Letermovir (AIC246, MK‐8228) is a human cytomegalovirus terminase inhibitor indicated for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients that is also being investigated for use in other transplant settings. Many transplant patients receive immunosuppressant drugs, of which several have narrow therapeutic ranges. There is a potential for the coadministration of letermovir with these agents, and any potential effect on their pharmacokinetics (PK) must be understood. Five phase 1 trials were conducted in 73 healthy female participants to evaluate the effect of letermovir on the PK of cyclosporine, tacrolimus, sirolimus, and mycophenolic acid (active metabolite of mycophenolate mofetil [MMF]), as well as the effect of cyclosporine and MMF on letermovir PK. Safety and tolerability were also assessed. Coadministration of letermovir with cyclosporine, tacrolimus, and sirolimus resulted in 1.7‐, 2.4‐, and 3.4‐fold increases in area under the plasma concentration–time curve and 1.1‐, 1.6‐, and 2.8‐fold increases in maximum plasma concentration, respectively, of the immunosuppressants. Coadministration of letermovir and MMF had no meaningful effect on the PK of mycophenolic acid. Coadministration with cyclosporine increased letermovir area under the plasma concentration–time curve by 2.1‐fold and maximum plasma concentration by 1.5‐fold, while coadministration with MMF did not meaningfully affect the PK of letermovir. Given the increased exposures of cyclosporine, tacrolimus, and sirolimus, frequent monitoring of concentrations should be performed during administration and at discontinuation of letermovir, with dose adjustment as needed. These data support the reduction in clinical dosage of letermovir (to 240 mg) upon coadministration with cyclosporine.
Background:
Letermovir is approved for prophylaxis of cytomegalovirus infection and disease in cytomegalovirus-seropositive hematopoietic stem-cell transplant (HSCT) recipients.
Objective:
HSCT recipients are required to take many drugs concomitantly. The pharmacokinetics, absorption, distribution, metabolism, and excretion of letermovir and its potential to inhibit metabolizing enzymes and transporters In vitro were investigated to inform on the potential for drug‒drug interactions (DDIs).
Methods:
A combination of in vitro and in vivo studies described the absorption, distribution, metabolism, and routes of elimination of letermovir, as well as the enzymes and transporters involved in these processes. The effect of letermovir to inhibit and induce metabolizing enzymes and transporters were evaluated In vitro and its victim and perpetrator DDI potentials were predicted by applying the regulatory guidance for DDI assessment.
Results:
Letermovir was a substrate of CYP3A4/5 and UGT1A1/3 in vitro. Letermovir showed concentration-dependent uptake into organic anionic transporting polypeptide (OATP)1B1/3-transfected cells and was a substrate of P-glycoprotein (P-gp). In a human ADME study, letermovir was primarily recovered as unchanged drug and minor amounts of a direct glucuronide in feces. Based on the metabolic pathway profiling of letermovir, there were few oxidative metabolites in human matrix. Letermovir inhibited CYP2B6, CYP2C8, CYP3A, and UGT1A1 in vitro, and induced CYP3A4 and CYP2B6 in hepatocytes. Letermovir also inhibited OATP1B1/3, OATP2B1, OAT3, OCT2, BCRP, BSEP, and P-gp.
Conclusion:
The body of work presented in this manuscript informed on the potential for DDIs when letermovir is administered both intravenously and orally in HSCT recipients.
This communication describes a significant expansion in the scope of Stille reactions of Csp3-X electrophiles, specifically, that Pd/P(t-Bu)2Me catalyzes the room-temperature cross-coupling of a variety of functionalized, beta-hydrogen-containing alkyl bromides with an array of alkenyltin reagents. The structure of the phosphine (P(t-Bu)2Me) is well suited for facilitating oxidative addition and avoiding beta-hydride elimination, while the fluoride serves to activate the tin reagent for efficient transmetalation.
As rifampicin can cause the induction and inhibition of multiple metabolizing enzymes and transporters, it has been challenging to accurately predict the complex drug–drug interactions (DDIs). We previously constructed a physiologically‐based pharmacokinetic (PBPK) model of rifampicin accounting for the components for the induction of cytochrome P450 (CYP) 3A/CYP2C9 and the inhibition of organic anion transporting polypeptide 1B (OATP1B). This study aimed to expand and verify the PBPK model for rifampicin by incorporating additional components for the induction of OATP1B and CYP2C8 and the inhibition of multidrug resistance protein 2. The established PBPK model was capable of accurately predicting complex rifampicin‐induced alterations in the profiles of glibenclamide, repaglinide, and coproporphyrin I (an endogenous biomarker of OATP1B activities) with various dosing regimens. Our comprehensive rifampicin PBPK model may enable quantitative prediction of DDIs across diverse potential victim drugs and endogenous biomarkers handled by multiple metabolizing enzymes and transporters.
Letermovir is a human cytomegalovirus terminase inhibitor for cytomegalovirus infection prophylaxis in hematopoietic stem cell transplant recipients. Posaconazole (POS), a substrate of glucuronosyltransferase and P-glycoprotein, and voriconazole (VRC), a substrate of CYP2C9/19, are commonly administered to transplant recipients. Because coadministration of these azoles with letermovir is expected, the effect of letermovir on exposure to these antifungals was investigated. Two trials were conducted in healthy female subjects 18 to 55 years of age. In trial 1, single-dose POS 300 mg was administered alone, followed by a 7-day washout; then letermovir 480 mg once daily was given for 14 days with POS 300 mg coadministered on day 14. In trial 2, on day 1 VRC 400 mg was given every 12 hours; on days 2 and 3, VRC 200 mg was given every 12 hours, and on day 4 VRC 200 mg. On days 5 to 8, letermovir 480 mg was given once daily. Days 9 to 12 repeated days 1 to 4 coadministered with letermovir 480 mg once daily. In both trials, blood samples were collected for the assessment of the pharmacokinetic profiles of the antifungals, and safety was assessed. The geometric mean ratios (90%CIs) for POS+letermovir/POS area under the curve and peak concentration were 0.98 (0.83, 1.17) and 1.11 (0.95, 1.29), respectively. Voriconazole+letermovir/VRC area under the curve and peak concentration geometric mean ratios were 0.56 (0.51, 0.62) and 0.61 (0.53, 0.71), respectively. All treatments were generally well tolerated. Letermovir did not affect POS pharmacokinetics to a clinically meaningful extent but decreased VRC exposure. These results suggest that letermovir may be a perpetrator of CYP2C9/19-mediated drug-drug interactions.
Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection in allogeneic hematopoietic stem-cell transplant (HSCT) recipients. In vitro, letermovir is a time-dependent inhibitor and an inducer of cytochrome P450 (CYP)3A, and an inhibitor of CYP2C8 and organic anion transporting polypeptide (OATP)1B. A stepwise approach was taken to qualify the interaction model of an existing letermovir physiologically based pharmacokinetic model to predict letermovir interactions with CYP3A and OATP1B. The model was then used to prospectively predict the interaction between letermovir and CYP2C8 substrates such as repaglinide, a substrate of CYP2C8, CYP3A, and OATP1B. The results showed that letermovir modestly increased the exposure of CYP2C8 substrates. These results were used to inform the US prescribing information in the absence of clinical drug-drug interaction studies. In addition, midazolam interactions with letermovir at therapeutic doses were also simulated to confirm that letermovir is a moderate CYP3A inhibitor.
Dedicated to Professor Manfred T. Reetz on the occasion of his 60th birthdayWhereas nickel-and palladium-catalyzed methods for crosscoupling aryl and vinyl halides and sulfonates with a range of organometallic reagents have reached a fairly high level of sophistication, [1] comparable progress has not yet been achieved for reactions of alkyl halides and sulfonates.[2]Recently, we and others have begun to address this shortcoming by describing catalysts for certain Suzuki, [3] Negishi, [4,5] Kumada, [6,7] Stille, [8] and Hiyama [9] couplings of primary alkyl electrophiles. With the exception of Suzuki's observation that [Pd(PPh 3 ) 4 ] effects cross-couplings of alkyl iodides with R-(9-BBN), [3a] the palladium-based catalysts that were reported for coupling alkyl electrophiles have all employed a hindered trialkylphosphane (PCy 3 or P(tBu) 2 Me) as the ligand.To increase the likelihood of expanding the still-limited scope of cross-couplings of alkyl electrophiles, we have been exploring the use of new classes of ligands for these processes. Herein, we establish that, in the presence of alkyldiaminophosphanes (PR(NR' 2 ) 2 ), we can accomplish palladiumcatalyzed Stille cross-couplings of alkyl bromides and iodides not only with vinyl stannanes, but also with aryl stannanes [Eq. (1)], a class of reaction partners that are not efficiently coupled by Pd/PR 3 (PR 3 = trialkylphosphane).As a consequence of the electron-richness and the ready accessibility of alkyldiaminophosphanes (PR(NR' 2 ) 2 ), [10] we
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