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 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 nirmatrelvir, thereby providing increased plasma concentrations of nirmatrelvir.
Nirmatrelvir 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. Nirmatrelvir 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 nirmatrelvir with SARS-CoV-2. Studies to evaluate selection of resistance to nirmatrelvir 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 nirmatrelvir 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 pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy participants.
Ritonavir is administered with nirmatrelvir as a pharmacokinetic enhancer resulting in higher systemic concentrations of nirmatrelvir.
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.
Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean nirmatrelvir 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 nirmatrelvir/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 nirmatrelvir (approximately 15% increase in mean Cmax and 1.6% increase in mean AUClast) relative to fasting conditions following administration of a suspension formulation of nirmatrelvir coadministered with ritonavir tablets.
The protein binding of nirmatrelvir in human plasma is approximately 69%.
The protein binding of ritonavir in human plasma is approximately 98-99%.
In vitro studies assessing nirmatrelvir without concomitant ritonavir suggest that nirmatrelvir is primarily metabolised by CYP3A4. Nirmatrelvir does not reversibly inhibit CYP2D6, CYP2C9, CYP2C19, CYP2C8 or CYP1A2 in vitro at clinically relevant concentrations. Nirmatrelvir is not an inducer or substrate of other CYP enzymes other than CYP3A of which nirmatrelvir/ritonavir is an inhibitor. Administration of nirmatrelvir with ritonavir inhibits the metabolism of nirmatrelvir. In plasma, the only medicinal product-related entity observed was unchanged nirmatrelvir. 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 nirmatrelvir when administered with ritonavir was renal excretion of intact medicinal product. 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. In plasma, the only drug-related entity quantifiable was unchanged nirmatrelvir.
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 nirmatrelvir/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 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.
Compared to healthy controls with no hepatic impairment, the PK of nirmatrelvir in subjects with moderate hepatic impairment was 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) was 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.
CYP3A4 was the major contributor to the oxidative metabolism of nirmatrelvir, when nirmatrelvir was tested alone in human liver microsomes. Ritonavir is an inhibitor of CYP3A and increases plasma concentrations of nirmatrelvir 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 nirmatrelvir.
Nirmatrelvir does not reversibly inhibit CYP2D6, CYP2C9, CYP2C19, CYP2C8, or CYP1A2 in vitro at clinically relevant concentrations. In vitro study results showed nirmatrelvir may be inducer of CYP3A4, CYP2B6, CYP2C8 and CYP2C9. The clinical relevance is unknown. Based on in vitro data, nirmatrelvir has a low potential to inhibit BCRP, MATE2K, OAT1, OAT3, OATP1B3 and OCT2. There is a potential for nirmatrelvir to inhibit MDR1, MATE1, OCT1 and OATP1B1 at clinically relevant concentrations.
No nonclinical safety studies have been conducted with nirmatrelvir in combination with ritonavir.
Studies of repeated dose toxicity and genotoxicity revealed no risk due to nirmatrelvir. 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 nirmatrelvir/ritonavir.
No carcinogenicity studies have been conducted with nirmatrelvir.
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.
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