Nirmatrelvir/ritonavir is a treatment for COVID-19 consisting of nirmatrelvir, which has anti-SARS-CoV-2 activity, and ritonavir, a booster to maintain blood levels. Ritonavir is known to be a potent inhibitor of cytochrome P450 3A (CYP3A), and interactions with CYP3A-metabolized drugs, such as the immunosuppressant tacrolimus, can be problematic. Ritonavir\'s inhibition of CYP3A is irreversible due to covalent binding, and its inhibitory effects are expected to persist until replaced by new CYP3A. Here, we report a case where the combination of nirmatrelvir/ritonavir and tacrolimus resulted in toxic tacrolimus blood levels. A patient on tacrolimus for systemic lupus erythematosus (SLE) developed COVID-19 and was prescribed nirmatrelvir/ritonavir. After starting the combination of nirmatrelvir/ritonavir and tacrolimus, the patient\'s tacrolimus blood levels became abnormally high, leading to the discontinuation of these drugs due to symptoms of tacrolimus toxicity. Even after ritonavir blood levels had fallen below the detection limit, the decline in tacrolimus blood levels was delayed. The CYP3A inhibition of ritonavir persists even when its blood concentration decreases, emphasizing the need for careful consideration of concomitant medications before starting nirmatrelvir/ritonavir therapy. Adjustments or discontinuation may be necessary.

Patients suffering from chronic pain may respond differently to analgesic medications. For some, pain relief is insufficient, while others experience side effects. Although pharmacogenetic testing is rarely performed in the context of analgesics, response to opiates, non-opioid analgesics, and antidepressants for the treatment of neuropathic pain can be affected by genetic variants. We describe a female patient who suffered from a complex chronic pain syndrome due to a disc hernia. Due to insufficient response to oxycodone, fentanyl, and morphine in addition to non-steroidal anti-inflammatory drug (NSAID)-induced side effects reported in the past, we performed panel-based pharmacogenotyping and compiled a medication recommendation. The ineffectiveness of opiates could be explained by a combined effect of the decreased activity in cytochrome P450 2D6 (CYP2D6), an increased activity in CYP3A, and an impaired drug response at the µ-opioid receptor. Decreased activity for CYP2C9 led to a slowed metabolism of ibuprofen and thus increased the risk for gastrointestinal side effects. Based on these findings we recommended hydromorphone and paracetamol, of which the metabolism was not affected by genetic variants. Our case report illustrates that an in-depth medication review including pharmacogenetic analysis can be helpful for patients with complex pain syndrome. Our approach highlights how genetic information could be applied to analyze a patient\'s history of medication ineffectiveness or poor tolerability and help to find better treatment options.

BACKGROUND: Drug-drug interaction management is complex. Nirmatrelvir/ritonavir is a potent cytochrome P450 (CYP) 3A inhibitor and influences pharmacokinetics of co-administered drugs. Although there are several reports about drug-drug interactions of nirmatrelvir/ritonavir, an influence of a concomitant use of nirmatrelvir/ritonavir and another potent CYP3A inhibitor on tacrolimus remains unclear. Here, we experienced a lung transplant patient with the novel coronavirus disease 2019 (COVID-19). In this patient, nirmatrelvir/ritonavir was administered, and the inhibitory effect of itraconazole on CYP3A was prolonged.
METHODS: We present a case in forties who had undergone lung transplantation. He was administered itraconazole and tacrolimus 1.0 mg/d, with a trough value of 8-12 ng/mL. The patient contracted the COVID-19, and a nirmatrelvir/ritonavir treatment was initiated. During the antiviral treatment, tacrolimus administration was discontinued for 5 d. Tacrolimus was resumed at 1.0 mg/d after completion of the nirmatrelvir/ritonavir treatment, but the trough value after 7 d was high at 31.6 ng/mL. Subsequently, the patient was placed on another 36-h tacrolimus discontinuation, but the trough value decreased to only 16.0 ng/mL.
CONCLUSIONS: Co-administration of ritonavir caused a prolonged decrease in tacrolimus clearance through its inhibitory effects on CYP3A in a patient taking itraconazole. Management of drug-drug interaction by pharmacists can be important for patients with multiple medications.

Solid organ transplant recipients have increased cancer risk due in part to chronic immunosuppression and opportunistic oncogenic viral infections. The management of drug interactions in transplant recipients being treated for cancer is important both to minimize the likelihood of drug-related toxicities and to optimize therapeutic outcomes. We present a case of a 41-year-old woman with a stable living-related kidney transplant maintained on an immunosuppressive regimen of cyclosporine, mycophenolate mofetil, and prednisone, who was subsequently diagnosed with a metastatic lobular breast carcinoma and papillary thyroid cancer and started palbociclib, a time-dependent CYP3A inhibitor. After initiation of palbociclib, cyclosporine trough and peak concentrations were increased by 159% and 81%, respectively, relative to the average cyclosporine concentrations pre-palbociclib. Using the Drug Interaction Probability Scale (DIPS), the interaction between palbociclib and cyclosporine was rated as \"probable.\" Dose reductions of immunosuppressive agents that are CYP3A substrates are warranted if palbociclib is initiated, followed by close monitoring of blood concentrations. This report also highlights the challenges of coadministering a time-dependent inhibitor with a narrow therapeutic index drug that is metabolized by the same enzyme, particularly when the inhibitor is given in cycles with off-treatment periods.

We have previously demonstrated that clementines have in vitro drug interaction potential. To assess the clinical relevance of clementine-drug interaction, two single case experiments with repetitive phenotyping of CYP3A activity were conducted. Although an increment of 43% in the estimated midazolam clearance (eCLmet) was observed during the first experiment in a renal transplant patient on tacrolimus after 4-d consumption of clementines (1 kg/d), and an increment of +89% of eCLmet was observed during chronic consumption of clementine juice in a healthy male volunteer, these changes lie within the range of intra-individual variability. Therefore one cannot assure a potential drug interaction due to the clementines, but prescribers should be cautious unless further data emerges. In contrast to the juice used for the in vitro assay comprising several flavonoids, this juice only contained hesperidin and narirutin indicating that the drug interactions potential of clementines might depend on the composition varying from batch to batch.

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Mechanism-based inactivation (MBI) of CYP450 enzymes is a unique form of inhibition in which the enzymatic machinery of the victim is responsible for generation of the reactive metabolite. This precondition sets up a time-dependency for the inactivation process, a hallmark feature that characterizes all MBI. Yet, MBI itself is a complex biochemical phenomenon that operates in different modes, namely, covalent binding to apoprotein, covalent binding of the porphyrin group and also complexation of the catalytic iron. Using lapatinib as a recent example of toxicological interest, we present an example of a mixed-function MBI that can confound clinical drug-drug interactions manifestation. Lapatinib exhibits both covalent binding to the apoprotein and formation of a metabolite-intermediate complex in an enzyme-selective manner (CYP3A4 versus CYP3A5), each with different reactive metabolites. The clinical implication of this effect is also contingent upon genetic polymorphisms of the enzyme involved as well as the co-administration of other substrates, inhibitors or inducers, culminating in drug-drug interactions. This understanding recapitulates the importance of applying isoform-specific mechanistic investigations to develop customized strategies to manage such outcomes.