A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir

Clinical Pharmacokinetics, Год журнала: 2024, Номер 63(1), С. 27 - 42

Опубликована: Янв. 1, 2024

Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that used as an oral antiviral disease 2019 (COVID-19) treatment. To sustain unbound systemic trough concentrations above in vitro 90% effective concentration value (EC90), nirmatrelvir coadministered with 100 mg ritonavir, pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvir's cytochrome P450 (CYP) 3A4-mediated metabolism which results renal elimination becoming primary route when dosed concomitantly. exhibits absorption-limited nonlinear pharmacokinetics. When ritonavir patients mild-to-moderate COVID-19, reaches maximum 3.43 µg/mL (11.7× EC90) approximately 3 h on day 5 dosing, geometric mean 1.57 (5.4× EC90). Drug interactions nirmatrelvir/ritonavir (PAXLOVIDTM) are primarily attributed to ritonavir-mediated CYP3A4 inhibition, lesser extent CYP2D6 P-glycoprotein inhibition. Population pharmacokinetics quantitative systems pharmacology modeling support twice daily dosing 300 mg/100 for days, reduced 150 dose moderate impairment. Rapid clinical development response emerging COVID-19 pandemic was enabled by innovations research, including adaptive phase 1 trial design allowing direct pivotal development, fluorine nuclear magnetic resonance spectroscopy delineate absorption, distribution, metabolism, excretion profiles, innovative applications model-informed drug accelerate development.

Язык: Английский

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Proof-of-concept studies with a computationally designed M ^pro inhibitor as a synergistic combination regimen alternative to Paxlovid

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(17)

Опубликована: Апрель 15, 2024

As the SARS-CoV-2 virus continues to spread and mutate, it remains important focus not only on preventing through vaccination but also treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a main protease (M pro ) DAA, has been significant for treatment patients. A limitation this however, is that antiviral component, nirmatrelvir, rapidly metabolized requires inclusion CYP450 3A4 metabolic inhibitor, ritonavir, boost levels active drug. Serious drug–drug interactions can occur Paxlovid patients who are taking other medications by CYP4503A4, particularly transplant or otherwise immunocompromised most at risk development severe symptoms. Developing an alternative improved pharmacological properties critical these By using computational structure-guided approach, we were able optimize 100 250 μM screening hit potent nanomolar inhibitor lead compound, Mpro61. In study, further evaluate Mpro61 as starting examination its mode binding M . vitro profiling established lack off-target effects, inhibition, well potential synergy currently approved alternate antiviral, molnupiravir. Development subsequent testing capsule formulation oral dosing in B6-K18-hACE2 mice demonstrated favorable properties, efficacy, molnupiravir, complete recovery from challenge SARS-CoV-2, establishing promising preclinical candidate.

Язык: Английский

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Ritonavir: 25 Years’ Experience of Concomitant Medication Management. A Narrative Review

Infectious Diseases and Therapy, Год журнала: 2024, Номер 13(5), С. 1005 - 1017

Опубликована: Апрель 12, 2024

Ritonavir is a potent inhibitor of the cytochrome P450 3A4 enzyme and commonly used as pharmacokinetic (PK) enhancer in antiviral therapies because it increases bioavailability concomitantly administered antivirals. Decades experience with ritonavir-enhanced HIV and, more recently, COVID-19 demonstrate that boosting doses ritonavir are well tolerated, an established safety profile. The mechanisms PK enhancement by result potential for drug–drug interactions (DDIs) several classes drugs, thus making co-medication management important consideration enhanced therapies. However, rates DDIs contraindicated medications low, suggesting these risks manageable infectious disease specialists who have use enhancers. In this review, we provide overview ritonavir's action describe approaches resources available to mitigate adverse events manage concomitant medication both chronic short-term settings.

Язык: Английский

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Pharmacovigilance of Drug–Drug Interactions with Nirmatrelvir/Ritonavir

Infectious Diseases and Therapy, Год журнала: 2024, Номер unknown

Опубликована: Окт. 26, 2024

Язык: Английский

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Clinical Evaluation of Drug–Drug Interactions with Obeldesivir, an Orally Administered Antiviral Agent

Clinical Pharmacology & Therapeutics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 31, 2025

Obeldesivir is an oral nucleoside analog prodrug inhibitor of SARS‐CoV‐2 RNA‐dependent RNA polymerase and other viral polymerases. Here, two Phase I studies evaluated potential drug–drug interactions between obeldesivir substrates or inhibitors cytochrome P450 drug transporters in healthy participants. When was tested as a precipitant, pharmacokinetic parameter point estimates for midazolam (CYP3A4 inhibition/induction), caffeine (CYP1A2 inhibition), metformin (organic cation transporter 1 inhibition) exposures were within 80–125% no‐effect bounds representing the interval which systemic exposure change does not warrant clinical action based on EMA/FDA guidance. Dabigatran (P‐glycoprotein substrate) pitavastatin anion transporting polypeptide 1B1/1B3 decreased by approximately 25% 30%, respectively, with coadministration; these considered clinically relevant, changes are associated dose precautions US prescribing information drugs. object, GS‐441524, parent monophosphate metabolite obeldesivir, ritonavir cyclosporin A (breast cancer resistance protein coadministration. Famotidine (gastric acid suppression) coadministration GS‐441524 26%; this range observed previous III relevant. well tolerated, adverse events mild to moderate. These findings indicate that has low interactions. remains promising treatment against broad spectrum viruses given its antiviral activity favorable safety profile.

Язык: Английский

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A Case Report of Severe Bradycardia Associated With Nirmatrelvir-ritonavir Drug-drug Interactions

Cardiology Discovery, Год журнала: 2025, Номер unknown

Опубликована: Фев. 7, 2025

Abstract With the increasing use of nirmatrelvir-ritonavir in older COVID-19 patients, adverse drug reactions due to drug-drug interactions have become more frequent. This report describes a patient who experienced severe bradycardia and hypotension following concurrent heart rate-control medications during an active infection. suggests that clinicians should be cautious when dealing with try their best avoid serious reactions.

Язык: Английский

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Evaluating Drug Interactions between Ritonavir and Opioid Analgesics: Implications from Physiologically Based Pharmacokinetic Simulation

Pharmaceuticals, Год журнала: 2024, Номер 17(5), С. 640 - 640

Опубликована: Май 15, 2024

Several commonly used opioid analgesics, such as fentanyl, sufentanil, alfentanil, and hydrocodone, are by report primarily metabolized the CYP3A4 enzyme. The concurrent use of ritonavir, a potent inhibitor, can lead to significant drug interactions. Using physiologically based pharmacokinetic (PBPK) modeling simulation, this study examines effects different dosing regimens ritonavir on pharmacokinetics these opioids. findings reveal that co-administration significantly increases exposure fentanyl analogs, with over 10-fold increase in alfentanil sufentanil when given ritonavir. Conversely, effect is modest, likely due additional metabolism pathways. Additionally, demonstrates steady-state hydrocodone its active metabolite hydromorphone be increased up 87% 95%, respectively, extended-release formulation particularly affected. These insights from PBPK provide valuable guidance for optimizing minimizing risk toxicity combination ritonavir-containing prescriptions.

Язык: Английский

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Virologic Response and Safety of Ibuzatrelvir, a Novel SARS-CoV-2 Antiviral, in Adults With COVID-19

Clinical Infectious Diseases, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Abstract Background Despite effective vaccines and treatments for COVID-19, clinical burden persists. An unmet need exists additional agents with safety profiles allowing use across a broad population. Ibuzatrelvir is an orally bioavailable SARS-CoV-2 Mpro inhibitor demonstrated in vitro antiviral activity low potential concerns, including drug–drug interactions. Methods This phase 2b, double-blind, randomized trial enrolled US adults aged 18 to <65 years symptomatic COVID-19 no risk factors severe disease. Participants were 1:1:2:2 receive 100, 300, or 600 mg ibuzatrelvir placebo twice daily 5 days. Nasopharyngeal specimens collected on days 1 (baseline), 3, 5, 10, 14, 21; adverse events (AEs) recorded through day 33. The primary end point was change RNA level (viral load [VL]) from baseline among participants VL ≥4 log10 copies/mL. Results Of 240 enrollees, 237 received ≥1 dose; 199 included the analysis. Placebo-adjusted least squares mean (80% confidence interval) (log10 copies/mL) at significant all doses: 100 mg, ‒0.7 (‒1.1 ‒0.3) copies/mL, P = .02; 300 ‒0.8 (‒1.3 ‒0.3), .01; ‒1.2 (‒1.5 ‒0.8), < .0001. AEs occurred similar percentages of groups. No deaths any cause treatment-related serious 33, reported dysgeusia. Conclusions All 3 doses associated robust acceptable profile, supporting continued development. Clinical Trials Registration NCT05799495.

Язык: Английский

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Budget impact of oral nirmatrelvir/ritonavir in adults at high risk for progression to severe COVID-19 in the United States

Journal of Managed Care & Specialty Pharmacy, Год журнала: 2023, Номер 29(12), С. 1290 - 1302

Опубликована: Дек. 1, 2023

BACKGROUND: Nirmatrelvir/ritonavir (NMV/r) is indicated for the treatment of mild-to-moderate COVID-19 in adults who are at high risk progression to severe COVID-19. NMV/r has also been authorized emergency use by US Food and Drug Administration pediatric patients (aged 226512 years weighing least 40 kg) Understanding budget impact introducing with key interest payers. OBJECTIVE: To estimate annual a commercial health plan setting current Omicron era. METHODS: A model was developed assess on care costs hypothetical 1-million-member insurance over 1-year period population; clinical cost inputs were derived from published literature focus studies recent era that included vaccinated population predominance variant. In base-case analysis, it assumed only effect reduction incidence (not severity) hospitalization or death; its potential post-COVID conditions assessed scenario analysis. Outcomes number hospitalizations, total cost, per patient year (PPPY) costs, member month (PMPM) costs. Sensitivity analyses conducted uncertainty around inputs. RESULTS: An estimated 29,999 eligible sought oral antiviral 1 year. The availability reduce hospitalizations 647 $2,733,745, $91 PPPY, $0.23 PMPM. saving when including -$1,510,780 impact, PPPY -$50, PMPM -$0.13. results most sensitive under supportive care, NMV/r. CONCLUSIONS: Treatment result substantial offsets because reductions modest overall savings.

Язык: Английский

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Telemedicine for Prescribing Nirmatrelvir/Ritonavir: Safety, Logistics, and Challenges

Open Forum Infectious Diseases, Год журнала: 2024, Номер 11(7)

Опубликована: Май 14, 2024

Abstract Nirmatrelvir/ritonavir can be a useful COVID-19 treatment but is challenging to prescribe safely because of drug-drug interactions. This study describes our experience prescribing nirmatrelvir/ritonavir within small interdisciplinary team with specific focus on management Ascertaining and communicating modifications concomitant medications key safety element.

Язык: Английский

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