertility and early embryonic development study, there were no nirmatrelvir effects on fertility, reproductive performance at doses up to 1,000 mg/kg/day representing 5x clinical exposures at the authorized dose of Paxlovid.
Embryo-foetal developmental (EFD) toxicity studies were conducted in pregnant rats and rabbits administered oral nirmatrelvir doses of up to 1000 mg/kg/day during organogenesis [on Gestation Days (GD) 6 through 17 in rats and GD 7 through 19 in rabbits]. No biologically significant developmental effects were observed in the rat EFD study. At the highest dose of 1000 mg/kg/day, the systemic nirmatrelvir exposure (AUC24) in rats was approximately 9x higher than clinical exposures at the authorised human dose of Paxlovid. In the rabbit EFD study, lower foetal body weights (9% decrease) were observed at 1000 mg/kg/day in the absence of significant maternal toxicity findings. At 1000 mg/kg/day, the systemic exposure (AUC24) in rabbits was approximately 11x higher than clinical exposures at the authorised human dose of Paxlovid. No other significant developmental toxicities (malformations and embryo-foetal lethality) were observed at up to the highest dose tested, 1000 mg/kg/day. No developmental effects were observed in rabbits at 300 mg/kg/day resulting in systemic exposure (AUC24) approximately 3x higher than clinical exposures at the authorised human dose of Paxlovid.
In the pre- and postnatal developmental study, body weight decreases (up to 8%) were observed in the offspring of pregnant rats administered nirmatrelvir at maternal systemic exposure (AUC24) approximately 9x higher than clinical exposures at the authorized human dose of Paxlovid. No bodyweight changes in the offspring were noted at maternal systemic exposure (AUC24) approximately 6x higher than clinical exposures at the authorized human dose of Paxlovid.
Ritonavir: Ritonavir produced no effects on fertility in rats.
Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on GD 6 through 17 and 6 through 19, respectively). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at systemic exposures (AUC) approximately 4x higher than exposure at the authorised human dose of Paxlovid. Increased incidences of early resorptions, ossification delays and developmental variations, as well as decreased foetal body weights were observed in rats in the presence of maternal toxicity, at systemic exposures approximately 4x higher than exposure at the authorised human dose of Paxlovid. In rabbits, resorptions, decreased litter size and decreased foetal weights were observed at maternally toxic doses approximately 11x higher than the authorised human dose of Paxlovid, based on a body surface area conversion factor. In pre- and post-natal development study in rats, administration 0, 15, 35, and 60 mg/kg/day ritonavir from GD 6 through Post-natal Day 20 resulted in no developmental toxicity, at ritonavir doses 3x higher than the authorised human dose of Paxlovid, based on a body surface area conversion factor.
Continue with Google