Runcong Zhang,1,2,* Jing Fan,1,2,* Lu Han,3,4,* Juehui Mao,4,5 Liang Sun,1,2 Yuetian Yu,2,6,7 Weibin Fan,1,2 Jiao Xie,2,8 Bin Lin,1,2,7 Nengming Lin1,2,9 

1Department of Pharmacy, Changxing People’s Hospital, Changxing, People’s Republic of China; 2Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Changxing, People’s Republic of China; 3School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 6Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 7Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Hangzhou, People’s Republic of China; 8Department of Pharmacy, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 9Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Bin Lin, Department of Pharmacy, Changxing People’s Hospital, Changxing, 313100, People’s Republic of China, Tel/Fax +86-572-6267652, Email lb_wzmc@126.com Nengming Lin, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, 310006, People’s Republic of China, Tel/Fax +86-572- 56007905, Email lnm1013@zju.edu.cn

Purpose: Nirmatrelvir/ritonavir (N/R) is the first drug to receive emergency authorization for the treatment of COVID-19 infection. We aimed to develop a population pharmacokinetic (PopPK) model to evaluate the effects of potential covariates and explore dosing regimen.
Patients and Methods: Sparse data of serum concentrations of N/R were obtained from 129 patients with COVID-19 infection receiving oral 300/100 mg N/R twice daily for 5 days. Plasma samples were assayed using ultra-high-performance liquid chromatography–tandem mass spectrometry. The PopPK model was developed using a nonlinear mixed effects approach utilizing the NONMEM 7.4 software. Monte Carlo simulation was conducted to optimize the dosage regimen.
Results: A one-compartment model with first-order absorption and first-order elimination provided the best fit for the data. Allometric scaling of parameters on creatinine clearance (CrCl) and body weight were identified as covariates that significantly influenced exposure-efficacy after oral administration of nirmatrelvir. Monte Carlo simulation using the final model generated concentration-time profiles for virtual patients (1,000 per group) with varying renal functions and body weight. Furthermore, we developed a web-based dashboard to visualize the dynamic changes in nirmatrelvir concentration and provide individualized dosage regimens.
Conclusion: This study showed that dosing regimen optimization of nirmatrelvir should be based on CrCl and body weight. Moreover, a web-based dashboard has been developed to facilitate individualized pharmacotherapy.

Keywords: population pharmacokinetics, nirmatrelvir, COVID-19, simulations, dosing regimen