Drug-induced CYP-induction as therapy for tacrolimus intoxication

Abstract

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.

Part I: Case series: Acute management of prescription and nonprescription drug overdoses

“…In other scenarios, broad-spectrum CYP inducers (e.g., phenytoin) have been administered to increase metabolic clearance of drugs such as tacrolimus. 14 Focused antidotes for reversing toxicity For each ingestion, there should be consideration as to whether an antidote is needed. There are about 50 antidotes available to manage poisonings.…”

Rescue Therapy for Supratherapeutic Concentrations of Calcineurin Inhibitors Using Potent Cytochrome P450 Inducers

“…The publications that did not explicitly describe the use of pharmacoenhancement were also excluded. After extensive screening, a total of 24 publications in which CYP inducers were used to counteract supratherapeutic concentrations of CNIs were identified as illustrated in Figure 8 below [13][14][15][16][17][18][19][20][21][22][23]26,[31][32][33][34][35][36][37][38][39][40][41]. These publications described 34 distinct clinical cases in which pharmacoenhancement was used to treat supratherapeutic concentrations of TAC (91.2% of cases) and CsA (8.8% of cases).…”

“…Since patients depend on these drugs over long periods without sustainable therapeutic drug monitoring measures, they constantly face a potential risk of supratherapeutic concentrations. This risk increases substantially when patients are inadvertently exposed to CYP 3A4 inhibitors [13][14][15][16][17][18]. In hospitalized patients, cases of iatrogenic overdoses have been reported [19][20][21][22].…”

CYP induction to reverse tacrolimus toxicity resulting from concomitant Paxlovid use

“…use of CYP inducers may be beneficial to enhance clearance. 7,8 In a case report of two kidney transplant recipients (KTR), rifampin and phenytoin were used for 3-4 days to counteract tacrolimus elevations due to CYP inhibition from other medication therapy. 7 The induction of CYP metabolism allowed tacrolimus levels to achieve therapeutic levels within 4-5 days, relieving patients of toxicities.…”

“…7,8 In a case report of two kidney transplant recipients (KTR), rifampin and phenytoin were used for 3-4 days to counteract tacrolimus elevations due to CYP inhibition from other medication therapy. 7 The induction of CYP metabolism allowed tacrolimus levels to achieve therapeutic levels within 4-5 days, relieving patients of toxicities. Similarly, a systematic review noted that phenytoin, and phenobarbital to a lesser extent, were often used and well tolerated to reduce CNI levels, although they suggest that a risk-benefit analysis be considered prior to use in patients.…”