問題:
Paxlovid® (nirmatrelvir 和 ritonavir) 是否可以與抗癌藥物 Trodelvy® (sacituzumab govitecan) 合併使用?是否會產生藥物相互作用?

回答:
Paxlovid® 和 Trodelvy® 的作用機制
Trodelvy®（sacituzumab govitecan）是一種抗體藥物複合體（antibody-drug conjugate, ADC），用於治療三陰性乳癌和泌尿上皮癌 [1]。該藥品為供靜脈注射用，外觀呈灰白色至淡黃色凍晶乾燥粉末，每瓶裝含有180 mg的藥品 [1]。三陰性乳癌的癌細胞表面有Trop-2受體過度表現，而Trodelvy® 是一種 Trop-2 導向的抗體藥物複合體， 藉由人源化抗體sacituzumab識別癌細胞表面 Trop-2 受體，將topoisomerase I 抑制劑 (govitecan, SN-38) 帶到癌細胞內，來達到毒殺癌細胞，降低傷及正常細胞的效果 [2]。SN-38經由 UGT1A1 代謝成葡萄醣醛酸代謝物 (SN-38G) [2]。
Paxlovid® 為針對COVID-19的抗病毒治療藥物，由兩種藥物組成：nirmatrelvir和ritonavir [3]。Nirmatrelvir是SARS-CoV-2蛋白酵素 (protease) 抑制劑，藉由阻斷冠狀病毒繁殖所需的酵素，讓病毒無法複製。Ritonavir抑制經由CYP3A4調節nirmatrelvir的代謝，使nirmatrelvir的血中濃度增加，加強在體內的抗病毒效用 [3]。

藥物相互作用
Trodelvy® 和Paxlovid® 之間的藥物相互作用涉及ritonavir對不同酶代謝速率的影響。Ritonavir是CYP3A4的抑制劑，但同時也是UGT1A1的誘導劑，因此可能加速SN-38的代謝，從而降低其血中濃度，並減弱Trodelvy® 的抗癌效果。
目前仍缺乏因ritonavir誘導SN-38代謝的研究，然而可以參考過去一項關於ritonavir和含有ethinyl estradiol 的口服避孕藥物合併使用的研究。Ethinyl estradiol同樣經由CYP3A代謝，而在該研究中，儘管ritonavir對CYP3A有抑制作用，為期兩週的 ritonavir 療程仍使血中ethinyl estradiol濃度顯著地下降 [4]，這表示ritonavir經誘導葡萄醣醛酸化 (glucuronidation) 路徑使ethinyl estradiol清除加速 [4]。根據該研究結果，能推測在合併使用Trodelvy® 和Paxlovid® 的癌症患者中也可以觀察到 ritonavir對 UGT1A1的酶誘導效應，導致 SN-38 的代謝加快。
同一篇研究也顯示，這個效應在給藥的六個小時內就會啟動，即使已離最後一劑 ritonavir 長達14天，效果仍存 [4]，因此不建議Paxlovid® 與其他藥物合併使用。其他文獻則指出，SN-38的平均半衰期為10.6小時 [5]，因此需等到Trodelvy® 給藥的三天後，血中濃度才會降到相當低的程度，而不受Paxlovid® 之影響。

Paxlovid® 與Trodelvy® 的使用建議
狀況1：若病人需要長期給Trodelvy®，不建議使用 Paxlovid®
狀況2：Trodelvy® 給藥後72小時內，不建議使用 Paxlovid®
狀況3：Trodelvy® 給藥後72小時以上，且不再使用此藥治療，則可使用Paxlovid®

Question: 
Can the antiviral drug, Paxlovid® (nirmatrelvir and ritonavir) be used in combination with the anticancer drug, Trodelvy® (sacituzumab govitecan)? Or are there drug-drug interactions to be aware of?

Answer:
Mechanisms of Action: Paxlovid® versus Trodelvy®
Trodelvy® (sacituzumab govitecan) is an antibody-drug conjugate (ADC) used in the treatment of certain types of cancer, including triple negative breast cancer and urothelial cancer [1]. It is available for intravenous administration as 180 mg off-white to yellow-colored lyophilized powder in single-dose vials for reconstitution [1]. The drug comprises an antibody component (sacituzumab) that specifically targets the Trop-2 antigen overexpressed on tumor cells, as well as a chemotherapy agent called SN-38 (govitecan), which inhibits topoisomerase I and causes tumor cell death [2]. The metabolism of SN-38 involves UGT1A1 deactivating SN-38 into SN-38G [2].
Paxlovid® is an antiviral treatment for COVID-19 consisting of two drugs: nirmatrelvir and ritonavir [3]. Nirmatrelvir acts as an inhibitor of SARS-CoV-2 protease and prevents viral replication, while ritonavir inhibits CYP3A4-mediated metabolism of nirmatrelvir [3]. By inhibiting CYP3A4, ritonavir increases the half-life and plasma concentration of nirmatrelvir, thereby enhancing its antiviral efficacy [3].

Drug-Drug Interaction
The drug-drug interaction between Trodelvy® and Paxlovid® concerns ritonavir’s effects on different enzymes’ rate of metabolism. 
While ritonavir acts as an inhibitor of CYP3A4, it is an inducer of UGT1A1, so it may accelerate the metabolism of SN-38, the active component of Trodelvy®, thus lowering its serum concentration and potentially diminishing its anticancer efficacy.
There is currently a lack of studies examining the decrease in SN-38 due to enzymatic induction by ritonavir. Nevertheless, a parallel can be drawn to a previous study on the concurrent use of ritonavir and oral contraceptives containing ethinyl estradiol, which is metabolized via CYP3A. In that study, a significant reduction in serum ethinyl estradiol concentration was observed following a concomitant, two-week course of ritonavir, despite its known inhibitory effect on CYP3A [4]. This suggested that ritonavir increased ethinyl estradiol clearance via the induction of the glucuronidation pathway [4]. Given such findings, it is reasonable to infer that ritonavir would similarly induce UGT1A1, thereby speeding up the metabolism of SN-38 in cancer patients concurrently treated with Trodelvy® and Paxlovid®. 
The same study also noted that ritonavir’s enzymatic induction occurred within six hours of administration and persisted at least 14 days after the last dose [4]. In addition, other literature reported a mean apparent terminal half-life of plasma SN-38 as 10.6 hours [5]. Therefore, its serum concentration would only decrease to sufficiently low levels unaffected by Paxlovid® approximately three days after Trodelvy® administration. 

Summarized Recommendations for the Concomitant Use of Paxlovid® and Trodelvy®
Scenario 1: If the patient requires long-term administration of Trodelvy®, Paxlovid® would not be recommended.
Scenario 2: If Trodelvv was administered within the past 72 hours, Paxlovid® would not be recommended.
Scenario 3: If more than 72 hours have passed since the last Trodelvy® administration, and if Trodelvy® will no longer be used for anticancer treatment, Paxlovid® may be used.


References

1.    US Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. FDA. 2020 [Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process
2.    Gilead Sciences. Trodelvy Mechanism of Action. Gilead Sciences. 2020 [Available from: https://www.trodelvyhcp.com/moa
3.    Pfizer. FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR PAXLOVIDTM. FDA. 2023 [Available from: https://www.fda.gov/media/155050/download
4.    Ouellet* D, Hsu A, Qian J, Locke CS, Eason CJ, Cavanaugh JH, et al. Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. British Journal of Clinical Pharmacology. 1998;46(2):111-6. doi:https://doi.org/10.1046/j.1365-2125.1998.00749.x
5.    Chabot GG, Abigerges D, Catimel G, Culine S, de Forni M, Extra JM, et al. Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials. Ann Oncol. 1995;6(2):141-51. doi:10.1093/oxfordjournals.annonc.a059109

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撰稿人：陳怡穎
審稿人：姜紹青
上傳日期：2024/07/18