A model-based pharmacokinetic assessment of drug–drug interaction between tacrolimus and nirmatrelvir/ritonavir in a kidney transplant patient with COVID-19

Tomida, Takeshi; Itohara, Kotaro; Yamamoto, Kazuhiro; Kimura, Takeshi; Fujita, Kohei; Uda, Atsushi; Kitahiro, Yumi; Yokoyama, Naoki; Hyodo, Yoji; Omura, Tomohiro; Yano, Ikuko

doi:10.1016/j.dmpk.2023.100529

Cited by 5 publications

(5 citation statements)

References 37 publications

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“…Tac, primarily metabolized by CYP3A4 and serving as a substrate for P-glycoprotein, undergoes first-pass intestinal metabolism, with an intestinal availability of 0.14 and a hepatic availability of 0.96 ( Tomida et al, 2023 ). Ritonavir inhibits P-glycoprotein, thereby diminishing Tac absorption and subsequently elevating Tac levels.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, ritonavir can disrupt Tac metabolism by irreversibly inhibiting CYP3A4 and P-glycoprotein activity, resulting in increased systemic exposure and reduced metabolic clearance of Tac ( Fishbane et al, 2022 ). A pharmacokinetic evaluation revealed that co-administration with NMV/r resulted in an 18.7-fold increase in Tac bioavailability and a 35% reduction in clearance ( Tomida et al, 2023 ). In healthy volunteers, steady-state concentrations of ritonavir (100 mg/day) led to a 17-fold and 57-fold elevation in the Tac concentration at 24 h (C 24 ) and the area under the plasma concentration-time curve (AUC 0-inf ), respectively, with Tac half-life extending from 32 h to 232 h ( Badri et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

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Case report and literature review: management of Paxlovid (nirmatrelvir/ritonavir)-induced acute tacrolimus toxicity in a patient with systemic lupus erythematosus

Jiang,

Yan,

Xia

et al. 2024

Front. Pharmacol.

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Despite the availability of effective vaccines and treatments for SARS-CoV-2, managing COVID-19 in patients with systemic lupus erythematosus (SLE) remains challenging, particularly considering drug-drug interactions (DDIs). Here, we present a case of DDIs between Tacrolimus (Tac) and nirmatrelvir/ritonavir (NMV/r) in a 32-year-old male with SLE. Following self-administration of NMV/r and resumption of Tac after 5 days, the patient experienced acute nephrotoxicity and neurotoxicity, accompanied by supratherapeutic Tac levels, despite Tac being withheld during NMV/r. The primary cause of this acute toxicity is attributed to ritonavir’s inhibitory effect on both CYP3A4 enzymes and P-glycoprotein. Upon admission, Tac was discontinued, and supportive therapies were initiated. Phenytoin, a CYP3A4 inducer, was administered to lower Tac levels under the guidance of clinical pharmacists, effectively alleviating the patient’s acute toxic symptoms. The half-life of Tac during the treatment of phenytoin was calculated to be 55.87 h. And no adverse reactions to phenytoin were observed. This case underscores the persistence of enzyme inhibition effects and demonstrates the effectiveness and safety of utilizing CYP3A4 enzyme inducers to mitigate Tac concentrations. Furthermore, it emphasizes the importance of healthcare providers and patients being vigilant about DDIs in Tac recipients. Lastly, it highlights the indispensable role of pharmacist involvement in clinical decision-making and close monitoring in complex clinical scenarios. Although our findings are based on a single case, they align with current knowledge and suggest the potential of individualized combination therapy in managing challenging COVID-19 cases in immunocompromised patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Case report and literature review: management of Paxlovid (nirmatrelvir/ritonavir)-induced acute tacrolimus toxicity in a patient with systemic lupus erythematosus

Jiang,

Yan,

Xia

et al. 2024

Front. Pharmacol.

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“…TAC has poor intestinal bioavailability and a high potential for strong interactions with P-glycoprotein inhibitors. The mechanism of interaction between NMV and TAC involves inhibition of CYP3A and P-glycoprotein in the small intestine, as well as systemic hepatic metabolism by CYP3A [ 19 ]. Both RTV and ESV inhibit P-glycoprotein, but the degree of inhibition may vary.…”

Section: Discussionmentioning

confidence: 99%

“…Because RTV potently inhibits CYP3A4 and CYP3A5, the intensity of the interaction may be greater when NMV/RTV is co-administered in patients with CYP3A5*3/*3 . Conversely, Tomida et al have reported the intensity of interaction with the concomitant use of NMV/RTV might be stronger in CYP3A5 *1 carriers, who would have relatively lower bioavailability and high clearance of TAC [ 19 ]. Although TAC concentrations increased in the present cases, the effect of CYP3A5 genetic polymorphisms on the drug interaction between TAC and RTV has not been reported; further studies are required.…”

Section: Discussionmentioning

confidence: 99%

Influence of ensitrelvir or nirmatrelvir/ritonavir on tacrolimus clearance in kidney transplant recipients: a single-center case series

Naganawa,

Katada,

Nakagawa

et al. 2024

J Pharm Health Care Sci

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Background Among the oral antivirals used for treating patients with mild-to-moderate novel coronavirus disease 2019 (COVID-19), nirmatrelvir/ritonavir (NMV/RTV) and ensitrelvir (ESV) are inhibitors of cytochrome P450 (CYP) 3A, and therefore, can cause drug–drug interactions with concomitant medications. Tacrolimus (TAC), a substrate of CYP3A4/5, is administered for a long period to prevent rejection after kidney transplantation. TAC should be discontinued while using NMV/RTV because blood TAC levels significantly increase when these drugs are concomitantly administered. However, the influence of ESV on blood TAC levels has not yet been reported, and the management of TAC doses during the use of ESV remains unclear. Case presentation We experienced three kidney transplant recipients with COVID-19, whose blood trough levels of TAC increased by the concomitant use of NMV/RTV or ESV. In two patients administering NMV/RTV, blood trough levels of TAC increased more than tenfold after combination therapy, whereas in one patient administering ESV, TAC level increased approximately threefold. Conclusions These cases suggest that TAC administration should be discontinued during NMV/RTV treatment to maintain blood TAC levels within the therapeutic range, and a reduced TAC dose is sufficient during ESV treatment.

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“…This is the first report of a post-lung transplant patient co-administered TAC-ER with NMV/r who showed abnormally high blood TAC levels above the detection limit. It has been reported that the blood TAC level may increase abnormally owing to increased bioavailability caused by inhibition of CYP3A4 and P-gp in the small intestine and decreased clearance caused by inhibition of CYP3A4 in the liver by NMV/r [ 11 ]. In particular, ritonavir is known to be a potent inhibitor of CYP3A4, the main metabolizing enzyme of TAC, and appears to be a major factor in the elevated blood TAC level in this case.…”

Section: Discussionmentioning

confidence: 99%

Abnormally Elevated Blood Tacrolimus Level Following the Concomitant Use of Nirmatrelvir/Ritonavir With Extended-Release Tacrolimus in a Post-lung Transplant Patient: A Case Report and a Literature Review

Yoshida,

Umemura,

Ito

et al. 2024

Cureus

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Although nirmatrelvir/ritonavir (NMV/r) reportedly increases blood levels of tacrolimus (TAC) due to CYP3A4 inhibition and other factors, reports on the use of NMV/r in combination with tacrolimus hydrate extended-release capsules (TAC-ER) in lung transplant patients are limited. Herein, we present a case with post-lung transplantation of elevated blood trough levels of TAC after concomitant use of NMV/r. A woman in her 60s had undergone lung transplantation. She had coronavirus disease 2019 (COVID-19) and was co-administered NMV/r and TAC-ER, with the trough level controlled at approximately 4 μg/mL. Upon the co-administration of NMV/r and TAC-ER, the patient developed diarrhea and vomiting and was hospitalized. TAC-ER was discontinued on day 6, and TAC level was measured on day 8 and had risen above 100 ng/mL. This level gradually decreased to 17.8 ng/mL on day 11 and 2.4 ng/mL on day 15; therefore, TAC-ER was resumed at 2.5 mg/day. On day 18, the TAC level was 5.2 ng/mL, which was within the target range, and the patient was discharged on day 19. This is the first report of a post-lung transplant patient co-administered TAC-ER with NMV/r, who showed abnormally high blood TAC levels above the detection limit. In patients using TAC-ER after lung transplantation, it may be useful to confirm that the TAC blood level is below the effective therapeutic range before resuming TAC-ER safely.

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A model-based pharmacokinetic assessment of drug–drug interaction between tacrolimus and nirmatrelvir/ritonavir in a kidney transplant patient with COVID-19

Cited by 5 publications

References 37 publications

Case report and literature review: management of Paxlovid (nirmatrelvir/ritonavir)-induced acute tacrolimus toxicity in a patient with systemic lupus erythematosus

Case report and literature review: management of Paxlovid (nirmatrelvir/ritonavir)-induced acute tacrolimus toxicity in a patient with systemic lupus erythematosus

Influence of ensitrelvir or nirmatrelvir/ritonavir on tacrolimus clearance in kidney transplant recipients: a single-center case series

Abnormally Elevated Blood Tacrolimus Level Following the Concomitant Use of Nirmatrelvir/Ritonavir With Extended-Release Tacrolimus in a Post-lung Transplant Patient: A Case Report and a Literature Review

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