Using known drug interactions to manage supratherapeutic calcineurin inhibitor concentrations

Lange, Nicholas W; Salerno, David M.; Berger, Karen; Tsapepas, Demetra

doi:10.1111/ctr.13098

Cited by 10 publications

(10 citation statements)

References 20 publications

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“…Our patient presented with progressively severe symptoms of tacrolimus neurotoxicity, beginning with calcineurin‐inhibitor pain syndrome characterized by symmetrical pain in the lower extremities, followed by tremors, worsening encephalopathy and psychosis . In the presence of severe symptoms (as reported by others) or persistently elevated tacrolimus concentrations with symptoms (as in this case), use of pharmacologic induction of tacrolimus metabolism is a viable therapeutic option . Phenytoin appears to be the agent of choice for inducing metabolism as it is a strong CYP3A4/5 inducer and has the additional benefit of anti‐seizure activity which is a possible manifestation of tacrolimus neurotoxicity.…”

Section: What Is New and Conclusionmentioning

confidence: 64%

“…8 In the presence of severe symptoms (as reported by others) or persistently elevated tacrolimus concentrations with symptoms (as in this case), use of pharmacologic induction of tacrolimus metabolism is a viable therapeutic option. 4,[9][10][11][12] Phenytoin appears to be the agent of choice for inducing metabolism as it is a strong CYP3A4/5 inducer and has the additional benefit of anti-seizure activity which is a possible manifestation of tacrolimus neurotoxicity. Rifampin was considered as an enzyme-inducing agent in this case but not selected due to concern for adverse effects and lack of anti-sei- The limitation to using enzyme inducers is that the onset is typically considered to be gradual but it is dependent on both the pharmacokinetics of the inducing agent and the turnover of the CYP enzyme.…”

Section: What Is Ne W and Con Clus I Onmentioning

confidence: 99%

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Treatment of prolonged tacrolimus toxicity using phenytoin in a haemodialysis patient

et al. 2019

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Summary What is known and objective Treatment of tacrolimus toxicity includes holding tacrolimus and supportive care. The objective is to describe considerations for pharmacologic induction of tacrolimus metabolism. Case description A 52‐year‐old male with a failed renal transplant on chronic haemodialysis developed tacrolimus toxicity due to a drug‐drug interaction with darunavir/ritonavir. Tacrolimus concentrations were >60 ng/mL for 10 days despite holding tacrolimus and darunavir/ritonavir. Development of encephalopathy prompted initiation of phenytoin to induce tacrolimus metabolism. Tacrolimus concentration was <2 ng/mL within 4 days and mental status normalized. What is new and conclusion Phenytoin metabolic induction is a therapeutic option for prolonged tacrolimus toxicity.

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Section: What Is New and Conclusionmentioning

confidence: 64%

Section: What Is Ne W and Con Clus I Onmentioning

confidence: 99%

Treatment of prolonged tacrolimus toxicity using phenytoin in a haemodialysis patient

et al. 2019

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“…In addition, the intestinal efflux-pump P-glycoprotein contributes to the PK variability, resulting in the reduction in drug absorption and change in disposition [108]. This leads to significant drug interactions with other CYP450 inducers/inhibitors, giving rise to a complex therapy [105,109].…”

Section: Pharmacological Aspects Of Cnismentioning

confidence: 99%

The Advantages of Polymeric Hydrogels in Calcineurin Inhibitor Delivery

2020

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In recent years, polymeric hydrogels (PolyHy) have been extensively explored for their applications in biomedicine as biosensors, in tissue engineering, diagnostic processes, and drug release. The physical and chemical properties of PolyHy indicate their potential use in regulating drug delivery. Calcineurin inhibitors, particularly cyclosporine (CsA) and tacrolimus (TAC), are two important immunosuppressor drugs prescribed upon solid organ transplants. Although these drugs have been used since the 1970s to significantly increase the survival of transplanted organs, there are concerns regarding their undesirable side effects, primarily due to their highly variable concentrations. In fact, calcineurin inhibitors lead to acute and chronic toxicities that primarily cause adverse effects such as hypertension and nephrotoxicity. It is suggested from the evidence that the encapsulation of calcineurin inhibitors into PolyHy based on polysaccharides, specifically alginate (Alg), offers effective drug delivery with a stable immunosuppressive response at the in vitro and in vivo levels. This not only may reduce the adverse effects but also would improve the adherence of the patients by the effective preservation of drug concentrations in the therapeutic ranges.

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“…Thus, the use of CYP inducers may counterbalance the effect of CYP inhibitors on CYP substrates. To our knowledge, utilizing CYP-inducing agents for the management of CNI toxicity has been reported in 11 publications [ 4 , 5 ]. Here, we report on 2 kidney transplant recipients treated with tacrolimus and CYP inhibitors who presented with signs of tacrolimus intoxication at admission and received CYP-inducing agents as rescue therapy ( Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Drug-induced CYP-induction as therapy for tacrolimus intoxication

Hoppe¹,

Holderied²,

Schönermarck³

et al. 2022

CNCS

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Management of calcineurin inhibitor (CNI) therapy in kidney transplant recipients may be complicated due to polypharmacy. As CNI undergo extensive metabolism by cytochrome-P450 enzymes (CYP), drug-mediated CYP inhibition poses a risk for elevated CNI blood concentrations. Here, we report on 2 kidney transplant recipients treated with tacrolimus who presented with signs of tacrolimus intoxication at admission. Patient A was started on antiviral medication ombitasvir, paritaprevir, ritonavir, and dasabuvir for hepatitis C virus treatment 3 days prior to hospitalization. Patient B was treated with clarithromycin for pneumonia. Both therapies cause drug-mediated CYP inhibition, and both patients displayed highly elevated tacrolimus serum concentrations and acute kidney injury (Table 1). After application of the CYP-inducing agents rifampicin and phenytoin, respectively, tacrolimus levels were rapidly reduced, and renal function recovered. Treating severe CNI intoxication is an infrequent yet emergent condition. These results add to the knowledge of therapeutic drug-induced CYP induction as rescue therapy.

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Using known drug interactions to manage supratherapeutic calcineurin inhibitor concentrations

Cited by 10 publications

References 20 publications

Treatment of prolonged tacrolimus toxicity using phenytoin in a haemodialysis patient

Treatment of prolonged tacrolimus toxicity using phenytoin in a haemodialysis patient

The Advantages of Polymeric Hydrogels in Calcineurin Inhibitor Delivery

Drug-induced CYP-induction as therapy for tacrolimus intoxication

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